P

Pharmacology of Antimalarial studies were performed by German scientists just Drugs, Current Anti-malarials before World War II. However, the drug was reported to be too toxic for human use and not Kesara Na-Bangchang1 and Juntra Karbwang2 introduced for general use at that time. By late 1Chulabhorn International College of Medicine, 1944, in the intensive search for an effective anti- Thammasat University, Pathumtanee, Thailand malarial drug during World War II, US workers 2Clinical Product Development, Institute of synthesized 25 different 4-aminoquinoline deriv- Tropical Medicine, Nagasaki, Japan atives, with the objective of discovering more effective and less toxic suppressive agents than quinacrine. Of these compounds, chloroquine Currently available antimalarial drugs can be clas- proved the most promising and later underwent sified into four broad categories according to their extensive clinical studies. Since then, chloroquine chemical structures and modes of action. had been used as the drug of choice for treatment of human malaria all over the world until the 1. Arylamino alcohol compounds: quinine, quin- advent of chloroquine resistance in Plasmodium idine, chloroquine, amodiaquine, mefloquine, falciparum in the early 1960s. Clinical treatment halofantrine, piperaquine, and lumefantrine failures of P. falciparum were first noted in 2. 8-Aminoquinoline: primaquine and Thailand almost at the same time as in South tafenoquine America. Chloroquine-resistant P. falciparum 3. Antifolate compounds: sulfadoxine, pyrimeth- has since then spread relentlessly to virtually all amine, proguanil, chlorproguanil, and areas of the world except Central America, North trimethoprim Africa, and parts of Western Asia. 4. Artemisinin compounds: artemisinin, artesunate, artemether, b-arteether, and dihydroartemisinin Chemistry and Physical Properties 5. Others: atovaquoneand antibacterial drugs Chloroquine [7-chloro-4-(4-diethylamino-1-methy- (tetracycline, doxycycline, and clindamycin) lbutylamino) quinoline: Fig. 1a] is a weakly basic tertiary amine synthetic antimalarial agent which is a 4-aminoquinoline derivative. It has a quinoline ring Arylamino Alcohol Antimalarials with a side chain identical with that of quinacrine. The chlorine atom in the seventh position appears to Chloroquine be crucial to the antimalarial activity of all Chloroquine was first synthesized by Bayer in 4-aminoquinoline antimalarials. The drug is used Germany as early as 1934. The initial clinical

© Springer Science+Business Media, LLC, part of Springer Nature 2019 P. G. Kremsner, S. Krishna (eds.), Encyclopedia of Malaria, https://doi.org/10.1007/978-1-4614-8757-9_149-1 2 Pharmacology of Antimalarial Drugs, Current Anti-malarials

Pharmacology of Antimalarial Drugs, Current Anti-malarials, Fig. 1 Chemical structures of (a) chloroquine and (b) mono-desethyl chloroquine

as a racemic mixture of equal amounts of S(+) and R in vitro, but it is less effective than the parent com- (À) chloroquine. pound against chloroquine-resistant strains. Chloroquine is a white or slightly yellow, odor- The mechanisms of action and resistance of less, crystalline powder with a bitter taste. It is chloroquine have not been fully elucidated. poorly soluble in water, but soluble in diluted Proposed mechanism(s) of action include DNA acid, chloroform, and ether. Chloroquine phos- binding, inhibition of various enzymes (e.g., phate is readily soluble in water at acidic mixed-function oxidase, heme polymerase, phos- pH. Chloroquine sulfate is soluble in a mixture pholipase, and glutathione-S-transferase) and/or of water and methanol but non-soluble in pure transporters, inhibition of protein synthesis, inter- water. The drug is sensitive to light and should ference with digestion of host-derived hemoglobin be protected from light. The molecular weights of in the parasite digestive food vacuole (acid lyso- the base, phosphate, sulfate, and hydrochloride some), and lysosomotropic effect. Interference salts are 320, 516, 436, and 393, respectively. with hemoglobin digestion process and alteration Structure-activity relationship (SAR) studies of of lysosomal pH appear to be important mecha- many derivatives of the 4-aminoquinolines show nisms of chloroquine action. During the process of that halogen substitutions at any position other hemoglobin digestion, the protein moiety of hemo- than seven reduce pharmacologic activity and globin is degraded to related peptides, and heme is toxicity. An aryl rather than an alkyl side chain transformed into hemozoin (HZ), a nontoxic crys- decreases the therapeutic ratio. Increasing alkyl talline polymer. Chloroquine is a weak base with side chain length above five carbons decreases pKa values of 8.1 and 10.2 and the protonation of the therapeutic ratio and increases toxicity. the drug encharged at the neutral pH of the blood. With the acidic pH for parasite food vacuole, chlo- roquine accumulates and binds hematin, a toxic Pharmacological Activities product of hemoglobin degradation, therefore pre- venting its incorporation into the hemozoin crystal. Antimalarial Activity and Mechanism of The free hematin interferes with the parasite detox- Action and Resistance Chloroquine is highly ification processes and thereby damages the Plas- effective and acts rapidly against asexual erythro- modium membranes by lipid peroxidation cytic forms of Plasmodium vivax, Plasmodium mechanism. ovale, Plasmodium malariae, Plasmodium Resistance to chloroquine in P. falciparum knowlesi, and chloroquine-sensitive P. falciparum. involves mainly the mutation in the parasite trans- (À)-Chloroquine is less active than (+)-chloroquine port gene pfcrt (Plasmodium falciparum chloro- enantiomer against chloroquine-resistant strains of quine resistance transporter) along with pfmdr1 P. falciparum. Chloroquine is also active against (Plasmodium falciparum multidrug resistance 1) gametocytes of P. vivax, P. malariae,andP. ovale and pfmrp1 (Plasmodium falciparum multidrug and immature forms of P. falciparum. The drug has resistance-related protein 1). The pfcrt gene is no effect against the exoerythrocytic tissue stages of located on chromosome 7 and encodes a 49 kDa malaria. Its major plasma metabolite mono- protein (PfCRT) localized in parasite’s food vac- desethylchloroquine (Fig. 1b)hassimilarantimalar- uole with ten predicted transmembrane domains. ial activity against chloroquine-susceptible parasites Pharmacology of Antimalarial Drugs, Current Anti-malarials 3

An amino acid substitution at position 76 from Chloroquine has potential for use as an adjunct lysine to threonine (K76 T), located on the first therapy with standard antiretroviral drugs. Syner- transmembrane domain, has been reported to be gistic activities have been demonstrated when directly associated with chloroquine-resistant chloroquine is used in combination with zidovu- P. falciparum isolates in wide geographic areas. dine, didanosine, and the protease inhibitors The pfmdr1 gene is located on chromosome 5 and (indinavir, ritonavir, and saquinavir). Chloroquine encodes a homologue of the mammalian multi- is associated with low levels of HIV RNA in drug resistance gene in P. falciparum, breast milk of the HIV-infected patients. In addi- P-glycoprotein homologue 1 (Pgh-1). Pfmdr1 tion to HIV, inhibitory activity against the repli- can modulate the degree of chloroquine resistance cation of severe acute respiratory syndrome in some parasite strains, suggesting that some (SARS) or coronavirus infections is shown alleles and overexpression of PfMDR1 may in vitro. enhance chloroquine concentration within the Chloroquine also has potential for use as a digestive food vacuole by active transport. The chemosensitizer in cancer in conjunction with pfmrp1 is located on chromosome 1 and encodes some conventional anticancer drugs, through inhi- a 1822 amino acid proteins PfMRP1 which is a bition of the function of membrane-associated transporter member of the ATP-binding cassette proteins belonging to the P-glycoprotein and (ABC) proteins similarly to PfMDR1. It is local- multidrug resistance (MDR) protein families. ized to the parasite plasma membrane. PfMRP1 Chloroquine is a potent autophagic drug that modifies drug responses but is not a major deter- may lead to cellular degradation of hepatocytes in minant of chloroquine resistance. Potential inhib- the liver with the concurrent production of itors of these parasite transport proteins which vacuoles. could effectively reverse chloroquine-resistant Chloroquine has been shown to inhibit glucose P. falciparum in clinical settings are being 6-phosphate dehydrogenase activity in vitro. investigated. Administration of chloroquine to rats also caused alterations in several hepatic and renal antioxidant enzymes, thereby inducing an oxidative stress in Other Pharmacological Activities and Clinical these organs. Uses Apart from malaria, chloroquine is com- monly used in patients with several inflammatory Therapeutic Indications for Malaria conditions, such as rheumatoid arthritis, systemic Chloroquine is one of the most successful and lupus erythematosus (SLE), discoid lupus widely used medications and with obvious health erythematosus, porphyria cutanea tarda, polymor- precautions, saving countless lives from malaria phous light eruptions, solar urticaria, recurrent since the 1940s. The drug was for several decades basal cell carcinoma of the skin, porphyria cutanea the antimalarial of choice because it was effective, tarda, and antiphospholipid antibody syndrome. well tolerable, safe, and low cost. However, its In the treatment of amoebic liver abscess, chloro- usefulness has rapidly declined in most malaria- quine may be used instead of, or in addition to, endemic areas of the world where chloroquine- other medications in case of unsatisfactory treat- resistant strains of P. falciparum and P. vivax have ment efficacy or intolerance following metronida- emerged and widespread. P. falciparum chloro- zole or another nitroimidazole within 5 days, as quine resistance was first suspected in the late well as in case of intolerance to metronidazole or a 1950s and confirmed in 1959 in Thailand. Almost nitroimidazole. The mechanism of action may simultaneously, resistance occurred in an inde- involve its inhibitory effect on pro-inflammatory pendent focus in Colombia and South America. cytokine release into human whole blood. This The use of chloroquine for treatment of effect may be of therapeutic benefit not only dur- P. falciparum infection is currently restricted to ing chronic inflammation but also in diseases that few countries in Caribbean and Central America, are related to infection-induced inflammation. and the World Health Organization (WHO) 4 Pharmacology of Antimalarial Drugs, Current Anti-malarials strongly recommends artemisinin-based combi- bearing on the incidence and pattern of adverse nation therapies (ACTs) for all P. falciparum con- reactions to the drug. Large doses used for the firmed cases in all endemic areas. Nevertheless, an treatment of rheumatoid arthritis are associated increase in chloroquine susceptibility has been with a higher frequency of adverse reactions reported after withdrawal of the drug as first-line than the lower doses used in malaria. The main treatment, indicating that in the absence of the adverse reactions reported after therapeutic or drug pressure, it is possible to restore chloroquine prophylactic regimens include abdominal discom- efficacy. The efficacy of chloroquine in the treat- fort (nausea, vomiting, and diarrhea), headache, ment of P. vivax and other non-P. falciparum is blurred vision, light-headedness, and fatigue. however still very high in most areas of the world Gastrointestinal disturbance can be minimized including Thailand. Chloroquine-resistant by taking the drug with food. Ocular toxicity P. vivax was first reported from Papua New observed in chloroquine treatment is associated Guinea in 1989, almost 30 years after the emer- with disruption of the blood-retinal barrier gence of P. falciparum resistance. It is now wide- (BRB). Serious adverse effect associated with spread and has rendered this drug ineffective in long-term use of chloroquine, either as prophy- parts of Indonesia and Papua New Guinea. Low laxis or treatment of rheumatoid arthritis, is irre- levels of resistance have also been reported from versible retinopathy (0.3–2% incidence). Pruritus Myanmar, South Korea, Vietnam, India, Turkey, especially of the palms and soles occurs fre- Ethiopia, and parts of southern Africa and South quently in Africans. Rare adverse reactions are America. Currently, chloroquine (or ACTs) is a photosensitization, aplastic anemia, agranulocy- therapeutic option for the treatment of adults and tosis, hepatitis, elevated liver enzymes, skin erup- children with uncomplicated P. vivax, P. ovale, tions, psychiatric disturbances, peripheral P. malariae,orP. knowlesi in areas with neuropathy, myopathy, and effect on neuromus- chloroquine-sensitive infections. Its use in combi- cular transmission (muscle weakness). There is nation, or not, with primaquine, the unique anti- some evidence that the drug may induce an auto- malarial drug that acts against the Plasmodium immune disorder particularly with long-term liver stage preventing relapses, is the first choice high-dose therapy. Several patients with autoim- in the majority of endemic areas of these mune diseases (rheumatoid arthritis and SLE) non-P. falciparum infections. Oral chloroquine is developed clinical, physiological, and pharmaco- given at an initial dose of 10 mg/kg body weight logical evidence for myasthenia gravis after pro- (bw), followed by 10 mg/kg bw on the second day longed use of chloroquine. Chloroquine may and 5 mg/kg bw on the third day (total dose of affect kidney function when taken either during 25 mg/kg bw). In the past, the initial 10 mg/kg bw treatment or prophylaxis of malaria through accu- dose was followed by 5 mg/kg bw at 6, 24, and 48 h. mulation in adrenal gland and the epithelial cells Chloroquine phosphate is available orally as tablets of the kidney. Chronic administration of chloro- containing either 250 or 500 mg of the phosphate quine has been reported to cause Na + retention (equivalent to 150 and 300 mg of base, possibly via increase in plasma aldosterone con- respectively). centrations and renal Na+ -K+ -ATPase activity. Chloroquine has been considered safe when The S(À)chloroquine is more toxic in humans used in normal therapeutic doses during preg- than R(+) chloroquine. nancy. No abortifacient or teratogenic effects Transiently high plasma chloroquine concentra- have been reported. tions after the rapid intravenous injection or large intramuscular doses of chloroquine (previously Adverse Reactions and Toxicity used for treatment of chloroquine-sensitive severe At therapeutic doses, chloroquine is generally P. f alc ip ar um malaria) are associated with cardio- well tolerated. Individual variations in the pattern vascular toxicity. Toxic manifestations appear rap- of distribution of chloroquine and its metabolite in idly within 1–3 h after injection and include the body are suspected to play an important circulatory arrest, shock, cardiac conduction Pharmacology of Antimalarial Drugs, Current Anti-malarials 5 disturbances, and ventricular arrhythmia. Abnor- In systemic circulation, about 50–70% of chloro- malities in the electrocardiogram (ECG), i.e., quine is bound to plasma protein, mainly to

QRS complex widening, flattening of the QRS, a1-acid glycoprotein. S(+)Chloroquine binds and ST segment depression, have been reported more to albumin (50%) than R(À)chloroquine after overdoses as well as in patients after thera- (35%). On the other hand, R(À)chloroquine peutic doses. Respiratory depression can also binds more to a1-acid glycoprotein (48%) than S occur. (+)chloroquine(35%). Chloroquine is extensively distributed throughout the body. The drug is Contraindications deposited in tissues (liver, spleen, kidney, lung, Chloroquine is contraindicated in individuals with retina, and skin) with about 200–20,000 times the known hypersensitivity to chloroquine or struc- plasma concentration. Highest concentrations of turally related aminoquinoline antimalarials. chloroquine are found in melanin-containing cells in the retina and skin. The drug remains in the skin Caution for 6–7 months after cessation of therapy at a time Chloroquine may exacerbate the severity of pso- when the drug is no longer detectable in the riasis, neurological (e.g., epilepsy) and gastroin- plasma. The extent of accumulation of the R(À) testinal disorders, and retinal, visual, or hepatic chloroquine in ocular tissues is greater than that of impairment. The drug should be administered in the S(+) enantiomer. Chloroquine readily crosses patients with these underlying conditions with the placenta and is excreted in small amount into caution. the breast milk. The milk-to-plasma ratio ranges from 1.96 to 4.26. Cord blood concentration is Pharmacokinetics similar to maternal blood level. Correlation is Pharmacokinetic parameters of chloroquine and its observed between saliva and plasma levels of active plasma metabolite monodesethylchloroquine chloroquine with saliva: plasma concentration following currently recommended doses for malaria ratio of 0.53. Due to its extensive tissue distribu- treatment and prophylaxis are summarized in tion (Vc/F), the apparent volume of distribution Table 1. Chloroquine is rapidly and almost (Vd/F) is extremely large (31–262 l/kg), but the completely absorbed from the gastrointestinal tract volume of the central compartment is relatively after oral administration in either healthy subjects or small. This results in transiently high plasma chlo- children with malaria. The oral bioavailability is roquine concentrations after parenteral adminis- almost complete, i.e., approximately 90%. Absorp- tration with wide peak-to-trough fluctuations. tion is relatively unaffected by concomitant inges- The distribution of chloroquine within the tion of food. However, intersubject variability of human blood is also important since the malaria 30–100% has been reported in extent of absorption, parasite is intraerythrocytic during schizogony. which may explain in part the individual variability Chloroquine preferentially concentrates in blood of chloroquine effectiveness and toxicity. In one components, e.g., erythrocytes, platelets, and study following a single oral dose of 300 mg chlo- granulocytes. Erythrocytic concentration is about roquine base, peak plasma chloroquine levels of two to five times of the concurrent plasma con- 56–102 ng/ml were attained within 1–6h.Inanother centrations. Concentration in parasitized erythro- study where 10 mg chloroquine per kg body bw was cytes is about 25 times of normal erythrocytes. administered in the form of tablets to children with Concentration in the whole blood is highest, malaria, a Cmax of about 250 ng/ml was reached in followed by serum and plasma. It is thought that 2 h with an absorption half-life of 0.56 h. Multiple chloroquine-induced redistribution of a neutral doses of 250 mg daily lead to stable plasma concen- aminopeptidase may be the cause of hemoglobin trations of 100–500 ng/ml. accumulation in endocytic vesicles of malaria The pharmacokinetics of chloroquine is com- parasites. plex with plasma levels determined by the rate of Clearance of chloroquine is mainly by renal distribution rather than by the rate of elimination. excretion (40–70%) and hepatic metabolism Pharmacology of Antimalarial Drugs, Current Anti-malarials, mean or median values reported Anti-malarials Current (World Drugs, Antimalarial of Pharmacology Health Organization, Division of Control of 6 Table 1 Pharmacokinetic parameters of antimalarial drugs and their active metabolites Tropical Diseases. Guidelines for the treatment of malaria. Third edition, 2015) in studies in healthy subjects and patients with malaria. Data are presented as range of Pharmacokinetic parameters Drug/metabolite Cmax (ng/ml) Tmax (h) AUC (ng.h/ml) CL/F (l/h/kg) Vd/F (l/kg) T1/2 (h) Amodiaquine 5.2–39.3 0.5–2.0 39.3–602 14–57.8 311–1010 3.3–12.4 Desethylamodiaquine 161–751 2.71–47.9 14,700–-40,339 0.61–0.74 62.4–252 90–240 Artemether 171–540 1.5–10.0 810–5800 0.44–138 (CL) 3.5–8.6 (Vd) 5.7–7.0 Dihydroartemisinin 15–405 1.3–7.4 190–5040 7.16–8.99 (CL) 2.05 (Vd) 5.1 Artemether 5.2–190 0.5–2.13 40–385 1.46–41.26 9.85–143.5 0.5–2.13 Dihydroartemisinin 26–205 0.8–3.0 90–382 3.48–13.61 1.038–35.6 0.8–3.0 Lumefantrine 4456–28,300 2.0–66.3 207,000–2,730,000 0.077–0.104 0.4–8.9 2–66.3 Desbutyllumefantrine 19.3–89.0 8.0–62.7 5400 10.0 730–977 8.062.7 Artesunate (iv) 1140–29,644 2 505,000–2,051,000 1.27–3.12 (CL) 0.08–0.24 (Vd) 9–25.2 Dihydroartemisinin 340–3007 9–17.4 1,107,000–2,559,000 0.73–2.16 (CL) 0.75–2.22 (Vd) 20.7–95.4 Artesunate (im) 660–2192 8 855,000 2.7–4.26 (CL) 0.44–2.16 (Vd) 11.5–48.2 Dihydroartemisinin 62.5–1584 1.4–40.5 1,496,000 1.08–1.21 (CL) 0.77–1.79 (Vd) 32–52.7 Artesunate (rectal) 90–894 42–54 692,000 5.9 2.06 51 Dihydroartemisinin 180–1279 12–138 2,402,000–2,786,000 1.5–2.64 0.6–2.8 18–81 Artesunate (oral) 34–451 30–84 113–419 0.61–15.4 0.63–3.35 54 Dihydroartemisinin 900–2043 54–120 1,217,000–3,745,000 0.63–1.66 1.45–3.00 48–150 Atovaquone 634–13,270 5.1–5.7 2.67–27.63 ug.days/ml 90–320 4.7–13 29–134 Proguanil 560–751 4.4–5.2 7200–15,400 710–1230 13.4–22.9 8.0–17.6 Cycloguanil 37–67 6.4–6.9 600–1800 – – 15.6–22.6 Chloroquine 283–1430 2.7–6.9 8200–140,000 0.23–0.80 31.8–262 108–291 Desethylchloroquine 89–220 – 23,100–64,300 0.1–0.16 12.6 175–290 Dihydroartemisinin 366–698 0.97–2.8 0.84–1.95 1.19–2.16 1.47–3.59 0.85–1.40 Piperaquine 71.6–730 1.48–5.7 24,100–49,500 0.85–1.85 529–877 13.5–28 days Doxycycline 3060–6900 1.5–6.0 39,000–108,400 29.5–112.0 0.75–1.83 8.8–22.4 Mefloquine (treatment) 1000–3279 15–72 12.8–63.6 ug.days/ml 0.016–0.174 7.87–31.8 8.1–15.2 days Mefloquine (prophylaxis) 722–2259 4.5–31 15.6–48.0 0.016–0.095 10.11–14.60 1.03–19.1 days ug.days/ml Primaquine 65–295 1.8–4.0 443–1978 0.31–1.19 2.92–7.94 3.5–8.0 Carboxyprimaquine 343–2409 4–8 3831–47,085 – – 15.7–16.9 Quinine 5270–17,900 1.0–5.9 9200–449,000 0.22–4.99 (CL) 0.45–4.24 (Vd) 3.21–26.0 Sulfadoxine 57,900–217,800 3.7–63 15,900–66,300 13.9–71.1 ml/day/kg 0.263–0.660 4.1–10.9 Pyrimethamine 86,000–860,000 2.4–41.1 21,787–106,065 335–1776 ml/h/kg 2.32–7.20 60–450 Pyronaridine 491–1816 1.3–1.7 16,300–42,500 0.55–1.25 39–105 147–242.6 Pharmacology of Antimalarial Drugs, Current Anti-malarials 7

(35–50%). Hepatic metabolism is largely by side clearance by both glomerular filtration and tubular chain de-ethylation, leading first to mono- secretion, in the forms of unchanged (about 50%) desethylchloroquine (30–40%) and then to or metabolized drugs (25%). The excretion is didesethychloroquine or bisdesethylchloroquine increased by acidification of the urine. The S(+) (5–10). Monodesethylchloroquine (Fig. 1b)is enantiomer is excreted by the kidneys preferen- the main metabolite of chloroquine with similar tially compared to the R(À) enantiomer. Approx- antimalarial activity against chloroquine- imately 8–25% and 5% are excreted in unchanged susceptible P. falciparum as the parent compound. form or metabolites in the feces and skin, respec- Bisdesethylchloroquine is further deaminated to tively. About 25–45% is stored long term in lean form an alcohol (the 4’-hydroxy compound) body tissues. The reported values of t1/2 of chlo- which is oxidized to the 4’-carboxylic acid deriv- roquine and metabolite vary considerably, ative. Successive dealkylation of the side chain depending largely on the duration of sampling ultimately produces the compounds 7-chloro-4- and the analytical methods used, i.e., 2.5 and aminoquinoquinoline, chloroquine side chain 10–60 days for 7 days and >56 days sampling,

N-oxide, and chloroquine di-N-oxide. Metabo- respectively. The elimination half-lives (t1/2)of lism of chloroquine involves the cytochrome chloroquine, mondesethylchloroquine, and P450 (CYP450) system, i.e., CYP2C8, bisdesethylchloroquine range from 20 to

CYP3A4/5, and, to a much lesser extent, 60 days. The t1/2 of the modesethyl metabolite is CYP2D6, although their quantitative in vivo con- longer than those of the parent compounds. Chlo- tribution remains unclear. All the metabolites are roquine and metabolites can be found in urine for toxicologically important. Metabolism of chloro- months after a single oral dose. quine occurs slowly, and the main metabolite varies in different species. Extrahepatic sites of Factors Associated with Altered Drug Exposure microsomal metabolism could also be of clinical and/or Treatment Response significance in view of the extensive tissue distri- Various pharmacokinetic studies suggest notice- bution of chloroquine and the extrahepatic distri- able interindividual variability in chloroquine and bution of CYP3A isoenzymes. monodesethylchloroquine concentrations, and The monodesethylchloroquine metabolite has this variability may influence the parasitological similar profiles of distribution and tissue binding treatment outcome. In most cases, blood/plasma as the parent drug and can be detected in plasma concentrations in patients with treatment failure 30 min after drug administration. Time to maximum tended to be lower than those with sensitive treat- blood concentration (tmax)of2–7 h after the oral ment outcome. In addition, this variability may dose occurs at approximately the same time as that also associated with increased chloroquine toxic- of chloroquine. The binding of mono- ity particularly retinopathy. desethylchloroquine to a1-acid glycoprotein is higher than that to albumin (21% vs 3%). The Malaria Infection There appears to be no phar- concentration of monodesethylchloroquine remains macokinetic difference of chloroquine, besides at a value of 25–40% of that of the parent compound the higher Cmax found in Thai patients with after the peak has been reached. At steady state, the malaria compared with healthy subjects following ratio of chloroquine to desethylchloroquine is an intravenous infusion of chloroquine diphos- 6–10%. Bisdesethylchloroquine concentration phate (15 mg base/kg bw). The binding of chlo- reaches 10–13% of chloroquine concentration. roquine to plasma protein is not altered in malaria Chloroquine exhibits a multiexponential elim- infection. ination pattern with a more rapid initial elimina- tion phase, followed by a slower phase. The Pregnancy The CL/F and Vd/F of chloroquine systemic clearance of chloroquine (CL/F) varies may be increased, while area under blood between 0.23 and 0.80 l/h/kg. Renal clearance concentration-time curve (AUC) decreased in accounts for up to 70% of the total systemic pregnant patients. Decreases of 25% and 45% in 8 Pharmacology of Antimalarial Drugs, Current Anti-malarials the AUCs of chloroquine and desethylchloroquine, Genetic Polymorphisms in Drug-Metabolizing respectively, suggest lower exposure that may Enzymes and Transporters The role of poly- compromise therapeutic efficacy. Recommenda- morphisms of CYP2C8, the key enzyme in chloro- tion to increase chloroquine daily dose to four quine biotransformation, as a factor that influences tablets (1,000 mg) regimen in pregnant women is treatment outcome has not yet been investigated. It proposed based on results of a population-based is, however, unlikely to be clinically relevant since pharmacokinetic study to improve clinical efficacy both parent compound and metabolite are pharma- of chloroquine. Clinical studies evaluating safety cologically active. The contribution of polymor- and potential harm to the fetus are needed. Data on phism in protein transporters particularly regarding the use of antimalarials by lactating mothers have chloroquine-induced adverse drug effects of the been limited. central nervous system (CNS) remains to be clarified. Children and Elderly Information on the influ- ence of age on the pharmacokinetics of chloroquine Drug Interactions There is evidence from has been limited. It has only been recognized in vitro and in vivo animal studies that chloroquine recently that the currently recommended on the is markedly antagonistic to some antimalarials such mg per kg bw doses of chloroquine achieve sub- as quinine, mefloquine, amodiaquine, and stantially lower plasma drug concentrations in artemisinin. On the other hand, the combination young children than in older patients. with sulfadoxine, pyrimethamine, and erythromy- cin is synergistic. Clinical relevance for the inter- Renal Diseases Kidney or liver dysfunction action of chloroquine with some of these drugs has decreases excretion of chloroquine and leads to been demonstrated. In clinical situation where con- greater drug retention and higher risk of chloro- comitant therapy of chloroquine with other antima- quine toxicity. In patients with renal insufficiency, larials cannot be avoided, monitoring of chloroquine elimination is reduced resulting in the chloroquine blood concentrations is suggested. prolongation of the t of the drug. Blood con- 1/2 Despite the encouraging results for the synergistic centrations at equilibrium level of chloroquine are effects of the combination of chloroquine and about 70% higher in patients with renal impair- erythromycin in vitro and in vivo, the combination ment. However, this pharmacokinetic alteration is of chloroquine and erythromycin does not prove of therapeutic relevance only when chloroquine is effective in the treatment of highly chloroquine- used for prophylaxis but not for treatment, as the resistant P. falciparum in Thailand or even less concentration-time profiles of chloroquine are chloroquine-resistant parasites in Kenya. largely governed by distribution phase rather Desferrioxamine, the only iron chelator used in than elimination phase during the first 3–4 days human medicine, has been shown to inhibit acute phase of infection. P.falciparum growth both in vitro and in an animal model. However, marked antagonism is observed Malnutrition In malnourished patients, the between desferrioxamine and chloroquine. metabolism of chloroquine is impaired and may Calcium channel blockers, tricyclic antidepres- result in high blood concentrations. sants, and antihistamines inhibit chloroquine transport by P-glycoprotein resulting in increased Ethnics In general, the pharmacokinetics of blood chloroquine levels and antimalarial activity. chloroquine does not differ substantially in differ- The antihistamine cyproheptadine has been ent ethnic groups. However, in one study, the rate shown to reverse resistance to chloroquine in of chloroquine excretion of during the first 7 h of P. falciparum both in vivo and in vitro. administration was higher in Thais as compared to Food appears to enhance the extent of chloro- British, Gambian, and Sudanese subjects. The quine absorption. The AUC and C of chloro- proportions of excreted monodesethylchloroquine max quine are significantly elevated when chloroquine to chloroquine were similar in all groups. Pharmacology of Antimalarial Drugs, Current Anti-malarials 9 was administered with rice-based meals, although methotrexate, as well as reduce therapeutic effect the rate of absorption is not affected. of thyroxine. On the other hand, the drug In animal studies, acetylsalicylic acid delayed increases plasma concentration of cyclosporine. the absorption of chloroquine, but distribution, Concurrent administration of chloroquine and plasma protein binding, and elimination were not ethanol has been shown to induce extensive dam- affected. Clinical relevance of these findings age to the proximal tubules and collective duct remains to be established. cells of the kidney, probably due to modulatory Concomitant therapy of chloroquine with effect of chloroquine on the renal tubular response some antacids or antidiarrheal agents results in to vasopressin, either directly by inhibiting cyclic poor bioavailability of chloroquine. AMP generation or indirectly via induction of Activated dimethicone does not appreciably nitric oxide production. affect the absorption of chloroquine, but calcium carbonate, kaolin, and magnesium trisilicate sig- Amodiaquine nificantly decrease the absorption of chloroquine. Amodiaquine is an analog of chloroquine, which Activated charcoal has been shown to drastically is effective against low-level chloroquine- reduce the absorption of chloroquine. The plasma resistant P. falciparum malaria. In the 1980s, the

AUC and Cmax of chloroquine were reduced by use of amodiaquine was discouraged due to rare 99% in the presence of activated charcoal. Activated but serious idiosyncratic hepatotoxicity and charcoal should have a role in reducing the absorp- agranulocytosis after long-term prophylaxis. In tion in chloroquine intoxication. the 1990s, its use was reconsidered following the The co-administration of primaquine with widespread development of chloroquine resis- chloroquine for radical treatment of P. vivax tance. It is now recommended by WHO to be malaria does not affect chloroquine or mono- used in combination with artesunate as one of desethylchloroquine pharmacokinetics but signif- the artemisinin-based combination therapies icantly increases plasma primaquine (ACTs) for the treatment of uncomplicated concentrations. This pharmacokinetic interaction P. falciparum and P. vivax in areas where the may explain previous observations of synergy in parasites are sensitive to amodiaquine. Recently, preventing P. vivax relapse. Similarly, non- WHO has recommended seasonal malaria che- clinically significant safety or pharmacokinetic/ moprevention (SMC) using a complete treatment pharmacodynamic interactions are found with of sulfadoxine-pyrimethamine and amodiaquine the co-administration of tafenoquine (antirelapse once a month for 4 months during the malaria drug alternative to primaquine) and chloroquine transmission season for children aged between in healthy subjects. 3 and 59 months. Cimetidine, but not ranitidine, impairs the elimination of chloroquine through inhibition of Chemistry and Physical Properties drug-metabolizing enzymes. Ranitidine is, there- Amodiaquine (4-[(7-Chloroquinolin-4-yl)amino]- fore, the H2-receptor antagonist of choice for ulcer 2-[(diethylamino)methyl]phenol: Fig. 2a)isa patients receiving chloroquine therapy. Plasma Mannich base 4-aminoquinoline that is similar in concentration of chloroquine is also increased chemical structure and mechanism of action to when co-administered with paracetamol. chloroquine. Amodiaquine is a yellow crystalline Alkalinization of urine decreases chloroquine powder, odorless (or almost odorless) with a bitter excretion. Acidification of the urine by oral inges- taste. Soluble 1 in 22 parts water 1 in 70 parts tion of ammonium chloride can increase renal ethanol (96%). The molecular weight is 355.9. excretion of chloroquine by 20–80%. Intramuscu- Amodiaquine is practically insoluble in benzene, lar injection of dimercaprol can also increase uri- chloroform, and ether. It is decomposed at temper- nary excretion of chloroquine. ature 150–160 C. The drug is used as a racemic Chloroquine has been shown to reduce bio- mixture of equal amounts of S(+) and R(À) availability of ampicillin, praziquantel, and amodiaquine. 10 Pharmacology of Antimalarial Drugs, Current Anti-malarials

Pharmacology of Antimalarial Drugs, Current Anti-malarials, Fig. 2 Chemical structures of (a) amodiaquine and (b) monodesethylamodiaquine

Pharmacological Activities period (4 months), seasonal malaria chemopre- vention (SMC) with monthly amodiaquine in Antimalarial Activity and Mechanism of combination with sulfadoxine-pyrimethamine is Action and Resistance Amodiaquine has anti- recommended for all children aged less than malarial activity on various Plasmodium stages 6 years during each transmission season. The similarly to that of chloroquine. It is active against combination is given at full treatment doses, i.e., asexual erythrocytic forms of P. vivax, P. ovale, a single dose of sulfadoxine-pyrimethamine P. malariae, P. knowlesi, and chloroquine- (25/12.5 mg) and 3 days of amodiaquine sensitive P. falciparum. It is also active against (10 mg/kg bw per day) at monthly intervals. gametocytes of P. vivax, P. malariae, P. ovale, and immature forms of P. falciparum. The drug has no Adverse Reactions and Toxicity activity against the exoerythrocytic tissue stages The adverse reactions of amodiaquine are gener- of malaria. Its major plasma metabolite mono- ally mild to moderate and are similar to chloro- desethylamodiaquine (Fig. 2b) has similar anti- quine. Hepatic problems or decrease in blood malarial activity. The mechanisms of action and counts may rarely occur. Toxicity from overdose resistance of amodiaquine have not been fully may include headache, seizures, and cardiac elucidated but are thought to be similar to arrest. chloroquine. Artesunate-amodiaquine is generally well- tolerated. Common adverse reactions include gas- Therapeutic Indications for Malaria trointestinal disturbances (nausea and abdominal Oral amodiaquine is currently available as a single pain), cough, anorexia, insomnia, fatigue, and tablet and a fixed-dose combination (ACT) in weakness. The incidence of gastrointestinal dis- tablets containing 25/67.5 mg, 50/135 mg, or turbances is higher compared with other ACTs. 100/270 mg of artesunate-amodiaquine. Less common adverse reactions are arrhythmia, Amodiaquine in combination with artesunate as bradycardia, vomiting, extrapyramidal effects, one of the ACTs is indicated for the treatment of retinopathy, and pruritus. Eye disorders uncomplicated P. falciparum and P. vivax malaria. (transient accommodation disorders and corneal The combination is also active against P. vivax, opacification) varying in types and severity have P. ovale, P. knowlesi, and P. malariae. The also been reported but regress upon termination of recommended dose regimen for ACT is a total treatment. Serious adverse reactions are neutrope- therapeutic dose range of 6–30 mg/kg bw per nia and hepatotoxicity. These serious effects are day artesunate and 22.5–45 mg/kg bw per day most often with prolonged use of amodiaquine for amodiaquine for 3 days. The combination may prophylaxis or prolonged use of artesunate- also be used as follow-on treatment in patients amodiaquine treatment. with severe malaria if oral medication is tolerated. Amodiaquine-SP is generally well tolerated in In areas with high malaria transmission in the sub- children. Common adverse reactions include Sahel region of Africa where the majority (>60%) vomiting, loss of appetite, fever, and mild-to- of clinical malaria cases occur during a short Pharmacology of Antimalarial Drugs, Current Anti-malarials 11 moderate skin reactions. No serious adverse reac- of amodiaquine and monodesethylamodiaquine tions have been reported. show wide (more than ten times) variation between individuals. Contraindications Amodiaquine should not be administered to Factors Associated with Altered Drug Exposure patients with known hypersensitivity to and/or Treatment Response amodiaquine and structurally related drugs. In addition, clinical use with this drug should be Malaria Infection The oral pharmacokinetic avoided in patients with history of hepatotoxicity, profiles of amodiaquine and mono- hepatic impairment, neutropenia, or retinopathy. desethylamodiaquine obtained from patients with malaria and healthy subjects are similar, Cautions except the absorption which is significantly Although there is no evidence for life-threatening delayed in patients from a mean of 0.5–1.75 h. cardiovascular complications of amodiaquine as what has been reported with overdose of chloro- Children Small studies did not find any effect of quine, caution should be made in treating patients age on plasma concentrations of mono- who have recently taken another antimalarial drug desethylamodiaquine or amodiaquine itself. How- with cardiovascular adverse reactions such as qui- ever, it was reported that treatment failure after nine, mefloquine, or even chloroquine. amodiaquine monotherapy was more frequent among children who were underweight for Pharmacokinetics their age. Pharmacokinetic parameters of amodiaquine and its active plasma metabolite following currently Pregnancy There are no data published on the recommended doses for treatment of uncompli- pharmacokinetics of amodiaquine in pregnant cated malaria and seasonal malaria chemopreven- women although it was previously used to treat tion are summarized in Table 1. malaria in pregnancy. After oral administration, amodiaquine hydro- chloride is rapidly absorbed and undergoes rapid HIV Coinfection Artesunate-amodiaquine com- and extensive metabolism by CYP2C8 to the bination is associated with severe neutropenia, active metabolite monodesethylamodiaquine particularly in patients coinfected with HIV and (Fig. 2b) and the secondary metabolite especially in those on zidovudine and/or 2-hydroxyamodiaquine which are eliminated by cotrimoxazole treatment. Concomitant use of renal excretion. Monodesethylamodiaquine is efavirenz increases exposure to amodiaquine and concentrated in red blood cells; whole blood to hepatotoxicity. Concomitant use of this ACT with plasma ratio is approximately 3:1. Both the parent these drugs should therefore be avoided. drug and metabolite are highly (>90%) plasma protein bound. It is likely that the distribution of Genetic Polymorphisms in Drug-Metabolizing monodesethylamodiaquine in man mirrors that of Enzymes Enzymatic and nonenzymatic forma- chloroquine, i.e., wide distribution into the body tion of highly reactive amodiaquinequinoneimine, tissues, particularly in the liver, spleen, kidney, a protein-arylating intermediate, is thought to be lungs, brain, and spinal cord. It also binds to responsible for serious organ-damaging melanin-containing cells in the eyes and skin. amodiaquine adverse reactions observed in some Although amodiaquine is three times more potent patients. The effects of CYP2C8 polymorphisms than monodesethylamodiaquine, mono- on amodiaquine efficacy and toxicity remain desethylamodiaquine remains longer in blood conflicting. Theoretically, a slower conversion of where it concentrates in red blood cells and is amodiaquine to monodesethylamodiaquine in the claimed responsible for the most of the antimalar- CYP2C8 poor metabolizers might predispose ial efficacy of amodiaquine. Blood concentrations patients to form this highly reactive intermediates 12 Pharmacology of Antimalarial Drugs, Current Anti-malarials and, thus, increased risk of toxicity. The pharma- Chemistry and Physical Properties cological activity of both amodiaquine and mono- Primaquine [8-(4-Amino-1-methylbutylamino)-6- desethylamodiaquine, their antiparasitic methoxy-quinoline: Fig. 3a] is an 8-aminoquinoline synergism, or their extrahepatic metabolism antimalarial. Primaquine is a racemate with equal might have hidden a CYP2C8 poor metabolizer partsofS(+)andR(À) forms because of the presence phenotype and prevented treatment failure. of an asymmetric carbon atom. The molecular weights of the base and diphosphate salts are 259 and 455. The diphosphate is the commercially Drug Interactions Amodiaquine has potential to available salt. It is soluble in water, and its solutions inhibit CYP2D6 and CYP2C9 activities. On the are stable, although some decomposition may take other hand, amodiaquine metabolism may be place on exposure to light and air. inhibited by CYP2C8 and CYP2A6 inhibitors. Plasma concentration of chloroquine including Pharmacological Activities CYP450 activities has been shown to be increased when co-administered with the anti-HIVefavirenz. Antimalarial Activity Primaquine is highly On the other hand, the concentration is decreased active against exoerythrocytic forms (hypnozoites) when co-administered with nevirapine. and sexual stages (gametocytes) of all Plasmodium With regard to pharmacodynamic interactions, species. It has weak activity against asexual blood increased risk for cardiotoxic effects may occur if stages of P. vivax but has negligible activity against amodiaquine is co-administered with antiarrhythmic P. falciparum. drugs. In addition, the risk for neutropenia may be Primaquine is active against primary tissue increased when amodiaquine is co-administered stages in the liver of all human Plasmodium spe- with zidovudine-containing regimens and cies and can be considered to be a causal prophy- trimethoprim-sulfamethoxazole combination. lactic agent. However, due to its toxicity, it has not been used for this purpose on a large scale. It is the Primaquine only compound available for clinical use in the Primaquine was first synthesized as the most potent treatment of hypnozoite tissue stages form of compound in a large series of quinoline derivatives P. vivax and P. ovale, to prevent relapses of these in 1946, by Elderfield and colleagues at Columbia two species. It is also the only active drug against University, and was later on investigated in humans mature gametocytes of P. falciparum and is used as part of the US government’s Malaria Project routinely in areas under active control of malaria conducted at the Stateville Penitentiary. The first transmission. Primaquine has no substantial effect mass use of primaquine was in the Korean War in on blood stage of human malaria unless toxic over 250,000 US soldiers as a tissue schizonticide concentrations are achieved. to eliminate long latency P. vivax infections with a The exact mechanism of action of primaquine 14-day primaquine course. Since then, primaquine as anti-hypnozoite and gametocytocide remains has gradually become the standard therapy in unclear. The main mechanism is proposed to be treating relapsing malaria and an important tool in through parasite metabolism in mitochondria, malaria transmission blocking (gametocytocidal eventually by interference with the ubiquinone activity) and elimination campaigns with high function as an electron carrier in the respiratory effectiveness. Its effectiveness has nevertheless chain. Another potential mechanism is the pro- always been challenged with availability, prescrib- duction of highly reactive metabolites that gener- ing practices, and patients’ compliance. Most ate intracellular oxidative potentials. Primaquine importantly, hemolytic toxicity particularly in indi- has been shown to bind to PfCRT and can thereby viduals with glucose-6-phosphate dehydrogenase inhibit chloroquine transport. This may explain (G6PD) deficiency is of concern, which the synergistic action between the two significantly decreases effectiveness of animalarials as well as the reversal of chloroquine primaquine. resistance. Biotransformation of primaquine Pharmacology of Antimalarial Drugs, Current Anti-malarials 13 appears to be necessary for their toxicity as well as Primaquine has been shown to exhibit efficacy. Selective generation of oxidative stress in leishmanicidal activity in vitro but has no clinical the parasitized cells is the most plausible mecha- application against leishmaniasis. Some deriva- nism for primaquine toxicity and efficacy. It is tives of primaquine, particularly 6-desmethyl-8- possible that primaquine may have two entirely aminoquinolines, have been generally more active different modes of action, one through the parent in vitro than the parent drug against macrophage- compound and another through its metabolite(s). contained leishmania. Different metabolites exhibit a varying degree of Both primaquine and 2-methyl-PQ derivative antimalarial activity. However, it is still unclear have been reported to be almost four times as whether these metabolites or the parent compound effective as the standard drug nifurtimox, against exert the most important antiparasitic action. Cur- Chagas model disease in mice. This anti- rent knowledges suggest that the 4-amino-1- trypanosomiasis activity of primaquine relies on methyl side chain is important in antimalarial activ- the metabolic formation of free radicals that ity. The 5-hydroxydemethylprimaquine (formed by increase the oxidative stress in T. cruzi. The drug deamination and oxidation of primaquine) is the is, however, not clinically used for the therapy of most active metabolite. Carboxyprimaquine is con- Chagas disease. siderably less active than primaquine against exo- Other biochemical and physiological activities erythrocytic stages of P. berghei in vitro. of primaquine demonstrated by in vitro or in vivo The resistance to primaquine is incredibly low. studies include inhibition of vesicular transport and This may be associated with its physical, chemi- blocking of the calcium-release-activated current, cal, or biological properties, together with its short blocking of the appearance of Ca2+influx currents half-life and ability to sterilize the parasite’s in response to Ca2+store depletion, blocking of gametocytes. Relapses of P. vivax malaria shortly Na+and K+cardiac channels, and inhibition of after primaquine therapy have been reported in the diverse types of voltage-gated ionic channels, as Western Pacific, Southeast Asia, India, and Cen- well as acetylcholine (ACh) receptors. tral and South America. Nevertheless, the fre- quency, intensity, and distribution of those Therapeutic Indications for Malaria isolated reports do not appear alarming. Primaquine is indicated for malaria on four differ- Primaquine resistance is commonly confused as ent clinical uses: (i) radical cure in individuals failure of therapy or inability to remove the infected with P. vivax or P. ovale; (ii) presumptive hypnozoite liver stage of P. vivax after the full antirelapse therapy (terminal prophylaxis) for per- course of therapy and correct therapeutic dose. sons extensively exposed to P. vivax or P. ovale; The other important factor in detection of therapy (iii) reduction of onward transmission of failure with primaquine is adherence to medica- P. falciparum malaria in programs to eliminate tion. The exact mechanism of resistance of P. falciparum malaria and in areas threatened by primaquine has not been identified. resistance of P. falciparum to artemisinins; and (iv) primary prophylaxis against all species of Other Pharmacological Activities and malaria. For radical cure of P. vivax and P. ovale Clinical Uses Primaquine is useful for prophy- infections, the efficacy is highly dependent on the laxis and treatment of moderate Pneumocystis concurrent administration of an effective blood carinii pneumonia (PCP) or as salvage therapy schizontocidal agent. Primaquine is not when given in combination with clindamycin. recommended for use as a single drug as it is not The drug interferes with the microbial electron effective against erythrocytic forms of Plasmodia; transport system by producing quinone metabo- the drug must be co-administered with blood lites that generate superoxides in vivo. The effec- schizonticides. Primaquine dosage is customarily tive daily dose for PCP treatment is 2 mg/kg bw of expressed in terms of the base. Primaquine phos- primaquine and 225 mg/kg bw of clindamycin. phate USP is supplied in tablets containing 7.5 and Lower doses are applied for prophylaxis. 15 mg of base. 14 Pharmacology of Antimalarial Drugs, Current Anti-malarials

Pharmacology of Antimalarial Drugs, Current Anti-malarials, Fig. 3 Chemical structures of (a) primaquine and (b) carboxyprimaquine

A 14-day course (0.25–0.5 mg/kg bw daily) of Review Group report summarizing published lit- primaquine with blood schizonticide (chloroquine eratures. This recommendation is later on or an ACT) is strongly recommended in children supported by evidence assessed from a systematic and adult patients (except pregnant women, review which suggests that the lower single dose infants aged lower than 6 months, women (0.1–0.25 mg/kgbw) of primaquine given with the breast-feeding infants aged less than 6 months, goal of reducing transmission of P. falciparum is women breast-feeding older infants unless they less likely to cause hemolytic effects in people are known not to be G6PD deficient, and patients with G6PD deficiency than the previous with G6PD deficiency) with P. vivax or P. ovale in 0.75 mg/kg bw dose and that severe hemolytic all transmission settings (except pregnant women, events are not very common. infants aged less than 6 months, and women breast-feeding infants aged less than 6 months) Adverse Reactions and Toxicity to prevent relapse. In patients with mild-to- Primaquine is generally well tolerated when the moderate G6PD deficiency, primaquine base is drug is administered in the usual therapeutic doses given at 0.75 mg/kg bw once a week for with minimal adverse reactions. Primaquine bio- 8 weeks, with close medical supervision during transformation plays an important role both its the first 3 weeks of treatment for potential toxicity and antimalarial action and involves chi- primaquine-induced hemolysis. In patients with ral recognition, even though exact mechanisms severe G6PD deficiency, risk-benefit assessment are not yet established. needs to be taken on an individual basis by expe- The common adverse reactions include dose- rienced tropical medicine physicians. When related gastrointestinal discomfort (nausea, G6PD status is not known and G6PD testing is vomiting, diarrhea, and abdominal cramps) and diz- not available, a decision to prescribe primaquine ziness. Abdominal distress from primaquine can be must be based on an assessment for the risks and alleviated by antacids and by administering the drug benefits of adding primaquine. In pregnant with a meal. The less well-documented adverse women, primaquine should be given on the basis reactions of primaquine are derangement of leuko- of G6PD status to prevent future relapse following cyte levels, i.e., dose-dependent granulocytopenia chloroquine weekly prophylaxis (until delivery or agranulocytosis, and effects on immune mecha- and breast-feeding are completed). nisms. Other rare adverse effects include hyperten- A single dose of 0.25 mg/kg bw primaquine sion, arrhythmias and corrected QT (QTc) interval with an ACT is currently recommended in patients prolongation, and symptoms related to the central with uncomplicated malaria in low-transmission nervoussystem.Theeffectsonhumanfetusare areas (except pregnant women, infants aged less unknown, but the use of primaquine in pregnancy than 6 months, and women breast-feeding infants is not recommended due to hemolytic effects. aged less than 6 months) to reduce diseases trans- Primaquine has been shown to be mutagenic in mission without G6PD testing. The change in Escherichia coli and Salmonella typhimurium test policy from the previously recommended dose systems. of 0.75 mg/kg bw in 2010 to 0.25 mg/kg bw in The two major serious adverse effects of 2015 was based partly on a WHO Evidence primaquine are the propensity to induce the Pharmacology of Antimalarial Drugs, Current Anti-malarials 15 formation of methemoglobin and hemolytic epi- the metabolic pathway to hydroxylated metabolites sodes when erythrocytes with deficiency in G6PD or other metabolites responsible for this effect. are present. The severity of primaquine-induced hematoxicity is related to dose and degree of Contraindications G6PD deficiency. Methemoglobinemia, a predict- Primaquine is contraindicated in patients with able dose-related adverse effect, occurs occasion- known hypersensitivity to primaquine and related ally with therapeutic dosage but is much more compounds as well as in patients with severe common with a higher than therapeutic dosage. G6PD deficiency or methemoglobinemia. Since Several of primaquine metabolites, except primaquine crosses the placenta and may cause carboxyprimaquine, have shown greater propen- hemolysis in G6PD-deficient fetus, it is not sity to cause methemoglobin formation than recommended for use during pregnancy or during primaquine itself. Acute intravascular hemolysis breast-feeding unless the G6PD status of the is by far the most serious toxic hazard of infant is known. Nonclinical data from studies primaquine which restricts the wider use of the conducted in bacteria and in animals treated with drug. It occurs as a consequence of oxidant stress primaquine show evidence of gene mutations and in individuals with G6PD deficiency, an inherited chromosomal/DNA damage, teratogenicity, and X chromosome-linked trait. Primaquine-induced injury to embryos and developing fetuses when hemolysis is characterized by severe anemia, primaquine is administered to pregnant animals. intravascular hemolysis with dark urine, and Primaquine is also contraindicated for children mild jaundice. Hemolysis appears usually on the under 4 years of age, and its administration second or third day of administration of requires a previous test for G6PD status. primaquine and continues for 5–7 days. The hematocrit level drops to 30% between days Caution 8 and 12 when about half of the red cells have Primaquine should not be given to subjects with been destroyed. Hemoglobinuria often accom- concurrent treatment with potentially hemolytic panies the hemolysis; serum bilirubin rises to drug or agents capable of depressing the myeloid 50–90 mM, and slight jaundice may appear; elements of the bone marrow. Heinz bodies occur commonly at first but disap- Different variants of G6PD deficiency are pear as the hemolysis intensifies. The symptoms associated with significantly different risks for are related to the effect of the anemia. The hemo- hemolysis. Decision to prescribe primaquine lysis is normally self-limiting upon withdrawal of must be based on an assessment of the risks and the drug. The degree of G6PD deficiency varies benefits of using primaquine in patients with mild- greatly ranging from moderate in Africans to-moderate G6PD deficiency or when the G6PD (African variant A) to very high in people of Med- status is unknown and G6PD testing is not avail- iterranean origin (Mediterranean variant B) and in able. If primaquine administration is considered, population groups scattered throughout Asia (Asian baseline hematocrit and hemoglobin levels must variants). Several phenolic analogs of primaquine be investigated before treatment, and close hema- have been proposed to cause hemolytic effect, e.g., tological monitoring (e.g., at day 3 and 8) is 5-hydroxyprimaquine, demethylprimaquine, and required. Adequate medical support to manage 5-hydroxydemethylprimaquine. It is still uncertain hemolytic risk should be available. Due to the whether the major metabolite carboxyprimaquine potential for QTc interval prolongation, electro- contributes significantly to the toxicity of cardiogram (ECG) should be monitored when primaquine, although it does not cause methemo- primaquine is administered in patients with car- globin formation in vitro. Carboxyprimaquine does diac disease, long QTc syndrome, a history of not inhibit drug metabolism in vitro; however, inhi- ventricular arrhythmias, uncorrected hypokalemia bition of the formation of carboxyprimaquine could and/or hypomagnesemia, or bradycardia lead to serious adverse effects, i.e., hemolytic ane- (<50 bpm) and during concomitant administra- mia or other unexpected toxicity due to the shift of tion with QTc interval prolonging agents. 16 Pharmacology of Antimalarial Drugs, Current Anti-malarials

Pharmacokinetics carboxyprimaquine are approximately 3–8and Pharmacokinetic parameters of primaquine and its 15–17 h, respectively. plasma metabolite carboxyprimaquine following The pharmacokinetics of primaquine and currently recommended doses in healthy subjects carboxyprimaquine after oral administration in and malaria patients are summarized in Table 1. man are unaffected by dose size, within the clin- Absorption after oral administration is rapid ically used dosage range. Primaquine does not and almost complete with bioavailability of inhibit or induce its own metabolism in man; about 96%. Cmax is achieved within 1–4hof multiple-dose studies indicate that primaquine dosing. Mean absorption half-life (t1/2a)is does not accumulate in the plasma over the 30 min. The concentration-time profiles in whole 14 days period of treatment. No significant con- blood and in plasma are similar. Primaquine is centrations of primaquine are found in the predose distributed throughout the body. The Vd/F is in plasma samples taken prior to the daily doses of the range of 3–8 l/kg. About 75% of primaquine is the drug. bound to proteins. Red cell concentration is rela- tively high. The drug also crosses the placenta, but Factors Associated with Altered Drug Exposure it is not extensively found in breast milk. and/or Treatment Response Primaquine is predominantly cleared by hepatic metabolism with renal elimination Malaria Infection A single oral dose of 45 mg accounting for less than 1% of the administered primaquine is rapidly absorbed in patients with dose over 24 h. The CL/F is approximately P. vivax or P. falciparum malaria. Acute 0.3–1.2 l/h/kg bw. Hepatic clearance of P. falciparum infection is associated with a reduc- primaquine is via two distinct pathways. Mono- tion in the CL/F of primaquine, while t1/2 amine oxidase (MAO-A) biotransforms remained unaffected. This change in the oral primaquine to the predominant but inactive clearance is possibly due to an impairment of the metabolite carboxyprimaquine (Fig. 3b). drug-metabolizing enzyme system and/or a reduc- Carboxyprimaquine is slowly eliminated and tion in the absorption across the gastrointestinal also further biotransformed via CYP2C19, tract. The pharmacokinetics of primaquine CYP2D6, and CYP3A4, which generates the appears to be unchanged in patients with P. vivax reactive intermediates responsible for antimalar- malaria. ial activities and methemoglobinemia and hemo- lytic toxicity, particularly the phenolic metabolite G6PD Status The status of G6PD enzyme activ- 5-hydroxyprimaquine. Carboxyprimaquine rea- ity does not influence the pharmacokinetics of ches plasma concentrations more than ten times primaquine. higher than those of the parent compound (at approximately 4–8 h). It accumulates with Ethnics Ethnic diversity of primaquine pharma- daily dosing of primaquine. In animal studies in cokinetics suggests potential heritability. In the isolated perfused rat liver preparation, the Koreans, the Cmax of primaquine has been formation of the carboxy metabolite of shown to be about five times higher and the primaquine was enantioselective. Stereoselective carboxyprimaquine concentration about two to metabolism also plays a role in both antimalarial five times lower than in Indian and Thai activity and toxicity. Both primaquine and populations. Different exposure has also been carboxyprimaquine are excreted mainly via the seen between Caucasian and Thai males. biliary tract and can be found in feces within 24 h of administration. Primaquine itself is also Gender Conflicting results have been reported excreted in urine. (À)R primaquine is cleared on the effects of gender on the disposition of more extensively to carboxyprimaquine than the primaquine. Some studies reported increased

(+)S enantiomer. The t1/2 of primaquine and exposure and hence greater adverse reactions in women, while others reported no effect of gender. Pharmacology of Antimalarial Drugs, Current Anti-malarials 17

Renal Diseases The pharmacokinetics of a sin- primaquine pharmacokinetics in Thai patients gle oral dose of 15 mg primaquine does not appear with P. vivax malaria. Similarly, there appears to to be altered in patients with severely impaired be no pharmacokinetic interaction between renal function and end-stage renal dysfunction. primaquine and mefloquine when used at thera- peutic doses, despite mefloquine being a strong Genetic Polymorphisms in Drug-Metabolizing inhibitor of the formation of carboxymefloquine Enzymes Genetic polymorphisms that decrease in vitro. Co-administration of primaquine with CYP2D6 enzyme activity reduce bioactivation of quinine did not alter the pharmacokinetics of primaquine and may result in treatment failure. primaquine but quinine. Production and/or elimi- The treatment options for P. vivax infection in nation of carboxyprimaquine was reduced as indi- poor metabolizer are likely limited. Additionally, cated by the lower values of AUC within 24 h in the use of primaquine as a prophylactic agent in the presence of quinine. Primaquine plasma levels this population would likely be ineffective. On the and exposure have been shown to be increased other hand, extensive metabolizers would likely when primaquine is given with chloroquine, be successful with primaquine therapy as they dihydroartemisinin-piperaquine combination, have the lowest parent primaquine levels and and pyronaridine-artesunate combination therapy. highest production of reactive metabolites and The underlying mechanism is likely due to inhi- primaquine. Individuals with ultrarapid meta- bition of CYP2D6-mediated primaquine metabo- bolizers would be expected to display the most lism. Some of the blood stage antimalarial agents primaquine metabolism through the CYP2D6 that could interact with primaquine through pathway. Relationship between CYP2D6 meta- CYP450 metabolic pathways also have the poten- bolic status and clinical outcome of primaquine tial to interact with primaquine through therapy remains to be clarified. P-glycoprotein-mediated transport. Significant pharmacokinetic and pharmacody- Drug Interactions Primaquine drug-drug inter- namic interactions between primaquine and other actions are likely complex and involve a multitude drugs have been reported. The metabolic clear- of pharmacological factors besides hepatic metab- ance of antipyrine to its three main metabolites, olism, including transporter-mediated drug-drug i.e., 3-hydroxymethylantipyrine, 4-hydroxyan- interactions. Primaquine has been shown to inter- tipyrine, and norantipyrine, was significantly act with ABC transporters such as P-glycoprotein reduced after a single oral dose of 45 mg (MDR1) and multidrug resistance protein primaquine. There was no effect of primaquine 1 (MRP1). The impact that these drug-drug inter- on either conjugation (to paracetamol glucuronide actions have on primaquine efficacy is however and paracetamol sulfate) or oxidation, which sup- unclear. A number of antimalarials, particularly ports the safety of using paracetamol as an anti- those with a quinoline structure, i.e., mefloquine, pyretic in malaria patients. In vitro studies have chloroquine, quinine, and in particular shown that primaquine conversion into primaquine itself, are all well recognized as inhib- carboxyprimaquine is inhibited by ketoconazole. itors of hepatic CYP450 in vitro, in vivo in ani- On the pharmacodynamics aspect, artesunate mals, and in man. In the chemotherapy of malaria, has been shown to reduce the appearance of these antimalarials are usually co-administered gametocytemia in adult Thai patients infected either concurrently or sequentially. Metabolic with uncomplicated P. falciparum malaria, drug interaction between these drugs is therefore whereas its combination with primaquine resulted a major concern. Results from an in vitro study in shorter gametocyte clearance time. Further- showed that chloroquine, quinine, artemether, and more, pentobarbitone sleeping time and artesunate did not significantly inhibit the forma- zoxazolamine paralysis time were prolonged in a tion of carboxyprimaquine by human liver micro- dose-related manner after acute administration of somes. Prior treatment with chloroquine in the primaquine in the rat. Adverse hematological clinical situation had no effect on plasma 18 Pharmacology of Antimalarial Drugs, Current Anti-malarials

Pharmacology of Antimalarial Drugs, Current Anti-malarials, Fig. 4 Chemical structures of (a) quinine and (b) 3-hydroxyquinine

reactions may also occur in the presence of quinuclidine. The molecular weights of base, sul- myelosuppressants. fate, bisulfate, hydrochloride, and dihydrochloride are 324, 747, 782, 361, and 397, respectively. The Quinine salts are freely soluble in water. The drugs should be Quinine is the chief alkaloid of the bark of the stored in air-tight containers and be protected from Cinchona tree (Arbor febrifuga) indigenous to light. certain regions of South America. It was first used against fever in Peru, probably around Pharmacological Activities 1630. The bark was employed in 1638 to treat the wife of the Viceroy of Peru. Her miraculous Antimalarial Activity and Mechanism of cure resulted in the introduction of Cinchona into Action and Resistance Quinine is a potent Spain in 1639 for the treatment of ague. By 1640, blood schizontocidal (large rings and trophozo- the drug was being employed for fever in Europe. ites) against all species of Plasmodium and also Its use was first mentioned in European medical gametocytocidal against P. malariae, P. ovale, literature in 1643 by a Belgian. The name Cin- P. vivax, and P. knowlesi. Quinine has no tissue chona is reported to be a misspelling of schizontocidal or sporontocidal activity. The Chinchona, the name of the Portuguese countess metabolites exhibit lower antimalarial potency who allegedly used the compound first. than the parent drug. For almost two centuries, the bark was The molecular mechanism of action of quinine employed for medicine as a powder, extract, or against P. falciparum is only partially understood. infusion. It was not until the 1830s that the four Like chloroquine, quinine accumulates in the para- main active constituents of Cinchona bark were site digestive food vacuole and inhibits the heme isolated: two pairs of optical isomers quinine and detoxification process. Decreasing sensitivity to quinidine, together with cinchonine and quinine has also been reported in some areas cinchonidine. The Cinchona alkaloids have been where the drug has been used extensively for used ever since, for the treatment of malaria and malaria therapy. The genetic basis of quinine resis- arrhythmic heart conditions. tance involves multiple genes. Similar to chloro- quine resistance in P. falciparum, quinine resistance Chemistry and Physical Properties is also associated with mutations of the two trans- Cinchona contains a mixture of more than 20 alka- port proteins, PfCRT and PfMDR1. In addition, the loids. The most important of these are two pairs of transport protein PfNHE1 (Plasmodium falciparum optical isomers quinine and quinidine and cincho- sodium/proton exchanger 1) encoded by the P. nine and cinchonidine. Quinidine is a dextrorotatory falciparum Na+/H+ exchanger gene pfnhe on chro- diastereomer of quinine. Quinine, cinchonine, and mosome 13 is also involved. cinchonidine are levorotary. Quinine[6-methoxy-a-(5-vinyl-2-quinuclidinyl)- Other Pharmacological Activities and 4-quinolinemethanol: Fig. 4a] contains a quinoline Clinical Uses Apart from malaria, quinine is group attached through a secondary alcohol linkage also used to treat lupus and arthritis. The drug to a quinuclidine ring. A methoxy side chain is was previously frequently prescribed as an off- attached to the quinoline ring and a vinyl to the label treatment for leg cramps at night, but this Pharmacology of Antimalarial Drugs, Current Anti-malarials 19 has become less common due to a Food and Drug recommended for treatment of pregnant women in Administration warning that this practice is asso- the first trimester with uncomplicated P. vivax, ciated with life-threatening adverse reactions. P. ovale, P. malariae, or P. knowlesi. In the first Quinine has oxytocic potential to induce pre- trimester of pregnancy and children aged lower mature labor. It is therefore used to augment labor than 8 years, quinine-clindamycin combination is and also to induce abortion. used since tetracyclines are contraindicated. A 7-day oral quinine in combination with tetracy- Therapeutic Indications for Malaria cline, doxycycline, or clindamycin is used in the Quinine and its dextroisomer quinidine are one of treatment of uncomplicated P. falciparum malaria the most commonly used drugs for malaria treat- as an alternative treatment when an effective ACT ment worldwide. Quinine is a basic amine and is is not promptly available. The addition of these usually provided as a salt. Various existing prepa- antibiotics improves clinical efficacy of quinine, rations include the hydrochloride, dihydrochloride, probably through mechanisms involving both sulfate, bisulfate, and gluconate. All quinine salts pharmacokinetic and pharmacodynamic interac- can be given by oral or intravenous (IV) routes of tions, and allows for shortening of treatment reg- administration. Quinine gluconate may also be imens. Nevertheless, patients’ compliance is the given intramuscularly (IM) or rectally (PR). major problem with all these 7-day regimens as it Parenteral quinine (IV and IM) is indicated for is difficult to achieve without hospitalization. the treatment of severe malaria. Parenteral quinine Once the malaria symptoms have subsided, proved safe and effective in the treatment of patients are reluctant to continue taking quinine severe falciparum malaria if rate-controlled intra- because of cinchonism; poor compliance and sub- venous infusion is used. Slow intravenous infu- sequent incomplete treatment of patients who sion of quinine dihydrochloride 10 mg/kg bw over remain parasitemic are favorable to the selection 4 h is now the standard method of administering of parasites less sensitive to quinine. quinine in severe malaria. A loading dose of qui- nine (20 mg/kg bw quinine dihydrochloride Adverse Reactions and Toxicity equivalent to 16.7 mg base), infused over 4 h, Quinine has a narrow therapeutic window. Serious has proved to be a safe method of achieving adverse reactions are infrequent, but minor immediate therapeutic plasma concentrations for adverse effects are common. In general, patients P. falciparum. The loading dose of quinine is with malaria, particularly children, tolerate high however contraindicated in patients with previous blood concentrations of quinine well. Adverse treatment with quinine, quinidine, or mefloquine reactions are less frequent than in healthy subjects within 48 h. In other areas where the parasite is due to the increased plasma protein binding of still sensitive to quinine, a loading dose may not quinine in patients with malaria. Most of the be necessary. In areas with excessive use of qui- adverse reactions are concentration dependent nine, it is too dangerous to give loading dose and become more frequent at high plasma con- routinely in every patient. Severe cardiac arrhyth- centrations. The characteristic symptom complex mia has been seen in patients who were treated of cinchonism commonly occurs, which in its with quinine prior to receiving a loading dose. mild form consists of tinnitus, headache, light- In pregnancy, quinine can still be used safely headedness, nausea, vomiting, and slight distur- and effectively in the treatment of acute uncom- bance of vision. This symptom complex is tran- plicated falciparum malaria. No abortion is sient and frequently occurs when plasma quinine observed when quinine is administered to preg- levels exceeded 5 mg/l, but it disappears sponta- nant women during the first trimester. In the sec- neously after discontinuation of the drug. With the ond and third trimester, increase in uterine higher doses, these adverse reactions become contractions and fetal distress may occur during more severe. The eighth nerve damage occurs the first 24 h after the start of treatment when fever with vertigo and decreased auditory acuity. Visual is probably still high. A 7-day quinine is strongly damage with blurred vision, disturbances of color 20 Pharmacology of Antimalarial Drugs, Current Anti-malarials perception, night blindness, and diplopia indicate Quinine has been used to augment labor and also optical nerve involvement. Anorexia, vomiting, to induce abortion. However, the abortifacient constipation, abdominal pain, and diarrhea may doses of quinine are two to three times greater occur after therapeutic doses of quinine. These than those used for malaria. In addition, it has gastrointestinal effects are due both to the local been demonstrated that malaria itself may have irritant effect of quinine on the gastrointestinal more oxytocic effect than quinine. Pregnancy tract and the central effects of quinine on the therefore is not a contraindication to the use of chemoreceptor trigger zone. Quinine is also a quinine in the treatment of malaria. common cause of drug-induced thrombocytope- Less frequent but more serious adverse reac- nia and the most common cause of drug-induced tions of quinine include urticaria, asthma, throm- thrombotic microangiopathy. bocytopenia, bronchospasm, angioedema, and Quinine and its diastereoisomer quinidine hemolysis. Interrupted and recurrent quinine ther- including some of the metabolites apy in nonimmune individuals with P. falciparum (3-hydroxyquinidine, 2’-oxyquinidine, and quin- infections seems to predispose them to the com- idine N-oxide) possess cardiovascular effects. plication of blackwater fever, a syndrome of Quinidine is more likely to produce cardiac effects severe hemolytic anemia, hemoglobinuria, than quinine. The most serious reactions are asso- oliguria, and jaundice. Occasionally, quinine and ciated with rapid injection of a large dose, leading its stereoisomer quinidine have also been reported to toxic blood concentrations which result in to aggravate weakness in myasthenia gravis. The hypotension, cardiac conduction disturbances use of quinine for treatment of cramp up to (heart block, ventricular fibrillation), or even 60 days can be associated with rare but life- death. When the drugs are administered by slow threatening adverse effects. Its used for this pur- intravenous infusion or orally, these life- pose is therefore restricted in some countries. threatening adverse reactions are rare. The only Quinine poisoning is uncommon but can cause effects are minor ECG changes (lengthening of serious retinal and cardiovascular toxicity. the QTc interval, widening of the QRS complex, and T-wave flattening). These potentially danger- Contraindications ous adverse effects must be of concern particu- Quinine is contraindicated in patients with known larly in patients with history of pre-existing hypersensitivity to quinine, any of the cinchona quinine or quinidine therapy. Whenever paren- alkaloids, or other structurally related drugs. teral therapy is used in severely ill patients, car- diac monitoring is recommended. Young children Caution with severe malaria might be more susceptible to Although there is little evidence of cardiotoxicity quinine cardiotoxicity than older children. in patients with malaria, quinine should be used Cinchona alkaloids stimulate insulin release with caution in patients who have heart rhythm from pancreatic islet cells, resulting in low levels disorders or heart disease. Quinine metabolites of blood glucose in malaria patients. However, may cause oxidative hemolysis, and its use in malarial infection itself may also produce hypo- patients with G6PD deficiency should be with glycemia, particularly in severe infections. During caution. Plasma quinine may accumulate in intravenous quinine therapy, potentiation of these patients with hepatic or renal diseases, and caution effects can be seen more frequent in severe is also advised in treating these patients with falciparum malaria. Pregnant women and children quinine. also appear particularly prone to quinine-induced hypoglycemia. Blood glucose levels should be Pharmacokinetics monitored when the drugs are being used in preg- Pharmacokinetic parameters of quinine following nant patients, children, or severely ill patients. currently recommended doses for treatment of An overestimated property of quinine is its uncomplicated and severe malaria are summa- oxytocic potential to induce premature labor. rized in Table 1. Pharmacology of Antimalarial Drugs, Current Anti-malarials 21

Quinine is rapidly absorbed following both plasma concentrations. Quinine concentration- oral and parenteral routes. Cmax is reached 1–6h time profiles for plasma, red cells, and saliva are after a single oral dose. A loading dose of parallel, giving similar estimation of t1/2 in all 20 mg/kg bw immediately reaches 93% of Cmax three media. Quinine does not freely cross the and 75% of the steady-state trough levels. Rapid blood-brain barrier. The concentrations in CSF intravenous injection results in high toxic concen- have been reported between 2% and 7% of the trations which affect the cardiovascular system. corresponding plasma concentrations. The ratio of Constant quinine dihydrochloride infusion of CSF/plasma free quinine concentrations is 20 mg (salt)/kg bw over 4 h as a loading dose, approximately 0.55. followed by 10 mg (salt)/kg bw intravascular Hepatic biotransformation accounts for about infusion over 2 h, given 8 hourly for 7 days give 80% of its total clearance. Quinine undergoes exten- satisfactory concentration profiles with reduced sive hepatic biotransformation, predominantly via risk for cardiovascular toxicity. Intramuscular CYP3A4/5 as well as CYP2C9, CYP1A2, and injection and oral administration produce plasma CYP2D6 into several metabolites. 3-hydroxylation concentrations lower than those following intra- mainly via hepatic CYP3A4/5 to its primary metab- venous infusion. Intramuscular quinine is slowly olite, 3-hydroxyquinine (Fig. 4b), has been shown to absorbed with tmax of about 5 h. A loading dose of contribute 5–10% of the antimalarial activity. 20 mg (salt)/kg bw provides a satisfactory plasma Formation of the minor metabolites (10S)-11- concentration and can be considered as alternative dihydroxydihydroquinine and 2Ľ-quininone) is route of administration if the intravenous route is also dependent on CYP3A4/5, while the formation not possible. of (10R)-11-dihydroxydihydroquinine might be Pharmacokinetics of quinine after intravenous linked to CYP2C9. The drug and its metabolites injection is generally described by two exponen- appear in the urine within 1 h of drug administration, tial terms with a rapid distribution phase with a and little remains in the body after 48 h. Elimination short half-life of about 2 min and a slower t1/2 from the body is rapid with CL/F of about similarly to that after the oral dose. The Vc/F is 0.2–5 ml/min/kg. About 20% of quinine is excreted approximately one-third of the Vd/F. Due to this unchanged in the urine, and small amounts may pharmacokinetic property, it is therefore appear in the bile and saliva. Renal excretion suggested that intravenous administration of qui- involves by both glomerular filtration and tubular nine should be given by rate-controlled infusion in secretion. There appears to be stereoselective net order to avoid potentially toxic blood concentra- renal tubular secretion of quinidine over quinine tions early in the distribution phase. which indicates stereoselectivity of the renal tubular Quinine is distributed throughout most of the transport process. body fluids and is detectable in cerebrospinal fluid (CSF), breast milk, and placenta. Approximately Factors Associated with Altered Drug Exposure 85% of the drug is bound to plasma proteins, and/or Treatment Response mainly to a1-acid glycoprotein. Unlike chloro- quine, and mefloquine, quinine is not concen- Malaria Infection The pharmacokinetics of qui- trated in red cells. The concentration in nine is significantly altered by malaria infection. erythrocytes is between one-fifth and one-third The absorption is not affected, but the CL/F is of that in plasma. Quinine is measurable in saliva reduced from 0.2 to 5 ml/min/kg in healthy sub- within a few minutes of oral dosing or intravenous jects to about 1.4 and 0.9 ml/min/kg in uncompli- infusion. It remains detectable for up to 36 h after cated malaria and cerebral malaria, respectively. a 500 mg dose. Saliva concentrations could there- The excretion of quinine is inversely related to fore be used as a noninvasive method to measure disease severity and most impeded in severe patients’compliance. Concentrations in saliva malaria infection. It is likely that the main factor which represent the unbound fraction of quinine that influences the decreased clearance of quinine are approximately one-quarter to one-third of the is the impairment of CYP3A4/5 function. The Vd 22 Pharmacology of Antimalarial Drugs, Current Anti-malarials

is contracted (1.1 l/kg) in cerebral malaria. The t1/2 Elderly Subjects Disposition kinetics of quinine is prolonged during acute infection with a mean of is altered in healthy elderly subjects when com- 16 h or even longer in severe malaria (18 h). pared to those of younger adult subjects. The rate Consequently, elevation of plasma drug concen- of drug absorption is not altered, but the CL/F is trations is observed which is also proportional to significantly reduced (26% reduction). The lower the severity of the disease. Despite such high CL/F in the elderly group indicates the decreased plasma concentrations in severe falciparum hepatic biotransformation of quinine in old age, malaria, there is no apparent quinine toxicity. since the renal clearance of drug is not altered.

This is explained by the increase in plasma protein This results in a prolongation of the t1/2 (about binding of quinine to a1-acid glycoprotein in 18.4 h). Plasma protein binding of quinine patients with cerebral malaria (93%). The extent remains unchanged despite the lower plasma of increase in plasma protein binding of quinine is albumin. This is due to the fact that quinine relatively lower in uncomplicated malaria (90%). binds extensively to a1-acid glycoprotein rather Despite the marked reduction of quinine clearance than albumin. Significant drug accumulation may in severe malaria, maintenance dose reduction is occur after multiple dosing of malaria treatment. not recommended in the initial phase of treatment The clinical significance of this finding is unclear, because severe infections cause high early fatality but it emphasizes the need for caution in the rates. The danger of inadequate treatment over- administration of quinine to elderly patients. weighs the risk of toxicity. The dose should be reduced in severe malaria only when there is evi- Malnutrition Intestinal malabsorption is a fea- dence of severe cardiotoxicity or persistent renal ture of kwashiorkor. This condition significantly failure after 3 days of treatment (by this time affects the pharmacokinetics of quinine. The lon- enough quinine is available for consistent parasit- ger apparent absorption half-life (t1/2a)andtmax icidal activity). Dose reduction by one-third after and the lower Cmax observed in patients with 3 days has been suggested to prevent further rise kwashiorkor suggest slower and lower absorption in plasma quinine concentrations in such cases. In of quinine in this group of patients, although the the presence of severe arrhythmia, discontinua- contribution from differences in distribution tion of quinine treatment should be considered if kinetics cannot be excluded. Quinine is eliminated effective alternative drugs such as artemisinin more slowly in children with kwashiorkor, and drugs are available. therefore, t1/2 is significantly prolonged. Enlarged fatty liver is common in kwashiorkor, and this is associated with reduced activity of some of the Children The disposition of quinine changes oxidative liver enzymes. with age with slightly higher concentrations observed in children aged lower than 2 years. In Pregnancy Quinine is one of the first-line drugs children with malaria, the Vd is contracted (30% recommended for use during the first trimester of smaller) and the CL is increased. As a result of pregnancy. The pharmacokinetic properties of these changes, shorter t is observed in children. 1/2 quinine are not different between pregnant and The decline in plasma concentrations of quinine in nonpregnant women with uncomplicated malaria. the latter half of the treatment course (10 mg base/ In severe malaria, the Vd/F is generally reduced kg bw every 8 h for 7 days) is associated with by about 30%, and elimination is more rapid. treatment failure when values fall below the puta- Alterations in plasma protein and tissue protein tive minimum inhibitory concentration (MIC). binding associated with malaria infection and For this reason it has been suggested that the pregnancy itself may be responsible for the reduc- individual dose of quinine in children should be tion in the Vd. Placental cord plasma quinine increased to 15 mg base/kg body weight in the concentrations range between 1 and 4.6 mg/l, second half of the treatment course. which correlate well with maternal plasma qui- nine concentrations. The mean ratio of cord Pharmacology of Antimalarial Drugs, Current Anti-malarials 23 plasma to maternal plasma quinine concentration Drug Interactions Various studies suggest sig- is 0.32 and considered safe for breast-feeding. nificant pharmacodynamic and pharmacokinetic Breast milk-to-plasma ratio ranges from 0.11 interactions between quinine and other drugs to 0.53. including other antimalarial drugs. The QTc inter- val may be prolonged when quinine is given with antiarrhythmic drugs such as flecainide and Hepatic Diseases Hepatic metabolism of qui- amiodarone. In addition, ventricular arrhythmia nine is reduced in hepatic insufficiency. Pharma- may occur when the drug is given with antihista- cokinetics of quinine during the acute phase of mines (e.g., terfenadine) or antipsychotic drugs hepatitis-B infection is significantly different from (e.g., thioridazine). Quinine has been shown to those in healthy subjects. The t is prolonged 1/2 potentiate the oral anticoagulants by inhibition of (17 h) and CL/F is reduced. However, the phar- prothrombin synthesis. macokinetics obtained during acute hepatitis is With regard to pharmacokinetic interactions, sys- not different from those during the recovery temic exposure of quinine is unchanged when qui- phase. Despite a return of liver function tests to nine is co-administered with sulfadoxine- normal during convalescence after hepatitis, the pyrimethamine (SP) and oral contraceptive steroids. clearance of quinine remains impaired. This sug- On the other hand, plasma quinine concentrations gests that curative regimens of quinine used in the are increased when co-administered with tetracy- routine treatment of falciparum malaria may not cline, quinidine/cinchonine, cimetidine, ketocona- be suitable for malaria patients with acute hepati- zole, omeprazole, nifedipine, troleandomycin, and tis or even those who have had hepatitis within the erythromycin. The mechanism involved is mainly past 3 months. The combined effects of acute through hepatic CYP450 inhibition. Plasma quinine hepatitis and malaria on the kinetics of quinine concentrations in the presence of tetracycline are suggest caution with its dosage in patients with significantly higher than those with quinine alone. both conditions. The addition of the course of tetracycline (250 mg, 6 hourly for 7 days) to the conventional regimen of Renal Diseases Quinine clearance is reduced in quinine (600 mg 8 hourly for 7 days) has an influ- acute renal failure complicating malaria, but this is ence on the maintenance of plasma quinine concen- the result of pharmacokinetic changes related to trations above the MIC throughout the 7-day period the acute infection rather than due to reduced renal of treatment. Higher plasma concentrations of each function per se, as urinary quinine clearance com- component have also been observed when quinine, prises only 20% of the total clearance. quinidine, and cinchonine were given in Hemofiltration has no significant influence on combination. the total body clearance of quinine. Drugs which have been shown to reduce sys- temic exposure of quinine include rifampicin, iso- niazid, lopinavir/ritonavir (LPVr), and activated Genetic Polymorphisms of Drug-Metabolizing charcoal. Acidification of the urine also increases Enzymes Substantial variation of quinine phar- the excretion rate of quinine by about twofold macokinetics between individuals was observed resulting in low systemic exposure. Rifampicin in children from Ghana with severe malaria. The and isoniazid decrease plasma quinine concentra- possible involvement of polymorphisms of drug- tions, possibly by the induction of hepatic metab- metabolizing enzymes has been proposed but olism of quinine. Following 1 week pre-treatment remains to be confirmed. One study showed that with rifampicin and isoniazid, the CL/F of quinine 3-hydroxylation metabolite of quinine is substan- is significantly increased, and the t is shortened. tially lower in healthy people from Tanzania har- 1/2 The combined therapy of quinine and rifampicin boring the CYP3A5*3/*3 low-expression for P. falciparum, however, resulted in faster par- genotype. asite clearance which could be due to antimalarial 24 Pharmacology of Antimalarial Drugs, Current Anti-malarials activity of rifampicin rather than drug interaction, Mefloquine since induction of CYP3A4-mediated quinine During the Second World War, the US Army metabolism activity by rifampicin takes several initiated a program for the discovery and devel- days. Quinine penetrates relatively poorly into opment of new antimalarial drugs. The most the cerebrospinal fluid (CSF) in patients with promising chemical class to emerge from this cerebral malaria, with a concentration of approx- extensive research program was found to exhibit imately 2–7% of plasma concentrations. phototoxic adverse effects, and thus its further Co-administration of rifampicin and quinine may development was precluded. In 1960, following also decrease quinine concentrations in the CSF the emergence of chloroquine-resistant due to inducing effect of rifampicin on the efflux P. falciparum in Southeast Asia, the search con- protein P-glycoprotein. Rifampicin should, there- tinued, and the compound selected from this class fore, not be combined to antimalarial for malaria was WR 142490. It was proved both to be safe and treatment despite its intrinsic antimalarial activity. reliably effective. This compound was later Concomitant use of antimalarial and antiretro- named mefloquine. Since then, the development viral drugs is increasingly frequent in malaria and of mefloquine was continued by the World Health HIV-endemic regions. The reduction in systemic Organization (WHO) in collaboration with exposure of quinine and 3-hydroxyquinine with Hoffmann-La Roche and the US Walter Reed concomitant LPV/r use (ritonavir-boosted Institute of Research (WRIR). The initial phase lopinavir) raises concerns of suboptimal expo- I and II clinical trials were carried out between sure. The rate of elimination of a therapeutic 1972 and 1978 in many tropical countries includ- dose of quinine is increased when activated char- ing Zambia, Brazil, Vietnam, and Thailand. coal is administered at regular intervals commenc- Results showed mefloquine to be safe, generally ing 4 h after therapeutic dose of quinine (600 mg). well tolerated, and therapeutically effective in a

Activated charcoal shortens quinine t1/2 and single dose of 750–1500 mg against both increases CL by approximately 50%. Recently, it chloroquine-resistant and chloroquine-sensitive has been shown that repeated oral charcoal (50 g, P. falciparum, with initial cure rates approaching 4 hourly) is highly effective and is only one 100%. approach in enhancing the removal of quinine in symptomatic patients with acute quinine poison- Chemistry and Physical Properties ing to reduce the risk of potentially dangerous Mefloquine (Fig. 5a) is a 4-quinolinemethanol complications. derivative which has two asymmetric carbon Quinine inhibits the activity of CYP2D6 as atoms in the molecule and is used clinically as a well as P-glycoprotein and biliary excretion. It racemic mixture (50:50) of the erythro isomers has been shown to interact with antipyrine, (dextrorotatory 11R, 2’S and levorotatory 11S, 2’R). digoxin, ampicillin-cloxacillin, and rifampicin Mefloquine is poorly soluble in water (10 g/l at  upon co-administration. Quinine inhibits biliary 6 C). The molecular weight of the base is 378. excretion and may theoretically alter rifampicin t1/ The hydrochloride salt (MW 415) is a white, 2. Chronic administration of quinine shortens odorless, and bitter tasting powder. It is slightly plasma antipyrine t1/2. Quinine increases digoxin soluble in water. The drug has a tendency to bind plasma levels, probably by reducing its nonrenal to cell membranes, proteins, and plastics. clearance. Quinine reduced the bioavailability and the antimicrobial activity of ampicillin-cloxacillin Pharmacological Activities upon co-administration, which may have thera- peutic implications. The MIC of both antibiotics Antimalarial Activity and Mechanism of in the presence of quinine was five- to sevenfold Action and Resistance Mefloquine is a potent increased, indicating a decrease in antimicrobial and long-acting blood schizontocidal antimalarial activity by quinine. against all human species of Plasmodium includ- ing multidrug-resistant strains of P. falciparum. In Pharmacology of Antimalarial Drugs, Current Anti-malarials 25

Pharmacology of Antimalarial Drugs, Current Anti-malarials, Fig. 5 Chemical structures of (a)mefloquine and (b) carboxymefloquine

addition, it is active against gametocytes of susceptibility to mefloquine is associated with P. vivax, P. ovale, P. malariae,andP. knowlesi. increased pfMDR1-mediated import into parasite However, it has no effect against exoerythrocytic food vacuole. This suggests that a primary target forms of malaria. Its major plasma metabolite (s) of action of mefloquine resides outside diges- carboxymefloquine (Fig. 5b) has no significant tive food vacuole. Inhibition of the import of antimalarial activity. Mefloquine exhibits approx- many compounds into the food vacuole by mef- imately the same stage specificity of action as loquine has been shown. quinine, killing primarily the large rings and tro- phozoites of asexual parasites. Other Pharmacological Activities and The exact modes of antimalarial action and Clinical Uses Mefloquine exerts in vitro and resistance of mefloquine remains unclear. It is in vivo activity against Mycobacterium avium thought that mefloquine may share some mecha- complex including strains with multidrug resis- nisms with chloroquine and quinine. Three possi- tance. In addition, it is also found to be effective ble mechanisms of action of mefloquine have against Schistosomes. A single dose of meflo- been proposed: the impairment of NADPH oxida- quine possesses potential effect against three tion process through its interaction with phospho- major species of schistosomes (Schistosoma lipids in the parasite membrane, the interaction mansoni, Schistosoma haematobium, and with ferriprotoporphyrin IX (FPIX), and the Schistosoma japonicum) infecting humans. action on the parasite food vacuoles, raising When used as IPTp for malaria prevention, mef- intravesicular pH and thereby interfering with loquine shows promising activity against con- food digestion of the parasites. A more recent comitant S. haematobium leading to reduction of proposal is inhibition of endocytosis of the cytosol egg excretion in pregnant women. by the parasite. Mefloquine was first introduced as first-line treatment for P. falciparum malaria in Thailand Therapeutic Indications for Malaria in 1984. However, despite its restricted clinical Mefloquine is currently recommended by WHO uses, significant resistance developed within for the chemoprophylaxis of malaria caused by all 6 years. Resistance is now spread to several Plasmodium species. In addition, it is also malaria-endemic areas particularly Southeast recommended for treatment of uncomplicated Asian countries. Resistance of P. falciparum to malaria in combination with artesunate (one of mefloquine is shown to be mediated by amplifi- the ACTs). As there is no parenteral form of cation of pfmdr1, leading to overexpression of the mefloquine, the drug is generally not used in encoded digestive membrane transporter severe malaria. In addition, mefloquine is PfMDR1. Studies on transgenic parasites later contraindicated in cerebral malaria due to CNS on demonstrate that reduced parasite toxicity. 26 Pharmacology of Antimalarial Drugs, Current Anti-malarials

For prophylaxis, mefloquine is likely to be an unlikely to be a function of mefloquine blood effective chemoprophylactic agent for long-term concentrations as there is evidence that the inci- use (4–6 weeks). Its use is recommended for dence of this symptom is decreased when an anti- 6 months and beyond with clinical controls. It is emetic, metoclopramide, is given prior to the only prophylactic drug recommended for first- mefloquine administration, despite an increase in trimester pregnancies and considered safe Cmax and systemic exposure of mefloquine. throughout pregnancy. The dose of 250 mg base Vomiting within the first hour after drug adminis- (274 mg mefloquine hydrochloride) weekly has tration has been shown to result in low plasma been recommended, but the maintenance of this concentrations which lead to treatment failure. dose level beyond 12 weeks may entail accumu- Diarrhea after mefloquine is usually mild in the lation and increase incidence of adverse reactions. majority of cases, occurring in 10–50% of patients For treatment of uncomplicated malaria, a total who are treated with mefloquine, with an average therapeutic dose of 4 (2–10) mg/kg bw per day duration of 2–3 days. artesunate and 8.3 (5–11) mg/kg bw per day mef- Mefloquine has been associated with seizures, loquine, given once a day for 3 days, is anxiety, irritability, dizziness, paranoia, suicidal recommended. Formulations are currently avail- ideation, depression, hallucinations, and violence able as fixed-dose artesunate-mefloquine combi- during therapeutic dose regimen and long-term nation as pediatric tablets containing 25 mg malaria prophylaxis. Such neuropsychiatric reac- artesunate and 55 mg mefloquine hydrochloride tions generally resolve after discontinuation of the (50 mg base) and adult tablets containing 100 mg drug. The estimated incidence of seizures, artesunate and 220 mg mefloquine hydrochloride encephalopathy, or psychotic reactions ranges (200 mg base). To reduce vomiting, mefloquine from 1 in 10,000 healthy people receiving chemo- dose should be split over 3 days as in current prophylaxis, 1 in 1000 malaria patients in Asia, fixed-dose combination. 1 in 200 malaria patients in Africa, to 1 in 20 patients recovering from cerebral malaria. Adverse Reactions and Toxicity Less frequently reported adverse reactions Mefloquine is generally well tolerated when given include effects on blood and lymphatic alone or in combination with artesunate. The (agranulocytosis, aplastic anemia), nervous majority of adverse reactions after therapeutic or (syncope, convulsions, abnormal coordination, prophylactic dose of mefloquine are mild, tran- memory impairment, sensory and motor neuropa- sient, and require no specific treatment. Severe thies including paresthesia, tremor and ataxia, and adverse reactions are rare. Adverse reactions encephalopathy), cardiovascular (tachycardia, pal- appear to be associated with high concentrations pitation, QTc prolongation, bradycardia, irregular of the (À) enantiomer rather than the racemic heart rate, extrasystoles, A-V block, and other tran- mefloquine and are more frequent in females sient cardiac conduction alterations), eye and ear than males. (visual disturbances, tinnitus, and hearing impair- Nausea, vomiting, abdominal pain, and diar- ment), gastrointestinal (dyspepsia), and immune rhea are the most common adverse effects after (hypersensitivity reactions ranging from mild cuta- mefloquine in patients with malaria. Nausea and neous events to anaphylaxis) systems. Hypersensi- vomiting are dose related, being more likely in tivity reactions including anaphylaxis and adult patients receiving higher dosage than pneumonitis have also been associated with the 15 mg/kg bw. Vomiting is rarely observed in use of mefloquine. As with most medications, healthy subjects after drug administration. Onset hypersensitivity reactions, ranging from mild cuta- of nausea and vomiting from mefloquine is rapid neous events to anaphylaxis, cannot be predicted. (within the first few hours after drug administra- Rare reactions include edema, chest pain, tion); it is therefore suspected to be the result of a asthenia, malaise, fatigue, chills, pyrexia, local effect (i.e., gastric irritation) rather than a anorexia, muscle weakness, muscle cramps, central effect of mefloquine. In addition, nausea is myalgia, arthralgia, drug-related hepatic disorders Pharmacology of Antimalarial Drugs, Current Anti-malarials 27

(from asymptomatic transient transaminase eleva- the use of mefloquine in nursing women should be tions to hepatic failure), and blood disorders with caution. (decreased hematocrit, transient elevation of transaminases, leukopenia or leukocytosis, and Pharmacokinetics thrombocytopenia). There has been no evidence Pharmacokinetic parameters of mefloquine fol- of hemolytic effect of mefloquine in subjects with lowing currently recommended doses for prophy- G6PD deficiency. laxis and treatment of uncomplicated malaria are Mefloquine is not mutagenic or carcinogenic. summarized in Table 1. However, it is teratogenic and embryotoxic in exper- Oral absorption of mefloquine is relatively imental animal. However, data from published stud- slow. The absolute oral bioavailability of meflo- ies in pregnant women have shown no increase in quine cannot be determined since an intravenous the risk of teratogenic effects or adverse pregnancy formulation is not available. The bioavailability of outcomes following mefloquine treatment or pro- the tablet formulation compared with an oral solu- phylaxis during pregnancy. Prophylactic doses of tion is over 85%. When taking mefloquine with mefloquine in the second or third trimesters of preg- food, the extent and rate of absorption of meflo- nancy appear to be effective and are not associated quine are increased leading to about a 40% with adverse maternal or fetal outcomes. However, increase in bioavailability, increased in Cmax, and gastrointestinal adverse reactions including nausea shortened tmax. Plasma concentrations peak and vomiting are common in pregnant women 8–15 h after a single oral dose of mefloquine. treated with mefloquine. There is considerable enterohepatic circulation

impacting on tmax and Cmax leading to high vari- Contraindications ability of plasma/blood concentrations. At the Mefloquine is contraindicated in patients with a prophylactic dose of 250 mg once weekly, maxi- known hypersensitivity to mefloquine or structur- mum steady-state plasma concentrations of ally related compounds, (e.g., quinine, quinidine, 1000–2000 ng/ml are reached after 7–10 weeks. chloroquine, or amodiaquine). The drug should Mefloquine is extensively bound to plasma not be prescribed for follow-up treatment after proteins and also to tissue and red cell mem- cerebral malaria. Mefloquine prophylaxis is branes. Plasma protein binding is 98%, mainly contraindicated in patients with active depression to a1-acid glycoprotein. The Vd/F is relatively or a history of psychiatric disturbances (including large, indicating extensive tissue distribution. depression, generalized anxiety disorder, psycho- Mefloquine may accumulate in parasitized eryth- sis, schizophrenia, or other major psychiatric dis- rocytes at an erythrocyte-to-plasma concentration orders) or a history of convulsions, since the drug ratio of about 2. Mefloquine also crosses the may precipitate these conditions. placenta. The biotransformation of mefloquine occurs in Caution the liver by CYP3A4 into two inactive metabolites, Patients with hepatic impairment who receive carboxymefloquine (2-8-bis-trifluoromethyl-4- mefloquine should be monitored carefully for the quinoline carboxylic acid: Fig. 5b) and hydroxyme- potential of the increased risk of adverse reac- floquine. The main metabolite carboxymefloquine tions. Caution should also be made in administer- is inactive against P. falciparum. This metabolite ing mefloquine to patients with cardiac disease or appears in plasma 2–4 h after a single oral dose of in concurrent with drugs that alter cardiac conduc- mefloquine. Its concentrations rise steadily and tion (e.g., antiarrhythmics, b-adrenergic blocking exceed those of the patent drug after in about agents, calcium channel blockers, antihistamines 2–3days.Cmax of carboxymefloquine in plasma, (astemizole, terfenadine), tricyclic antidepres- approximately three to five times higher than that sants, phenothiazines, and the antimalarial drugs of mefloquine, is reached after 2 weeks. quinine, halofantrine, and mefloquine). As small Carboxymefloquine is eliminated from plasma at a amount of mefloquine is excreted in breast milk, rate that is similar to that of mefloquine. The 28 Pharmacology of Antimalarial Drugs, Current Anti-malarials relatively high plasma concentration of carboxyme- uncomplicated falciparum malaria. In severely ill floquine is explained by its small Vd/F. It is unlikely patients, i.e., cerebral malaria, absorption may be that much of carboxymefloquine penetrates the incomplete despite the apparent rapidity in the rate CNS, as it is not detectable in the CSF. of absorption. The Vd/F is contracted and CL/F is Mefloquine has been shown to be a substrate reduced during an acute phase of malaria infec- and/or inhibitor of the transporters P-glycoprotein tion. However the effect on clearance is less pre- (MDR1), multidrug resistance protein (MRP), as dictable as the elimination rate is increased in well as breast cancer receptor protein (BCRP). patients with malaria. Indirect evidence from a

This is important because MRP1 and MRP4 few studies suggests that the shorter t1/2 of meflo- (and MRP5 and BCRP) in red blood cells might quine in patients with uncomplicated falciparum affect red cell mefloquine concentrations and drug malaria may be caused by an interruption of effectiveness as well as the development of drug enterohepatic recycling (EHC) of mefloquine in resistance to mefloquine. By contrast, MDR1 malaria. The pharmacokinetic alterations might be more important in establishing meflo- resulting from the interruption of EHC by broad- quine safety as it controls mefloquine concentra- spectrum antibiotics ampicillin and tetracycline tions and entry of the drug into the brain. closely resemble those observed in patients with

The t1/2 of mefloquine varies between 2 and uncomplicated malaria. 4 weeks with an average of about 3 weeks. The value remains unchanged during long-term pro- Ethnics Pharmacokinetic variability of meflo- fl phylaxis. Me oquine is excreted into bile and quine has been observed among various ethnic fl feces. Urinary excretion of unchanged me oquine populations. Mefloquine concentration in healthy fl and carboxyme oquine accounts for about 9% Thai subjects is higher than that in Caucasian and 4% of the dose, respectively. Concentrations subjects, while comparable pharmacokinetics is of other metabolites could not be measured in the reported among Brazilian, Caucasian, and African – fl urine. Low concentrations (3 4%) of me oquine subjects. In practice, however, these are of minor are excreted in breast milk following a dose equiv- importance with regard to drug efficacy. alent to 250 mg of the free base. The multiple-dose kinetics of mefloquine is similar to single-dose pharmacokinetics. This Children No relevant age-related changes have fl suggests that there is no auto-induction or auto- been observed in the pharmacokinetics of me o- fi inhibition of the metabolic clearance mechanisms quine. Clinical experience has not identi ed dif- of mefloquine. The pharmacokinetics of meflo- ferences in responses between the elderly and quine is also highly stereospecific. Following the younger patients. Children with uncomplicated administration of a single oral dose of 1000 mg falciparum malaria showed a good absorption mefloquine to a healthy male Caucasian, plasma with blood concentrations comparable to those and whole blood concentrations of R(À)meflo- seen in adults. quine were greater than those of the S(+) enantio- mer. The ratios of R(À) and S(+) mefloquine in Pregnancy Although the rate of mefloquine plasma and whole blood ranged from 1.7 at 2 h to absorption in late pregnancy is unchanged, Cmax 11.5 at 504 h and from 1.5 at 2 h to 3 at 504 h, and systemic availability are significantly reduced respectively. during the first 2 days of mefloquine administra- tion. The oral bioavailability of mefloquine in late Factors Associated with Altered Drug Exposure pregnancy may be altered as a result of delayed and/or Treatment Response gastric emptying, decreased motility of the gas- trointestinal tract, or changes in plasma/tissue pro- Malaria Infection Pharmacokinetics of meflo- tein binding. The expansion of the Vd/F or the quine appears to be altered in malaria. Absorption increase in CL/Fcould be due to an increase in the of the drug is usually not changed in glomerular filtration rate. Suboptimal dosing Pharmacology of Antimalarial Drugs, Current Anti-malarials 29 could partially explain the poorer treatment Drug Interactions The use of drug combinations responses observed among pregnant women. has shown to delay in emergence of mefloquine resistance in vivo in animals and in vitro when Genetic Polymorphisms in Drug Trans- used with sulfadoxine-pyrimethamine (MSP) and porters A prospective clinical trial in Caucasian with primaquine. Combination of artemisinin with travelers taking mefloquine prophylaxis. mefloquine has been shown to produce potentiation revealed the link between polymorphisms of in vitro, in vivo in mice infected with resistant the P-gp (MDR1) efflux protein in the brain and strains, and in humans presenting with complicated incidence of neuropsychiatric adverse reactions of falciparum malaria. The combination of mefloquine mefloquine. Individuals with genetic defect in the with chloroquine or desethylchloroquine exhibited mdr1 gene (ABCB11236TT/2677TT/3435TT hap- pronounced antagonistic effect in vitro with both lotype) were associated with a particularly high chloroquine-sensitive and chloroquine-resistant risk of neuropsychiatric reactions, which were not P. falciparum. Clinically significant QTc interval related to mefloquine serum concentrations. prolongation has not been reported with mefloquine A lower expression of MDR1 in individuals car- alone. However, concomitant administration of mef- rying ABCB1 T variants resulted in lower meflo- loquine, quinine, quinidine, chloroquine, or quine efflux from the brain, exposing individuals halofantrine may produce electrocardiographic to high tissue concentrations related to neuropsy- abnormalities. Inhibition of KvLQT1/minK in the chiatric symptoms. This finding might suggest the human heart by mefloquine may in part explain the important role of local MDR1 expression at the synergistic prolongation of QTc interval observed. blood-brain barrier which leads to the accumula- Caution should also be made with other drugs that tion of mefloquine in the brain without affecting alter cardiac conduction (see also the section “Cau- systemic exposure. This genetic polymorphism tion”) since they may contribute to a prolongation of might also affect stereoselectivity of MDR1 and the QTc interval. Concomitant administration of consequently cerebral or plasma mefloquine mefloquine with drugs known to lower the epilep- (R)/(S) ratio without changing total plasma con- togenic threshold (antidepressants, bupropion, anti- centrations. As mefloquine is also a potent MDR1 psychotics, tramadol, quinine, quinidine, or inhibitor, propensity of drug interaction may chloroquine) may increase the risk of convulsions. occur when mefloquine is used concurrently When mefloquine is taken concurrently with with other drugs that are substrates or inhibitors oral live typhoid vaccines, attenuation of immu- of MDR1 (e.g., HIV protease inhibitors, MDR1 nization cannot be excluded. Vaccinations with substrates). attenuated live bacteria should therefore be com- pleted at least 3 days before the first dose of Renal Diseases No pharmacokinetic study has mefloquine. been performed in patients with renal insuffi- Blood (plasma or whole blood) concentrations ciency since only small proportion of the drug is of mefloquine have been shown to be increased eliminated renally. Mefloquine and carboxyme- when co-administered with metoclopramide, keto- floquine are not significantly removed by conazole, quinine, ampicillin, and tetracycline. The hemodialysis. risk of QTc prolongation and other adverse reac- tions of mefloquine may also be expected if these Hepatic Diseases The pharmacokinetics of mef- drugs are taken during mefloquine therapy for pro- loquine in patients with compromised hepatic phylaxis or treatment of malaria. The antiemetic function has not been investigated. Mefloquine metoclopramide, through stimulation of gastric is extensively metabolized in the liver by the emptying rate, increases the absorption of meflo-

CYP450 system, and it is possible that the elimi- quine, resulting in higher Cmax and AUC in the nation of mefloquine may be prolonged in patients first 24 h of treatment. Metoclopramide would with impaired hepatic function, leading to higher seem to have an important role in prevention of plasma levels. vomiting before antimalarial administration in 30 Pharmacology of Antimalarial Drugs, Current Anti-malarials malaria patients. Co-administration of ketoconazole, Mefloquine has been reported to interact with a strong inhibitor of CYP3A4, increases plasma other drugs when given concurrently. Mefloquine concentrations of mefloquine (AUC by 79% and reduces plasma concentration of the anti-HIV rito-

Cmax by 64%) and prolongs t1/2 (by 39%). Meflo- navir. Concomitant administration of mefloquine quine concentration has been reported to rise and anticonvulsants may reduce seizure control abruptly after the cessation of quinine administra- by lowering the plasma levels of the anticonvul- tion. Competition for plasma and red cell binding sants. Therefore, patients concurrently taking site(s) of mefloquine might explain this interaction. anticonvulsant medication, including valproic Cardiotoxicity is therefore a major concern as there acid, carbamazepine, phenobarbital, phenytoin, is a report of the sudden death of a patient who and mefloquine, should have the blood level of concurrently administered mefloquine and quinine. their anticonvulsants monitored and the dosage In the chemotherapy of malaria, tetracycline adjusted appropriately. has an important role in the treatment of A single case in the literature reports a transient falciparum malaria when given in combination severe psychiatric disturbance, suggesting an with other blood schizonticides. When tetracy- adverse reaction to mefloquine associated with a cline is given in combination with quinine, chlo- heavy ingestion of alcohol (600 ml of whisky). roquine or sulfadoxine-pyrimethamine, and Carboxymefloquine has been shown to induce mefloquine, the cure rate is improved. Pharmaco- drug-metabolizing enzyme and transporter kinetic interaction studies demonstrated that the expression by activation of pregnane X receptor t1/2, mean residence time (MRT) and apparent in vitro. Thus, the clinical use of mefloquine may volume of distribution at steady state (Vdss/F) of result in pharmacokinetic drug-drug interactions mefloquine are all reduced when co-administered via its metabolite carboxymefloquine. Whether with tetracycline. In addition, Cmax and AUC are these in vitro findings are of clinical relevance increased during the course of tetracycline admin- has to be addressed in future clinical drug-drug istration. Competition between these drugs for interaction studies. biliary excretion could conceivably occur. Systemic exposure of mefloquine has been shown to be significantly decreased in the pres- Antifolates ence of rifampicin. Rifampicin induces meflo- quine metabolism, decreasing its AUC by 68% Antifolate drugs include various combinations of and t1/2 by 63%. The AUC and CL/F of dihydrofolate reductase (DHFR) enzyme inhibitors, carboxymefloquine metabolite are increased by such as pyrimethamine, proguanil, chlorproguanil, 30% and 25%, respectively. Simultaneous admin- and cycloguanil, and dihydropteroate synthase istration of mefloquine and rifampicin should (DHPS) enzyme inhibitors, such as sulfadoxine, therefore be avoided. sulfalene, and dapsone. Currently, only the The concomitant administration of the antimalar- sulfadoxine-pyrimethamine antifolate combination ials primaquine, sulfadoxine-pyrimethamine as well and the combination of antifolate proguanil and as oral contraceptive steroids, and antipyrine does atovaquone are recommended for malaria treatment not alter the pharmacokinetics or adverse reaction and/or prophylaxis. profile of mefloquine. Pharmacokinetics of oral dihydroartemisinin and mefloquine when given Sulfadoxine-Pyrimethamine concurrently are similar, except for the absorption rate of mefloquine which is faster in the presence of Chemistry and Physical Properties dihydroartemisinin. The pharmacokinetics of Sulfadoxine (4-Amino-N-{5,6-bis[(~2~H_3_) artemether, dihydroartemisinin, lumefantrine, and methyloxy]pyrimidin-4-yl}benzene-1-sulfonamide: mefloquine are also unchanged when mefloquine Fig. 6a) appears as white or creamy white, almost is co-administered with artemether or artemether- odorless crystalline powder. The molecular weight is lumefantrine combination. 310.3. It is not dissolved well in water. Pharmacology of Antimalarial Drugs, Current Anti-malarials 31

Pyrimethamine (2,4-Diamino-5-(4-chlorophe- In areas of moderate-to-high malaria transmis- nyl)-6-ethylpyrimidine: Fig. 6b) also appears as sion of Africa where sulfadoxine-pyrimethamine white, almost odorless crystalline powder. The is still effective (no pfdhps540 mutation), inter- molecular weight is 248.7. mittent preventive treatment with this combina- tion (one to two tablets) is recommended to Pharmacology infants (aged lower than 12 months) (SP-IPTi) at the time of the second and third rounds of vacci- Antimalarial Activities and Mechanisms of nation against diphtheria, tetanus, and pertussis Action and Resistance Sulfadoxine is a sulfon- (DTP) as well as vaccination against measles. amide antibacterial which acts by inhibiting the In areas with high malaria transmission in the activity of dihydropteroate synthase (DHPS) and, sub-Sahel region of Africa, seasonal malaria che- therefore, synthesis of folic acid by bacteria and moprevention (SMC) with monthly amodiaquine- malaria parasite. On the other hand, pyrimeth- sulfadoxine-pyrimethamine (ACT) combination amine inhibits dihydrofolate reductase (DHF) is strongly recommended for all children aged and thereby the synthesis of folic acid by bacteria lower than 6 years during each transmission and malaria parasite. Both are active mainly season. against the later development stages of asexual From an operational perspective, it is noted Plasmodium parasite. that drugs used in IPTp, SMC, and IPTi should not be used as a component of first-line treatments Other Pharmacological Properties The combi- in the same country or region. nation of sulfadoxine and pyrimethamine is used in the treatment of toxoplasmosis. Adverse Reactions and Toxicity Sulfadoxine-pyrimethamine combination is gen- Therapeutic Indications for Malaria erally well tolerated at the recommended doses. Sulfadoxine-pyrimethamine is indicated in areas Most adverse reactions are those associated with of moderate-to-high malaria transmission inten- sulfonamides. These include gastrointestinal dis- sity for intermittent preventive treatment (IPT) of turbances (nausea, vomiting, abdominal pain, and malaria in pregnant women and in infants. It is diarrhea), headache, dizziness, skin reactions also used in combination with amodiaquine for (photosensitivity, rash, pruritus, and urticaria), seasonal malaria chemoprevention in children in and slight hair loss. Erythema multiforme, areas with highly seasonal malaria transmission Stevens-Johnson syndrome, and toxic epidermal and in the few areas in which it remains effective. necrolysis may also occur at rare frequency. Sulfadoxine-pyrimethamine can be used with Leucopenia, thrombocytopenia, megaloblastic artesunate for the treatment of acute uncompli- anemia, hemolytic anemia (probably related to cated malaria in areas where the parasites are G6PD deficiency), crystalluria, hematuria, still sensitive to sulfadoxine-pyrimethamine. oliguria, hepatitis, serum sickness, allergic peri- In malaria-endemic areas in Africa, intermittent carditis, and pulmonary infiltrates resembling preventive treatment with sulfadoxine-pyrimeth- eosinophilic or allergic alveolitis have also been amine combination is strongly recommended in all reported. women (SP-IPTp) as part of antenatal care. At least three doses of sulfadoxine-pyrimethamine are Contraindications administered during pregnancy, a single oral dose Sulfadoxine-pyrimethamine alone or combination of three tablets each (one tablet contains 25 mg therapy with amodiaquine or artesunate is sulfadoxine and 500 mg pyrimethamine). Dosing contraindicated in the following conditions: known should start in the second trimester, and doses hypersensitivity to pyrimethamine, sulfonamides, should be given at least 1 month apart, with the and structurally related compounds; megaloblastic objective of ensuing that at least three doses are anemia due to folate deficiency; premature or new- received. born infants in the first 2 months of life; 32 Pharmacology of Antimalarial Drugs, Current Anti-malarials

Pharmacology of Antimalarial Drugs, Current Anti-malarials, Fig. 6 Chemical structures of (a) sulfadoxine and (b) pyrimethamine

HIV-infected patients receiving cotrimoxazole pro- Factors Associated with Altered Drug Exposure phylaxis against opportunistic infections; and preg- and/or Treatment Response nancy in the first trimester. Children The pharmacokinetics information of sulfadoxine-pyrimethamine in children with Caution malaria has been limited, although it is recognized The use of sulfadoxine-pyrimethamine should be that the currently recommended mg/kg bw dose of discontinued if skin eruption, cytopenia, or a bac- sulfadoxine-pyrimethamine achieves substan- terial or fungal superinfection occurs. Repetitive tially lower plasma drug concentrations in young administration of the medication to patients with children than in older patients. blood dyscrasia and renal or hepatic failure should be performed with caution as the drugs may accu- mulate to toxic levels. Pregnancy The pharmacokinetics of sulfadoxine and pyrimethamine when administered as a fixed- dose combination are altered in pregnant women. Pharmacokinetics Pregnant patients appear to have higher CL/F and Pharmacokinetic parameters of sulfadoxine and Vd/F of both drugs, resulting in lower AUC and pyrimethamine following currently recommended shorter t than nonpregnant adults. These changes doses for the treatment, seasonal chemoprevention, 1/2 in pharmacokinetics may be associated with high or intermittent preventive treatment of uncompli- rate of treatment failure in pregnant women. cated malaria are summarized in Table 1. Sulfadoxine and pyrimethamine are readily absorbed from the gastrointestinal tract after oral Drug Interactions Clinical effectiveness of administration. Plasma protein binding is about sulfadoxine-pyrimethamine is reduced when the

90%, mainly to albumin. The t1/2 of sulfadoxine drug is given with high-dose folic acid (>5mg). is longer than pyrimethamine (4–11 days and Concurrent treatment with trimethoprim- 60–450 h, respectively). The Vd/F of pyrimeth- sulfamethoxazole should be avoided due to amine is about ten times larger than sulfadoxine as increased risk of severe cutaneous reactions. Addi- it is concentrated in the kidneys, lungs, liver, and tive hematological toxicity may occur when spleen. Both sulfadoxine and pyrimethamine sulfadoxine-pyrimethamine is given in combina- cross the placental barrier and pass into breast tion with myelosuppressants such as methotrexate, milk. Both are metabolized by the liver, but daunorubicin, and cytarabine. enzymes responsible for this biochemical process The Vd/F of pyrimethamine is slightly are not well identified. It is only known that increased when sulfadoxine-pyrimethamine com- sulfadoxine undergoes varying degrees of acety- bination is co-administered with artesunate. This lation, hydroxylation, and glucuronidation. Renal interaction is unlikely to be clinically significant as clearance is the main route of excretion of both total systemic exposure and plasma concentrations drugs. up to day 7 are unaffected. Pharmacology of Antimalarial Drugs, Current Anti-malarials 33

Atovaquone-Proguanil believed to be active against “dormant” Atovaquone-proguanil is currently indicated for hypnozoites. Atovaquone acts as a competitive malaria prophylaxis. The combination may also inhibitor of ubiquinol, specifically inhibiting the be used for treatment of uncomplicated malaria in mitochondrial electron transport chain at the bc1 travelers outside malaria-endemic areas. In addi- complex. Inhibition of bc1 activity results in a loss tion, it is recommended for use in combination of mitochondrial function. Atovaquone exerts with artesunate and primaquine as an alternative potent antimalarial activity with IC50 (50% inhib- treatment of uncomplicated malaria in areas itory concentration) as low as 1–3.5 nM. where WHO recommended treatments are not Proguanil appears to be active against almost available or not effective. The atovaquone com- all stages of the malaria parasite life cycle, but ponent was initially developed as a potential anti- clinical use is limited to blood stages. In vivo, it is malarial for monotherapy. It was effective agent converted into an active triazine metabolite, with a broad-spectrum antiparasitic activity. cycloguanil (Fig. 7c), which acts by inhibiting A search for combination partner with potential parasite’s dihydrofolate reductase enzyme, simi- synergy with atovaquone identified the folate larly to that of pyrimethamine. inhibitor proguanil as a candidate. The combination of atovaquone and proguanil acts synergistically. The parent compound, pro- Chemistry and Physical Properties guanil, rather than the metabolite, cycloguanil, Atovaquone(2-(trans-4-(P-Chlorophenyl)cyclo- has been demonstrated to synergize the antimalar- hexyl)-3-hydroxy-1,4naphthoquinone: Fig. 7a)is ial activity of atovaquone, lowering the effective a hydroxynaphthoquinone with molecular weight concentration at which atovaquone collapses the of 366.8. Proguanil (N-(4-Chlorophenyl)-n’-(iso- mitochondrial membrane potential. Atovaquone- propyl)-imidodicarbonimidic diamide: Fig. 7b), proguanil is seldom used in endemic areas also known as chlorguanide or chloroguanide, is because of the propensity for emergence of high- a biguanide compound with molecular weight of grade resistance to atovaquone. It is well- 253.7. documented that de novo atovaquone resistance occurs very rapidly. This is due to a missense Pharmacology point mutation at position 268 in the cyt b gene, exchanging tyrosine for serine (Y268S) or, less Antimalarial Activities and Mechanism of frequently, asparagine (Y268N). The position Action and Resistance Atovaquone is active 268 in cytochrome b is highly conserved across against all stages of all Plasmodium species. It is all phyla and is located within the “ef” helix also active against liver stages, resulting in its component of the Qo site, which is putatively utility as a prophylactic drug. However, it is not involved in ubiquinol binding.

Pharmacology of Antimalarial Drugs, Current Anti-malarials, Fig. 7 Chemical structures of (a) atovaquone, (b) proguanil, and (c) cycloguanil 34 Pharmacology of Antimalarial Drugs, Current Anti-malarials

Other Pharmacological Activities Atovaquone Caution is clinically used for the treatment or prevention of The doses of atovaquone-proguanil should be Pneumocystis carinii pneumonia (PCP) in selected cautiously in elderly, based on hepatic, patients who are intolerant to trimethoprim- renal, or cardiac function, propensity of higher sulfamethoxazole combination. In addition, it is systemic exposure to cycloguanil, and a greater also used for the treatment or prevention of toxo- frequency of concomitant disease or concomitant plasmosis and babesia. drug therapy.

Therapeutic Indications for Malaria Pharmacokinetics Currently, the fixed-dose combination of The pharmacokinetic parameters of atovaquone in atovaquone-proguanil is used as a chemoprophy- the currently utilized formulation (MalaroneTM: lactic agent for preventing malaria in travelers. It 250 mg atovaquone/100 mg proguanil) for may also be considered for the treatment of malaria prophylaxis and treatment are summa- uncomplicated malaria in travelers outside rized in Table 1. malaria-endemic areas and for use in combination Atovaquone exhibits dose-limiting absorption with artesunate and primaquine as an alternative with maximum absorption observed using 750 mg treatment for uncomplicated malaria, where WHO tablets. Poor drug solubility is suggested as the recommended treatments are not available or not cause of this limited absorption. Furthermore, a effective. marked interpatient variability of atovaquone bio- availability is reported (107%), which is likely Adverse Reactions and Toxicity due to low drug solubility and the effects of Atovaquone-proguanil is generally well tolerated food. The absorption of atovaquone from the gas- with mild adverse reactions. Common adverse trointestinal tract is increased by about fourfold reactions include headache, cough, and gastroin- when atovaquone is taken with a high-fat meal testinal disturbance (nausea, vomiting, diarrhea, (two slices of toast with 56 g of butter). The drug and abdominal pain). Dizziness, oral ulceration, is therefore recommended to be taken with a high- blood disorders (neutropenia and anemia), and fat meal. There is no unexpected accumulation of skin reactions (photosensitivity rash and erythema atovaquone following repeated administration. multiforme) rarely occur. Other adverse reactions Proguanil is readily absorbed from the gastroin- which are occasionally reported are elevated testinal tract reaching Cmax within approximately levels of liver enzymes, hepatitis, hepatic failure, 5 h of administration. allergic reactions (anaphylaxis, angioedema, Atovaquone and proguanil are, respectively, Stevens-Johnson syndrome, and vasculitis), and 99%and 75% bound to plasma proteins with pancytopenia in patients with severe renal impair- high affinity to albumin. The long t1/2 of ment. A significant concern for the antimalarials 2–3 days is characterized by the enterohepatic targeting the parasite bc1 including atovaquone is circulation. The low drug clearance rate suggests host mitochondrial toxicity. In animal models, this that atovaquone may also accumulate in tissues, manifested itself as acute toxicity (presumed to be where it is protected from biliary clearance. Elim- cardiotoxicity). ination is primarily via the liver, with almost undetectable amounts (0.6%) of the parent drug Contraindications being eliminated via the kidneys. More than 90% Atovaquone-proguanil is contraindicated in of the drug excreted in bile (and feces) is in the patients with known hypersensitivity reactions to parent form. atovaquone or proguanil or structurally related Proguanil undergoes bioactivation by compounds. Due to increased risk of pancytope- CYP2C19 to the active metabolite, cycloguanil nia, it is contraindicated for use as malaria pro- (Fig. 7c). Cycloguanil inhibits Plasmodial phylaxis in patients with severe renal dihydrofolate reductase and influences DNA syn- insufficiency. thesis. Proguanil is also further inactivated by Pharmacology of Antimalarial Drugs, Current Anti-malarials 35

CYP2C19 and to a lesser extent CYP3A4 to these observations, it is proposed that the parent 4-chlorophenylbiguanide. The urinary proguanil- compound proguanil may have a significant cycloguanil metabolic ratio serves as a marker for intrinsic efficacy independent of its main metabo- differential CYP2C19 metabolic activity. Renal lite cycloguanil. Another plausible explanation excretion of proguanil is about 40 and 60% of may be that undefined metabolite other than the administered dose. cycloguanil, through another metabolic pathway, is responsible for the proguanil efficacy in poor Factors Associated with Altered Drug Exposure metabolizers. and Treatment Response Drug Interactions The pharmacokinetics of Children The CL/F values of both atovaquone atovaquone and proguanil and its metabolite and proguanil are related to body weight. While cycloguanil are unchanged when given as most of the pharmacokinetics of proguanil and atovaquone-proguanil combination. There is cycloguanil are comparable in adults and children, in vitro evidence of possible inhibition of the t1/2 of atovaquone is shorter in children. CYP3A4 by atovaquone. Plasma/serum concen- trations of aceprometazine, alimemazine, Pregnancy The plasma concentrations of chlorproethazine, chlorpromazine, and etoposide atovaquone and proguanil in pregnant women in can be increased when co-administered with the second and third trimesters are approximately atovaquone. The risk of QTc prolongation can be half of nonpregnant adults (with and without acute increased when atovaquone is combined with malaria) as a result of expansion of Vd/F and artemether. increase of CL/F. Pharmacokinetic interactions between atova- quone and antiretrovirals have been reported. Body Weight Based on the population-based Efavirenz, lopinavir, ritonavir, and saquinavir pharmacokinetic analysis, the CL/F of (all highly protein-bound drugs) reduced atovaquone has been shown to be increased in atovaquone plasma concentrations in HIV- patients with higher body weights (60% increase infected patients. On the other hand, a recent in an 80 kg compared with a 40 kg patient). The case study described an HIV-infected female CL/F of atovaquone appears to be higher in ori- with a marked increase in plasma concentrations ental (8.49 L/h) and Malay (9.13 L/h) subjects of the antiretrovirals etravirine (55%) and saquin- compared with Caucasian (1–7.6 L/h) subjects. avir (274%), but not raltegravir following atovaquone-proguanil prophylaxis. Atovaquone Genetic Polymorphism in Drug-Metabolizing has been shown to inhibit the glucuronidation of Enzymes The association between CYP2C19 zidovudine. Co-administration of atovaquone and gene polymorphism and variation in proguanil the nucleoside reverse transcriptase inhibitor and cycloguanil plasma concentrations has given (NRTI) zidovudine increased the exposure (33% rise to the hypothesis that patients with poor meta- increase in AUC) and decreased the oral clearance bolizer phenotype are at greater risk of treatment (25%) of zidovudine in HIV-infected patients. failure. The prevalence of the poor metabolizer Furthermore, patients taking atovaquone showed phenotype varies substantially among ethnics, a trend toward lower zidovudine/glucuronide and two variant alleles, CYP2C19*2 and plasma concentrations (6% decrease in AUC) CYP2C19*3, are largely associated with the poor and a significant decrease in the ratio between metabolizer phenotype. Studies in African and zidovudine/glucuronide and plasma concentra- Asian populations, however, have not revealed tions (30% decrease). Atovaquone exposure itself an association between proguanil CYP2C19 met- was unchanged. The increased zidovudine plasma abolic status and treatment or prophylaxis concentrations and reduced zidovudine responses as well as the incidence of adverse glucuronidation may potentially lead to increased reactions (mainly gastrointestinal). Based upon formation of the CYP450-mediated zidovudine 36 Pharmacology of Antimalarial Drugs, Current Anti-malarials metabolite 3-amino-3deoxythymidine, which antimalarial application was first described in the shows a sevenfold higher toxicity in bone marrow Handbook of Prescriptions for Emergencies in the cells compared with the parent drug. Caution is middle of the fourth century in China. The herb advised in patients taking additional drugs with was used as a tea for treatment of malaria in China similar toxicity profiles to zidovudine, particu- for over 1500 years. Artemisinin (quinghaosu) is larly hematological toxicity. the principal compound isolated from A. annua and Plasma concentration of atovaquone is reduced is further derivatized to the more active (four- to when given concurrently with metoclopramide fivefold) derivatives, i.e., artesunate, b-arteether, and tetracycline. Atovaquone exposure (AUC) and dihydroartemisinin. Dihydroartemisinin is has been shown to be markedly decreased (50%) also an active human plasma metabolite of in patients with Toxoplasma gondii infection con- artesunate and artemether. Artemisinin derivatives currently treated with the anti-TB drug rifampicin have constituted the key antimalarials that play an but to a lesser extent (34%) with rifabutin. The essential role in the control of malaria since the concomitant administration of atovaquone and emergence and widespread of multidrug-resistant rifampicin is therefore not recommended as rifam- P. falciparum malaria. Currently, artesunate, picin is a potent inducer of CYP2C19, and it artemether, and dihydroartemisinin are in clinical therefore could affect proguanil antimalarial uses for treatment of malaria, either as mono- activity. therapy (for severe malaria) or as components of Atovaquone causes an increase in free warfarin artemisinin-based combination therapies (ACTs) concentrations to super-therapeutic levels. Lack for uncomplicated malaria. ACTs are currently of pharmacokinetic interactions is reported the most powerful strategy to treat malaria and between atovaquone and the anticonvulsant prevent malaria-related deaths. With this successful phenytoin. discovery of artemisinins, Professor Tu was Proguanil may potentiate warfarin action but awarded the Nobel Prize in Physiology or Medi- may reduce effectiveness of live typhoid vaccine. cine in 2015 for the discovery of this effective The conversion of proguanil to cycloguanil is antimalarial compound. reduced in the presence of estrogen. Proguanil and cycloguanil have been shown to inhibit Chemistry and Physical Properties P-glycoprotein-mediated taxol transport without Artemisinin (Fig. 8) is a sesquiterpene lactone per- being substrates for P-glycoprotein. Interactions oxide with a characteristic endoperoxide moiety between these compounds and other substrates of essential for antimalarial activity. Artemisinin is P-glycoprotein would be expected. poorly soluble in water. Artesunate is a water- soluble hemisuccinate ester which can be adminis- tered by intravenous and intramuscular injection. Artemisinin and Derivatives and It is a colorless needle crystal or white crystalline Artemisinin-Based Combination powder, odorless, and almost tasteless. Artesunate Therapies (ACTs) can be dissolved in sodium bicarbonate solution, forming water-soluble sodium salt. Artemether and Artemisinin drugs, originated from the Chinese arteether (Fig. 8) are the methyl and ethylethers of herb qinghao (Chinese wormwood Artemisia dihydroartemisinin (Fig. 8) which possess physical annua L.), belong to a unique class of compounds, and chemical properties similar to artemisinin. Both sesquiterpene lactone endoperoxide, and are new are easily soluble in a variety of organic solvents generation of potent antimalarials. Qinghaosu has such as ethanol, acetone, and chloroform. Both been used for over 2000 years in Chinese tradi- ethers have the advantage of being more oil soluble tional medicine for the treatment of fever. Its than artemisinin. Pharmacology of Antimalarial Drugs, Current Anti-malarials 37

Pharmacology of Antimalarial Drugs, Current Anti-malarials, Fig. 8 Chemical structures of artemisinin and derivatives

Artemisinin and its derivatives decompose in rapidly cleared than other antimalarials. Deferves- protic solvents other than water. Artesunate is cence occurs within 1–2days,andparasitemia more water soluble than other artemisinins and disappears within 2–3 days after drug administra- therefore can be administered intravenously. tion. About 90% clearance of asexual erythrocytic Artemisinin drugs also show a remarkable thermal parasitemia is usually observed within 24 h. Total instability. The derivatives are more unstable than dose and duration of drug administration have an artemisinin. The drugs should be stored in air-tight influence on the cure rate. Correlation between  containers in a cool place below 25 C and pro- dosage regimen (total dose and duration), severity tected from light. Molecular weights of of the disease, and cure rate has been reported. The artemisinin, artemether, b-arteether, and artesunate longer the duration of treatment, and/or the lesser are 280, 296, 312, and 404, respectively. the severity of the infection, the higher is the cure rate. Currently, artemisinin monotherapy (artesunate Pharmacology and artemether) is only used for initial treatment of severe malaria but is not recommended for treat- Antimalarial Activities and Mechanisms of Action ment of uncomplicated malaria due to widespread and Resistance of multidrug-resistant P. falciparum and the neces- Artemisinin drugs have broad stage specificity sity for prolonged treatment regimens. For this against blood stage parasites from the ring stage purpose, they are typically used in combination to early schizonts. They are also active against the with other structurally unrelated antimalarial early gametocide stages but inactive against extra- drugs as ACTs. ACTs are co-formulations of a erythrocytic forms, sporozoites, liver schizonts, fast-acting, highly potent artemisinin and a slow- and merozoites. acting, less-potent partner drug (e.g., mefloquine, Artemisinin drugs are rapidly acting blood piperaquine, and lumefantrine) that are given orally schizontocidal antimalarials against either over 3 days. During their short half-life, chloroquine-sensitive or chloroquine-resistant artemisinins leave only residual parasites, which P. falciparum, P. vivax, P. ovale, and P. malariae. are further eradicated by the slowly eliminated Their potent gametocytocidal activities reduce partner drug. The combination is also believed to gametocyte carriage and therefore limit malaria inhibit the selection of de novo artemisinin- transmission from the treated infection. The resistant mutants. artemisinin compounds stop parasite development Artemisinin is a sesquiterpene lactone rapidly, thereby preventing subsequent containing a peroxide bridge that plays an essential cytoadherence and rosetting (both are thought to role in antimalarial effects. The precise molecular be important pathophysiological mechanisms in targets of action of artemisinins are not well severe malaria). Fever and parasites are more 38 Pharmacology of Antimalarial Drugs, Current Anti-malarials understood, but the prevailing theory is the cleav- artemisinins and in addition the selection of resis- age of the endoperoxide bridge which leads to the tance in P. falciparum against the partner drug. formation of reactive carbon radicals that subse- quently alkylate essential biomolecules of malaria Other Pharmacological Activities parasites. A previously proposed molecular mech- Apart from antimalarial activities, artemisinin anism of action for artemisinins is the inhibition of drugs have also been shown to exhibit a wide the malarial parasite’scalciumATPase range of pharmacological actions against viruses, (sarcoplasmic/endoplasmic reticulum calcium helminthes, fungi, and even a variety of cancer ATPase, SERCA). More recent investigations sug- cells. In addition, they also possess anti- gest newly identified protein targets in broad path- inflammatory and immunosuppressant activities. ways involved in the glycolysis, hemoglobin In vitro and in vivo studies demonstrated activ- degradation, antioxidant defense, and protein syn- ities of artemisinin and derivatives against other thesis, processes essential for parasite survival. protozoas (Leishmania spp., Trypanosoma spp., The emergence of P. falciparum resistance to Toxoplasma gondii, Neospora caninum, Eimeria artemisinin and derivatives has recently devel- tenella, Acanthamoeba castellanii, Naegleria oped in the Greater Mekong Subregion (GMS: fowleri, Cryptosporidium parvum, Giardia China, Cambodia, Laos PDR, Myanmar, lamblia, Babesia spp.), helminths (Schistosoma Thailand, and Vietnam). This worrisome develop- species and Fasciola hepatica), fungi (e.g., Cryp- ment threatens to make malaria practically tococcus neoformans), and viruses (e.g., human untreatable in this region and threatens to com- cytomegalovirus). promise global endeavors to eliminate this dis- Artemisinins exert selective cytotoxic effects ease. Initial widespread use of artemisinins as against a wide range of cancer types both in vitro monotherapy in the GMS is likely to be the key and in vivo. These effects appear to be mediated factor that contributes to their reduced efficacy by artemisinin-induced changes in multiple sig- and/or resistance reported in recent years along naling pathways, interfering simultaneously with the Thai-Cambodian and Thai-Myanmar borders. multiple hallmarks of cancer (cell cycle arrest, Artemisinin resistance is characterized as a delay apoptosis, angiogenesis, and cancer invasion and in parasite clearance time. Partial resistance to metastasis). Results from a limited number of artemisinin in P. falciparum was first reported in clinical trials in some types of cancer also support 2008, in Battambang Province in western Cam- their anticancer property. bodia. It was subsequently confirmed in 2009, in Artemisinins have been evaluated in animal Pailin Province, the well-known epicenter of anti- models of autoimmune diseases, allergic disor- malarial multidrug resistance. Artemisinin resis- ders, and septic inflammation. Their potent anti- tance has since been reported elsewhere in inflammatory effects have been attributed to the western Cambodia, western Thailand, southern regulation of both innate and adaptive immunity. Myanmar, Southern Vietnam, and China. Artemisinin family drugs can suppress T-cell acti- A recent series of clinical, in vitro, genomics, vation both in vitro and in vivo. In addition, they and transcriptomics studies in the GMS has shown have been shown to inhibit Toll-like receptors, that artemisinin resistance manifests as slow par- Syk tyrosine kinase, phospholipase Cg, PI3K/ asite clearance in patients and increased survival Akt, MAPK, STAT-1/3/5, NF-kB, Sp1, and of early ring-stage parasites in vitro. The molecu- Nrf2/ARE signaling pathways. Artemether sup- lar mechanism underlying this resistance pheno- presses T-cell proliferation and IL-2 production in type is single-nucleotide polymorphisms in the response to TCR engagement or mitogens in vitro. parasite’s “K13” gene. The K13 propeller gene is located on chromosome 13 and encodes a kelch protein. The mutation is associated with an upregulated “unfolded protein response” pathway that may antagonize the prooxidant activity of Pharmacology of Antimalarial Drugs, Current Anti-malarials 39

Therapeutic Implications for Malaria (i) Treatment of children and adults with uncomplicated P. falciparum malaria except Uncomplicated Malaria the first-trimester pregnant women. The The artemisinins rapidly relieve signs and symp- ACTs can be used safely in pregnant toms of acute malaria by rapidly clearing para- women during the second and third sitemia. Parasite numbers is reduced by 100- to trimesters. 1000-fold per asexual cycle of the parasite (ii) Nonimmune travelers with uncomplicated (a factor of approximately 10,000 in each 48-h P. falciparum malaria returning to non- asexual cycle). This action is fastest among the endemic settings. currently available antimalarial drugs. Because (iii) An alternative treatment to chloroquine in artemisinin and its derivatives are eliminated rap- adults and children with uncomplicated idly, when given alone, a 7-day course of treat- P. vivax, P. ovale, P. malariae,or ment is required. In 2001, the WHO initially P. knowlesi in areas with chloroquine- recommended the use of ACTs as first-line treat- sensitive infections. ment of uncomplicated malaria in areas where the (iv) First-line treatment of adults and children parasites were resistant to monotherapy with other with chloroquine-resistant P. vivax, as well drugs including chloroquine, sulfadoxine- as P. ovale, P. malariae,orP. knowlesi. pyrimethamine, and mefloquine. This recommen- dation was extended to the entire malaria-endemic The choice of ACTs in a country or region areas of the world in 2006, and the use of should be based on background of drug resistance artemisinin in monotherapy was banned to (particularly of the partner drugs), optimal efficacy, prevent the selection of artemisinin-resistant par- safety, and patients’ compliance. Fixed-dose com- asites. In 2012, five different 3-day ACTs, binations rather than co-blistered or loose, single- including dihydroartemisinin-piperaquine, agent formulations are recommended whenever artesunate-mefloquine, artemether-lumefantrine, possible. For young children and infants, pediatric artesunate-sulfadoxine-pyrimethamine, and art- formulations, with a preference for solid formula- esunate-amodiaquine, were deployed in 79 coun- tions rather than liquid formulations, are tries with endemic malaria. The concept of recommended. combination therapy relies on the rapid onset of Resistance of P. falciparum to the currently schizonticidal action of artemisinins to rapidly used ACTs has now emerged and is following a reduce parasitemia, leaving the residual para- similar pattern of resistance previously observed sitemia to be cleared by high concentrations of with other antimalarial drugs. Thus far, studies the partner drugs. This results in the protection of have documented evidence of P. falciparum resis- artemisinin by its partner drug from developing tance to artemisinins in five countries of the GMS, resistance and vice versa. An additional advantage i.e., Cambodia, Laos, Myanmar, Thailand, and from a public health perspective is the ability of Vietnam, and this was confirmed on the the artemisinins to reduce gametocyte carriage Cambodia-Thailand border. It is therefore, crucial and, therefore, the transmissibility of malaria. to monitor the efficacy and safety of newly for- This contributes to malaria control, particularly mulated ACTs in view of artemisinin resistance. in areas of low-to-moderate endemicity. Shorter Clinical uses of the currently used ACTs are as courses (1–2 days) are not recommended as they follows: are less effective, have less effect on gametocytes, and provide less protection for the slowly elimi- (i) Artemether-lumefantrine nated partner drug. Currently (since 2015), these five ACTs are The combination is available as dispersible or currently recommended by the WHO for treat- standard tablets containing 20 mg artemether and ment of uncomplicated malaria in all endemic 120 mg lumefantrine (the flavored dispersible areas in the following clinical situations: pediatric formulation facilitates use in young 40 Pharmacology of Antimalarial Drugs, Current Anti-malarials children) or as standard tablets containing 40 mg 160 mg piperaquine. The recommended dose reg- artemether and 240 mg lumefantrine in a fixed- imen for adults and children weighing >25 kg is a dose combination formulation. The advantage of total dose of 4 (2–10) mg/kg bw per day this ACT is that the combination partner, dihydroartemisinin and 18 (16–27) mg/kg bw lumefantrine, is not available as monotherapy per day piperaquine given once a day for 3 days. and has never been used alone for malaria treat- In children aged <25 mg/kg, a minimum of ment. The recommended adult dose regimen is 2.5 mg/kg body weight per day of artemether-lumefantrine given twice a day at a dihydroartemisinin and 20 mg/kg bw per day of total six doses for 3 days (four tablets per dose). piperaquine for 3 days is recommended. The patient should receive the initial dose, followed by the second dose 8 h later, and then (v) Artesunate-sulfadoxine-pyrimethamine one dose twice daily for the following 2 days. The drug should be taken immediately after food or The combination is available in blister-packed, fat-containing drink (e.g., milk) particularly in the scored tablets containing 50 mg artesunate and second and third days of treatment. fixed-dose combination tablets containing 500 mg sulfadoxine/25 mg pyrimethamine. (ii) Artesunate-amodiaquine There is no fixed-dose combination. A total ther- apeutic dose of 4 (2–10) mg/kg bw per day The combination is available as a fixed-dose artesunate given once a day for 3 days and a single combination in tablets containing 25/67.5 mg, administration of at least 25/1.25 (25–70/ 50/135 mg, or 100/270 mg of artesunate- 1.25–3.5) mg/kg bw per day sulfadoxine- amodiaquine. A total therapeutic dose range of pyrimethamine, given once a single dose on day 6–30 mg/kg bw per day artesunate and 1, are recommended. Clinical use of this ACT 22.5–45 mg/kg bw per day amodiaquine for should be avoided in uncomplicated 3 days is recommended. P. falciparum malaria patients coinfected with HIV/AIDS if they are being treated with the anti- (iii) Artesunate-mefloquine retroviral drugs efavirenz or zidovudine. The dis- advantage of this ACT is that it is not available as a The combination is available as a fixed-dose fixed-dose combination, which may compromise formulation of pediatric tablets containing 25 mg patients’ adherence and increase the risk for distri- artesunate and 55 mg mefloquine hydrochloride bution of loose artesunate tablets, despite the WHO (50 mg base) or adult tablets containing 100 mg ban on artesunate monotherapy. Resistance is artesunate and 220 mg mefloquine hydrochloride likely to be increased with continued widespread (200 mg base). A total therapeutic dose of use of sulfadoxine-pyrimethamine, sulfalene- 4(2–10) mg/kg bw per day artesunate and 8.3 pyrimethamine, and cotrimoxazole (trimethoprim- (5–11) mg/kg bw per day mefloquine, given once sulfamethoxazole). Its use is restricted to areas a day for 3 days, is recommended. to reduce where sulfadoxine-pyrimethamine is still active, vomiting, mefloquine dose should be split over which excludes all of Southeast Asian countries, 3 days, as in current fixed-dose combination. most of South American, East African, and West African countries. (iv) Dihydroartemisinin-piperaquine (vi) Artesunate-pyronaridine The combination is available as a fixed-dose combination in tablets containing 40 mg Apart from the five WHO recommended ACT dihydroartemisinin and 320 mg piperaquine and is another EMA (European Medicines Agency) a fixed-dose combination pediatric tablets recommended, US FDA approved, and WHO containing 20 mg dihydroartemisinin and pre-qualified and on the list of Essential Pediatric Pharmacology of Antimalarial Drugs, Current Anti-malarials 41

Medicines of WHO. The combination is available recommended to ensure equivalent exposure to as film-coated tablets (PyramaxTM, developed by the drug. Shin Poong Pharmaceutical, China, University of If artesunate is not available, artemether in Iowa, USA, and MMV). Each tablet contains preference to quinine is recommended for both 180 mg pyronaridine tetraphosphate and 60 mg children and adults with severe malaria. In situa- artesunate). Artesunate-pyronaridine combination tions where complete treatment of severe malaria is indicated in the treatment of acute, uncompli- is not possible but injections are available, a single cated malaria infection caused by P. falciparum or intramuscular dose of artesunate (if not available, P. vivax in adults and children weighing 20 kg or intramuscular artemether or quinine) is strongly more. A total therapeutic doses ranging from one recommended in adults and children with severe to four tablets given once a day for 3 days are malaria before transferal to an appropriate facility recommended. A granule formulation is available for further care. Where intramuscular artesunate is for children weighing between 5 kg and under not available, a single rectal dose of 10 mg/kg bw 20 kg. of artesunate is strongly recommended in children aged lower 6 years (do not use in older children and adults) before transferal to an appropriate Severe Malaria facility for further care. Parenteral artesunate is recommended for treat- ment of severe malaria. While the possible risk Adverse Reactions and Toxicity for teratogenicity limits the use of artemisinin Artemisinin drugs are generally well tolerated drugs in the treatment of uncomplicated malaria after both oral- and parenteral-dose administration in pregnant women in the first trimester, treatment in humans. Post-artemisinin delayed hemolysis is of severe malaria is recommended as it is poten- commonly found with artemisinins when used for tially lifesaving for the mother. Compared to qui- treatment of severe malaria. Although no deaths nine, artemisinins treatment in the first trimester is have been reported so far, this serious adverse not associated with an increased risk of miscar- reaction may lead to life-threatening anemia. Pre- riage or stillbirth. No difference in the prevalence clinical studies showed considerable toxicity of of major congenital anomalies is observed, artemisinin drugs at high doses particularly the although available data have been limited. The central nervous system and liver function abnor- benefits of using artemisinins to treat malaria in malities and reduction in the reticulocyte counts. early pregnancy are likely to outweigh the adverse Most of the effects returned to normal within 48 h. outcomes of partially treated malaria. Nevertheless, large clinical studies and meta- Artemether did not prove to be better than analyses do not show serious adverse effects in quinine on survival rate, and artesunate is the humans. The inconsistencies of results of the pre- first choice in low-transmission areas. Intravenous clinical and clinical studies are explained by the or intramuscular artesunate at 2.4 mg/kg bw per relationship between pharmacodynamics (toxic dose is strongly recommended in adults and chil- effects) and plasma concentrations of artemisinin dren with severe malaria (including infants, preg- drugs and active metabolite dihydroartemisinin. nant women in all trimesters, and lactating Most of the observed serious toxicity in experi- women) for at least 24 h until they can tolerate mental animals is acute toxicity associated with oral medication and then followed by a 3 days long-term rather than acute drug exposure. Rapid ACT (with a single-dose primaquine in areas with elimination of artemisinin drugs after oral-dose low transmission). Alternatively, a simplified administration represents a relatively safe route three doses of 4 mg/kg bw intravenous artesunate of administration compared to delayed drug (given at 0, 24, and 48 h) instead of five doses of release after intramuscular injection. Furthermore, 2.4 mg/kg are recommended. In children there are drug-related differences in toxicological weighing lower than 20 kg, a higher dose of profiles of artemisinins. Intramuscular application artesunate (3 mg/kg bw per dose) is strongly of artemether or -arteether, but not to artesunate, is 42 Pharmacology of Antimalarial Drugs, Current Anti-malarials safe and profiles acceptable plasma concentration- patients. Dihydroartemisinin-piperaquine was time profiles following intramuscular administra- reported to increase the QTc interval by 45.2, tion in severe malaria. 35.5, and 21.0 ms in healthy subjects following Adverse reactions of artemisinins that may the administration of each dose with high occur in clinical uses include hypersensitivity reac- (1000 kcal) or low (400 kcal) fat/calorie meal tions (estimated risk of 1 in 3000), mild gastroin- and fasting conditions, respectively. None had a testinal disturbance, dizziness, reticulocytopenia, QTc interval greater than 500 ms. and elevated liver enzyme activity. Although no ECG abnormalities have been found in most stud- Contraindications ies, bradycardia and very slight prolongation of the Artemisinin drugs are contraindicated in patients QTc interval have been reported. While studies in with known hypersensitivity to any artemisinin experimental animals show neurotoxicity after par- derivative. All ACTs should not be administered to enteral artemether, clinical, neurological, and path- patients with known hypersensitivity to artemisinins ological studies in humans have not shown similar and combination partners. Dihydroartemisinin- findings. piperaquine should not be used in patients with In experiment animals, dose-dependent fetal congenital QTc prolongation or who have a clinical toxicity was observed after administration of condition or are on medication that results in QTc artesunate in the first trimester and was more interval prolongation. likely to occur with increased duration of treat- ment. However, there is no evidence that Caution artemisinin derivatives are teratogenic in humans, Artemether should not be given to patients with but experience is limited. meningitis as a marked increase in the CSF con- Artemether-lumefantrine and dihydroartemi- centrations may occur. Artemether should also be sinin-piperaquine are the most intensively studied used with caution in patients with acute renal antimalarial drugs with regard to cardiotoxicity. failure due to possible drug accumulation. Artemether-lumefantrine has a wide therapeutic Due to limited information on safety profile in index and is generally well tolerated. Common patients aged over than 65 years or children adverse reactions are nausea, dizziness, and head- weighing less than 5 kg, clinical use of ache, which are not easily distinguishable from artemether-lumefantrine should be with caution. symptoms of acute malaria. It does not significantly Similarly, dihydroartemisinin-piperaquine should prolong QTc interval. No sudden death has been be used in patients aged over 70 years, infants attributed to cardiotoxicity following artemether- weighing lower than 5 kg, and patients with lumefantrine. renal or hepatic impairment with special caution Dihydroartemisinin-piperaquine is well toler- in view of the lack of evidence on the safety pro- ated. Common adverse reactions that may occur files of the drug in these groups. include nausea, vomiting, diarrhea, anorexia, ane- Although there is no evidence for iatrogenic mia, dizziness, headache, sleep disturbance, and toxicity of artemether-lumefantrine in patients cough. Although there was no evidence of with congenital or clinical conditions resulting in cardiotoxicity in large randomized trials and QTc prolongation, a family history of congenital extensive use of dihydroartemisinin-piperaquine, long QT syndrome or sudden death, electrolyte the partner drug piperaquine does prolong the QTc abnormalities such as hypokalemia or hypomag- interval on ECG (reflecting ventricular repolari- nesemia, the drug should not be used in these zation which may cause potentially life- patients as it may affect cardiac conductivity. threatening ventricular arrhythmia) by approxi- mately the same magnitude as chloroquine but Pharmacokinetics lower than quinine. One possible sudden cardiac The pharmacokinetic parameters of artemether death associated with dihydroartemisinin- (when given by intramuscular injection for treat- piperaquine was reported among 200,000 ment of severe malaria) and artesunate (when Pharmacology of Antimalarial Drugs, Current Anti-malarials 43

given by intravenous injection, intramuscular except delayed tmax of artesunate. Intramuscular injection, and rectal route for severe malaria, as artemether is absorbed slowly and erratically. well as oral route for uncomplicated malaria) Plasma protein binding of artemisinin drugs together with their active plasma metabolite ranges from 43% to 95% (44–93%, 93%, and dihydroartemisinin are summarized in Table 1. 95% for dihydroartemisinin, artesunate, and Artesunate (water soluble) is suitable for admin- artemether, respectively). Artesunate and istration by all routes, while artemether (water artemether are extensively converted to the active insoluble, lipid soluble) can be administered by plasma metabolite dihydroartemisinin which intramuscular, oral, or rectal (suppository) route. accounts for most of antimalarial activity. High Artemether (lipid soluble) is currently available concentrations can be found in the bile, liver, and for clinical use as oral and intramuscular formula- kidney. tions. Oral dihydroartemisinin is currently in clin- Artesunate and artemether are rapidly (within ical use as co-formulation with piperaquine (ACT). 15 min of dosing) metabolized in the liver to form The rectal administration has emerged as one of the the active metabolite dihydroartemisinin by important routes, especially in tropical countries CYP2A6, CYP3A4/A5, and CYP3A4 (secondary where it can be lifesaving. Nevertheless, there is contribution of CYP2B6 and CYP3A5), respec- large interindividual variation in the drug tively. Artesunate is biotransformed into its active bioavailability. plasma metabolite dihydroartemisinin by plasma Artemisinin and derivatives exhibit unique and esterases with possible contribution of CYP2A6. highly variable pharmacokinetic properties. All Dihydroartemisinin is rapidly inactivated to are rapidly absorbed and eliminated. The t1/2 is dihydroartemisinin-b-glucuronide by the phase II short ranging from 0.5 to 4 h. Tmax of artemisinin enzymes UGT1A9 and UGT2B7. The t1/2 of drugs vary from minutes to hours, depending on dihydroartemisinin is approximately 1–2h.Evi- the drug formulation and route of administration. dence also suggests rapid elimination of artesunate Bioavailability of artemisinin drugs is also highly (in minutes) and artemether (1–11 h). The concen- variable (<25–>85%), depending on the drug tration of artemether parent compound predomi- formulation, route of administration, health status, nates after intramuscular artemether in severe and the nature of malaria infection. The bioavail- malaria patients. ability of oral artesunate and artemether following Several artemisinin drugs are subject to auto- oral-dose administration is as low as low 30% due induction of the hepatic first-pass metabolism, to high first-pass metabolism. Oral artemether resulting in a decline in bioavailability after peaks in about 2–6 h. Oral dihydroartemisinin is repeated dosing, which might compromise treat- rapidly absorbed from the gastrointestinal tract ment. Artemether and dihydroartemisinin includ- with marked interindividual variation. Tmax is ing artemisinin have been shown to induce achieved at about 1–2h. CYP3A activity. Artemisinin and -arteether also Following an intravenous injection of activate CYP2C19, and artemisinin upregulates artesunate, high initial plasma concentration is CYP2B6. In vitro experiments using primary observed and is subsequently rapidly declined. human hepatocytes and in a human intestinal cell

Dihydroartemisinin concentration reaches tmax line suggest that activation of the xenosensors within 9–20 min after artesunate dosing. Intra- pregnane X receptor (PXR) and constitutive muscular artesunate produces lower Cmax of androstane receptor (CAR) is the underlying artesunate and delayed tmax of dihydroartemisinin. mechanism on CYP450 induction by Following oral administration, Cmax of artesunate artemisinins. Artesunate and artemisinin have and dihydroartemisinin are achieved within 1 and been shown not to interact with P-glycoprotein

1–2 h, respectively. Following rectal administra- (MDR1)-mediated taxol transport in Caco2 cells tion, pharmacokinetics of artesunate and or with MRP1 and BCRP in multidrug-resistant dihydroartemisinin are similar to oral artesunate, cells. Likewise, in rats, P-glycoprotein did not 44 Pharmacology of Antimalarial Drugs, Current Anti-malarials contribute to intestinal absorption or inducible The influence of pregnancy on amodiaquine and pharmacokinetics of artemisinin. piperaquine appears not to be clinically relevant. Sulfadoxine plasma concentration is significantly Factors Associated with Altered Drug reduced, and clearance rate is higher in pregnancy. Exposure and/or Treatment Response For pyrimethamine and mefloquine, available Variation of artemisinin pharmacokinetics data regarding pharmacokinetic changes in preg- between individuals of up to 50-fold has been nancy have been limited. Lower concentrations reported in both healthy subjects and malaria achieved in pregnant women may lead to reduced patients. This variation, however, does not corre- clinical efficacy and increased morbidity and mor- late with clinical outcome; similar parasite and tality. Higher failure rates have been shown in fever clearance rates are observed in all malaria pregnant women with both artemether and patients regardless of clinical outcome. The part- artesunate. Although the exact mechanism is ner drugs as components of the ACTs may mask unknown, these discrepancies may be due to phar- any potential artemisinin drug failures. There is macokinetic changes of both drugs that occur in evidence that pregnancy per se, malaria infection, pregnancy such as increases in the CL and Vd. It and race/ethnicity can alter the pharmacokinetic is essential that dose-optimization studies of properties of the ACT components. ACTs are performed in pregnant women, in order to maximize the clinical efficacy and toler- Genetic Polymorphisms of Drug-Metabolizing ability of these regimens. Enzymes and Transporters The genetic basis of such a large interindividual Metabolic Auto-induction pharmacokinetic variability of artemisinin drugs Several artemisinin drugs suffer from auto- has not clearly been addressed. Phenotypic con- induction of the hepatic first-pass metabolism, sequences of polymorphisms in drug-metabolizing resulting in a decline of bioavailability after enzymes CYP2B6 and UGT2B7 and transport repeated doses. The pharmacokinetics of the proteins (particularly P-glycoprotein) on the phar- artemisinin drugs have been shown to exhibit an macokinetics and effectiveness of artemisinin unusual time dependency during a 7-day oral drugs are yet to be determined. This is particularly daily regimen. important in view of high prevalence of CYP2B6 functional polymorphisms in several malaria- Renal Disease endemic countries. Pharmacokinetics of artemether is changed in

patients with acute with increased Cmax,AUC, Pregnancy while decreased Vd and longer t1/2 compared Pregnancy has been reported to alter the pharma- with nonrenal failures. Artemether should be cokinetic properties of artemisinin drugs as well used with caution in patients with acute renal as different components of the ACTs. Plasma failure due to concern about drug accumulation.

Cmax and AUC of oral dihydroartemisinin have been shown to be lower in pregnant women com- Interaction Between Artemisinins and Other Drugs pared with nonpregnant women. Results of a more Artemisinin and derivatives induce CYP2B6 and recent systematic analysis show lower Cmax and CYP2C19, CYP3A (3A4/3A5), and CYP2A6 and exposure (AUC) of dihydroartemisinin after oral inhibit CYP1A2. Clinical studies with the most administration of artemether, artesunate, and commonly used ACTs, artemether-lumefantrine, dihydroartemisinin in women in the second and artesunate-mefloquine, and artesunate-amodiaquine, third trimesters of pregnancy. With regard to the have so far not shown any clinical signifi- ACT combination partners, relatively low day cant interactions. Tafenoquine co-administration 7 plasma concentrations of lumefantrine are com- (as gametocytocide or tissue schizonticide) had no monly found following artemether-lumefantrine clinically relevant effects on dihydroartemisinin, combination, indicating a low drug exposure. piperaquine, artemether, or lumefantrine Pharmacology of Antimalarial Drugs, Current Anti-malarials 45 pharmacokinetics. The pharmacokinetics of Artesunate-mefloquine: Concomitant use of artemether, dihydroartemisinin, or mefloquine are the anti-TB drug rifampicin with mefloquine not significantly changed when oral artemether is may result to a marked decrease in exposure of givenwithmefloquine. Artesunate does not influence mefloquine, which may potentially decrease anti- atovaquone or proguanil pharmacokinetics, and the malarial efficacy of mefloquine. Patients taking triple-drug combination of atovaquone, proguanil, this drug should be followed up carefully to iden- and artesunate is well tolerated. tify treatment failure. Dihydroartemisinin-piperaquine: Consumption of a high-fat, high-calorie meal markedly increases Drug Interactions of ACTs piperaquine exposure (AUC ). High-fat meal Artemether-lumefantrine: Absorption of the hydro- 0-168h significantly accelerates the absorption of phobic lipophilic lumefantrine component of piperaquine, thereby increasing the risk for poten- artemether-lumefantrine combination varies widely tially arrhythmogenic delayed ventricular repolari- between individuals and is greatly enhanced with fat zation (prolongation of the QTc interval). It is co-administration. Decreased exposure to therefore a general recommendation that lumefantrine has been documented in young chil- piperaquine-dihydroartemisinin should not be dren (<3 years), pregnant women, large adults, administered at least 3 h before or after food con- smokers, and patients co-administered with meflo- sumption. Malnourished children are at increased quine, rifampicin, or efavirenz. These patients risk of treatment failure following treatment with should be closely monitored and their full adherence dihydroartemisinin-piperaquine due to decreased to medication ensured. On the other hand, increased plasma concentrations. Their response to treatment exposure to lumefantrine has been documented in should be closely monitored. In pregnant women, patients co-administered with lopinavir, ritonavir- dihydroartemisinin and piperaquine exposure are boosted lopinavir antiretroviral agents, but without reduced and may increase the risk of treatment increase in toxicity. No dose adjustment is indicated. failure. In addition, the increase in clearance of There is no pharmacokinetic interaction between piperaquine in pregnancy results in decreased t . tafenoquine and artemether-lumefantrine; both can 1/2 This may shorten the posttreatment prophylactic be co-administered safely. effect of dihydroartemisinin-piperaquine combina- Artesunate-amodiaquine: Treatment failure tion. However, as this pharmacokinetic change after amodiaquine monotherapy is more frequent does not affect primary efficacy, no dosage adjust- among children who are underweight for their ment is recommended. There is no pharmacoki- age. Therefore, their response to treatment should netic interaction between tafenoquine and be closely monitored. Furthermore, this ACT is dihydroartemisinin-piperaquine, and both can be associated with severe neutropenia, particularly in co-administered safely. patients coinfected with HIV and especially in Artesunate-sulfadoxine-pyrimethamine: The those on zidovudine and/or cotrimoxazole. Con- low dose of folic acid (0.4 mg daily) that is comitant use of efavirenz increases exposure to required to protect the fetuses of pregnant amodiaquine and hepatotoxicity. Concomitant use women from neural tube defects does not reduce of artesunate-amodiaquine with these drugs clinical efficacy of sulfadoxine-pyrimethamine. should be avoided. No significant changes in the On the other hand, higher dose (5 mg daily) sig- pharmacokinetics of amodiaquine or its metabo- nificantly reduces clinical efficacy of sulfadoxine- lite monodesetylamodiaquine have been observed pyrimethamine, and both drugs should not be during the second and third trimesters of preg- given concomitantly. nancy. No dose adjustment is recommended. No effect of age has been observed on the plasma Interaction Between ACTs and Antiretroviral Drugs concentrations of amodiaquine and mono- Treatment of malaria in patients coinfected with desetylamodiaquine. No dose adjustment by age HIV is a major concern due to potential pharma- is indicated. cokinetic as well as pharmacodynamic 46 Pharmacology of Antimalarial Drugs, Current Anti-malarials interactions. Several anti-HIV drugs are substrates significantly reduced (72%). On the other hand, and/or inhibitors of CYP3A and MDR1 (e.g., mefloquine Cmax and systemic exposure are signif- protease inhibitors) or CYP2B6 (efavirenz), so icantly reduced (19–37%). Lopinavir Cmax is signif- there is a potential risk of multiple drug interac- icantly reduced (22%) but without significant tions. Artesunate increases plasma concentration change in AUC. Drug treatments are generally of nevirapine. Artemether plasma concentration is well tolerated with no serious adverse events. The increased with ketoconazole but decreased with reduction in systemic exposure of all investigated darunavir/ritonavir, lopinavir/ritonavir, nevira- drugs raises concerns of an increased risk of treat- pine, efavirenz, etravirine, and rifampicin. ment failure rate in coinfected patients and should be With regard to the interaction between the ACTs further investigated. and antiretroviral drugs, the protease inhibitors (PIs) Non-nucleoside reverse transcriptase inhibi- tend to increase the exposure of lumefantrine and tors (NNRTIs) tend to decrease the exposures of decrease the exposure of artemether and its artemether, dihydroartemisinin, and lumefantrine active metabolite dihydroartemisinin when co- when co-administered with artemether- administered as artemether-lumefantrine. Co- lumefantrine. However, the exposure of nevira- administration of artemether-lumefantrine with pine is increased. Co-administration of artesunate- ritonavir-boosted lopinavir (LPV/r) significantly mefloquine with nevirapine increases artesunate reduces artemether Cmax and AUC but significantly exposure. increases lumefantrine exposure. Co-administration of etravirine reduced the AUC of artemether (38%), dihydroartemisinin (15%), and lumefantrine (13%) Other Currently Used Antimalarial Drugs at steady state. Co-administration of etravirine with artemether-lumefantrine may lower the antimalarial Tetracycline and Derivatives activity of artemether and should therefore be used Tetracyclines are synthetic antibiotics derived with caution. Co-administration of artemether- from a cycline naturally produced by Streptomy- lumefantrine with efavirenz or nevirapine results in ces bacteria. Doxycycline is a long-acting deriva- a reduction in artemether, dihydroartemisinin, tive. Tetracyclines are generally used in the lumefantrine, and nevirapine exposure. treatment of infections of the respiratory tract Co-administration of darunavir/ritonavir reduced and the intestines and are also used in the treat- the AUC of artemether (16%) and ment of chlamydia. Their most common current dihydroartemisinin (18%) but increased the AUC use is in the treatment of moderately severe acne of lumefantrine (28%) at steady state. Darunavir/ and rosacea. Doxycycline is also used as a pro- ritonavir can be co-administered with artemether- phylactic treatment for infection by Bacillus lumefantrine without dose adjustment but should anthracis (anthrax) and is effective against be used with caution. Co-administration of Yersinia pestis, the infectious agent of bubonic artemether-lumefantrine has no effect on etravirine, plague. Tetracyclines remain the treatment of darunavir, or ritonavir AUC. No drug-related seri- choice for infections caused by chlamydia ous adverse events are reported during the studies. (trachoma, psittacosis, salpingitis, urethritis, and There has been limited information on the interac- L. venereum infection), Rickettsia (typhus, Rocky tion between other ACTs and protease inhibitors. Mountain spotted fever), brucellosis, and spiro- Co-administration of artesunate-mefloquine with chetal infections (borreliosis, syphilis, and Lyme ritonavir decreases dihydroartemisinin exposure. disease). In addition, they may be used to treat Co-administration of artesunate-pyronaridine with anthrax, plague, tularemia, and Legionnaires’ dis- ritonavir increases ritonavir exposure. In the pres- ease. They may have a role in reducing the dura- ence of ritonavir-boosted lopinavir (LPV/r), tion and severity of cholera, although drug artesunate Cmax and systemic exposure (AUC) resistance is mounting and their effect on overall are significantly increased (45–80%), while the met- mortality is questioned. Tetracycline derivatives abolic ratio of dihydroartemisinin to artesunate is Pharmacology of Antimalarial Drugs, Current Anti-malarials 47

Pharmacology of Antimalarial Drugs, Current Anti-malarials, Fig. 9 Chemical structures of tetracycline and doxycycline

are currently being investigated for the treatment cause enamel hypoplasia in young children. How- of certain inflammatory disorders. ever, doxycycline has recently been Tetracycline and doxycycline (Fig. 9a and b) recommended by the American Association of are used for malaria treatment and prophylaxis, as Pediatrics to be used safely in children of all well as treating certain forms of human filariasis. ages if given less than 28 days. Hypersensitivity Both have molecular weight of 444.4. reactions such as urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, pericarditis, Antimalarial Activities and Therapeutic Indications and exacerbation of systemic lupus erythematosus for Malaria may occur. Rare severe adverse reactions that can Tetracycline and doxycycline are broad-spectrum be found include benign intracranial hypertension antibiotics which are inhibitors of protein synthe- in adults and hematological abnormalities such as tase by disrupting messenger RNA and transfer hemolytic anemia, thrombocytopenia, neutrope- RNA. Both are consistently active against all spe- nia, eosinophilia, and thrombophlebitis (with pro- cies of malaria. Tetracycline and doxycycline are longed intravenous administration). Expired slow-acting blood schizontocidal agents. Cur- tetracyclines or tetracyclines allowed to stand at rently, doxycycline is used in combination with a pH less than 2 are reported to be nephrotoxic due quinine or artesunate for treatment of to the formation of a degradation product, chloroquine-resistant and multidrug-resistant anhydro-4-epitetracycline causing Fanconi P. falciparum. Doxycycline remains effective in syndrome. combination with quinine or artesunate at a dose of 200 mg for 7 days. In addition, it is also indi- Contraindications cated for the prophylaxis of malaria at a dose of Doxycycline is contraindicated in patients with 100 mg/day starting at the day of arrival in known hypersensitivity to tetracyclines and endemic areas and continuing for up to 4 weeks related compounds. Doxycycline is categorized after returning. by the FDA as a class D drug in pregnancy. Fatal necrosis has been reported with doxycycline use Adverse Drug Reactions and Toxicity in pregnancy. Common adverse drug reactions of doxycycline As with all tetracyclines, it is contraindicated in include gastrointestinal disturbance (nausea, pregnancy through infancy, due to the potential vomiting, and diarrhea), particularly with higher for disrupting bone and tooth development. The doses. Oral doxycycline should be administered exception is in the treatment of anthrax or where with food to reduce gastric irritation. Other reac- other medications are contraindicated or tions that can occasionally occur are dry mouth, ineffective. glossitis, stomatitis, dysphagia, and esophageal ulceration. Esophageal irritation can be reduced Caution by administration of doxycycline with a full glass Doxycycline should be used with caution in of water. Doxycycline crosses the placenta and patients with gastric or intestinal diseases such may cause discoloration of teeth and possible as colitis, who may be at greater risk for pseudo- bone growth retardation in the fetus and in membranous colitis. In addition, the use of doxy- young infants. They also discolor teeth and cycline in patients with established systemic lupus 48 Pharmacology of Antimalarial Drugs, Current Anti-malarials erythematosus should be with caution as the drug may worsen the clinical conditions.

Pharmacokinetics Pharmacokinetic parameters of doxycycline fol- lowing dose regimens recommended for treatment and prophylaxis of malaria are summarized in Table 1. There is a marked interindividual variability in doxycycline pharmacokinetics, depending on age and the co-administered drugs. Doxycycline is highly lipophilic and is rapidly and almost completely absorbed after oral administration Pharmacology of Antimalarial Drugs, Current Anti- with bioavailability approaching 100%. Unlike malarials, Fig. 10 Chemical structure of clindamycin tetracycline, absorption of doxycycline is not markedly changed in the presence of food. How- anticonvulsants (carbamazepine, phenytoin, phe- ever, the rate and extent of absorption of doxycy- nobarbital), and chronic alcohol use may accelerate cline are markedly reduced when taken with milk doxycycline metabolism resulting in increased or other dairy products. Doxycycline should not drug exposure (AUC) and Cmax. The t1/2 is also therefore be administered with these products. shortened. Doxycycline is widely distributed in body fluids and tissues including the bone marrow, breast milk, livers, kidneys, gastrointestinal tract, Clindamycin and spleen. Penetration into sputum is 8–28% over 16 h. Penetration into saliva is poor, while Antimalarial Activities and Therapeutic Indications biliary concentration exceeds serum by manyfold. for Malaria The drug also crosses the placenta. Approxi- Clindamycin (Fig. 10) is a semisynthetic deriva- mately 80–95% of doxycycline binds to plasma tive of lincomycin, a natural antibiotic produced proteins. The drug is metabolized in the liver by by the actinobacterium Streptomyces lincolnensis. an unknown mechanism. No metabolites have It is obtained by 7(S)-chloro-substitution of the been identified to date. Tetracyclines including 7(R)-hydroxyl group of lincomycin. doxycycline undergo enterohepatic recirculation, Clindamycin is used as antibacterial drug, pri- resulting in slow clearance. Doxycycline is elim- marily Gram positive and anaerobic infections inated unchanged by both the renal and biliary caused by susceptible anaerobic bacteria, includ- routes. Bile concentrations may be 10–25 times ing dental infections and infections of the respira- those in plasma/serum. Approximately 35–60% is tory tract, skin, and soft tissue, peritonitis, and excreted in urine and the remainder in feces. The bone and joint infections. Topical application of clindamycin phosphate is used to treat mild-to- t1/2 of doxycycline is not affected by impaired renal function, renal failure, or hemodialysis. moderate acne. Therefore, dose adjustment is not required for For treatment of malaria, clindamycin is these patients. always used in combination with standard blood schizontocidal drugs particularly quinine and Factors Associated with Altered Drug Exposure artesunate for treatment of uncomplicated and fi and/or Treatment Response severe malaria. It is the rst-line treatment in fi Doxycycline absorption is decreased in the pres- rst-trimester pregnancies. Clindamycin should ence of antacids, bismuth subsalicylate, proton- not be used alone as an antimalarial drug due to pump inhibitors, and oral iron preparations. its slow action. Hepatic inducers such as rifampicin, Pharmacology of Antimalarial Drugs, Current Anti-malarials 49

Its mechanism of action involves inhibition of plasma proteins and accumulates in leukocytes, microbial protein synthesis by preferential bind- macrophages, and bile. It is widely distributed ing to the 50S ribosomal subunit and inferences throughout the body fluids and tissues, including with peptide chain initiation. It is active on the bone, but significant levels are reached in CSF. apicoplast and leads to delayed cell death. Clindamycin is metabolized in the liver by CYP3A4 into the active N-demethyl and sulfox- Adverse Reactions and Toxicity ide metabolites and some inactive metabolites. Clindamycin is generally well tolerated after oral About 10% of a dose is excreted in the urine as administration. Adverse reactions include nausea, active drug or metabolites and about 4% in feces. vomiting, abdominal pain or cramps, rash, or pru- The remainder is excreted as inactive metabolites. ritus. High dose (both intravenous and oral) of Excretion is slow and takes place over several clindamycin may cause a metallic taste in the days. The drug is not effectively removed from mouth. Rarely, clindamycin therapy has been the body by dialysis. associated with anaphylaxis, blood dyscrasia Clindamycin t1/2 may be prolonged and CL (leukopenia, agranulocytosis, eosinophilia, and reduced in neonates and patients with renal thrombocytopenia), erythema multiforme, poly- impairment. However, dose modification is not arthritis, jaundice, raised liver enzymes, hepato- considered necessary. toxicity, and renal dysfunction. Some parenteral There has been no data published on the phar- formulations contain benzyl alcohol, which may macokinetics of clindamycin in pregnant women, cause fatal “gasping syndrome” in neonates. although it is used to treat malaria in pregnancy.

Contraindications Factors Associated with Altered Drug Exposure Clindamycin is contraindicated in patients with and/or Treatment Response known hypersensitivity to clindamycin and struc- Clindamycin absorption is delayed with alumi- turally related compounds. num salts and kaolin. It is a weak-to-moderate inhibitor of CYP3A in vitro, and therefore poten- Caution tial for drug-drug interactions involving Clindamycin should be used with caution in clindamycin is low. Nevertheless, the use in patients with gastrointestinal diseases (increased patients HIV infection should be with caution. risk of pseudomembranous colitis) and severely Systemic drug exposure and plasma protein bind- ill elderly patients (increased risk of diarrhea). ing of clindamycin have been shown to be Close monitoring of adverse reactions is required increased, while CL/F and Vd/F reduced in HIV- when clindamycin is administered to neonates infected patients. (risk of toxic plasma drug concentrations). Dose Clindamycin prolongs effects of neuromuscu- optimization may be required when clindamycin lar blocking agents and may lead to respiratory is given to patients with moderate-to-severe liver depression. Possible antagonism and cross- disease due to impairment of drug clearance. resistance may occur with macrolides and chlor- Patients with HIV infection should be closely amphenicol. Clindamycin antagonizes parasym- monitored if clindamycin is to be given due to pathomimetics such as neostigmine. possibility of increased plasma drug exposure to toxic level. Lumefantrine

Pharmacokinetics Antimalarial Activities and Therapeutic Indications Pharmacokinetic parameters of clindamycin are for Malaria summarized in Table 1. Lumefantrine (benflumetol: Fig. 11)isafluorine Clindamycin is rapidly absorbed after oral derivative belonging to the arylamino alcohol administration, with an oral bioavailability of group of antimalarials structurally related to qui- approximately 90%. About 90% is bound to nine, mefloquine, and halofantrine. Mechanism of 50 Pharmacology of Antimalarial Drugs, Current Anti-malarials

Factors Associated with Altered Drug Exposure and/or Treatment Response Plasma lumefantrine concentrations achieved in children aged lower than 5 years are significantly lower than in older children and adults. This has been reported to be associated with increased risks of recrudescence and earlier reinfections. Lumefantrine disposition is also altered in women in the second and third trimesters of preg- nancy. Due to a significant increase in Vd/F, sys- temic drug exposure is markedly lower. The lower day 7 concentrations reported could be an impor- Pharmacology of Antimalarial Drugs, Current Anti- malarials, Fig. 11 Chemical structure of lumefantrine tant factor in clinical failure. Lumefantrine and amodiaquine are metabo- lized by CYP3A4 and CYP2C8, respectively, action is thought to be similar to the others in the and plasma concentration may be theoretically group by preventing heme detoxification within decreased by the inducers of these enzymes the parasite food vacuole, thus causing accumula- including rifampicin. tion of the toxic heme complex. It is effective against multidrug-resistant P. falciparum malaria. Piperaquine Combination of lumefantrine and artemether (ACT) has proved to be effective in treating Antimalarial Activities and Therapeutic Indications uncomplicated acute falciparum malaria. The for Malaria drug is not available as a single drug and has not Piperaquine (Fig. 12) is a bisquinoline antimalar- been used as monotherapy, which should slow the ial drug structurally related to chloroquine and selection and spread of resistance to this drug. other 4-aminoquinolines. The drug was synthe- sized independently in France and China in the Pharmacokinetics 1960s. Piperaquine replaced chloroquine for Pharmacokinetic parameters of lumefantrine as a malaria prophylaxis in China in 1978. Neverthe- component of artemether-lumefantrine combina- less, with the emergence of P. falciparum tion (ACT) following dose regimen piperaquine-resistant strains, piperaquine use recommended for treatment and prophylaxis of was decreased in the late 1980s. In the 1990s, malaria are summarized in Table 1. piperaquine was reconsidered as one of the com- Oral absorption of lumefantrine is increased ponents of short-course ACTs in combination when co-administered with fatty foods or milk with dihydroartemisinin, trimethoprim, and due to its highly lipophilic nature. This may lead primaquine (China-Vietnam 4 or CV4 and to a marked variation in drug absorption among China-Vietnam 8 or CV8). individuals. Its bioavailability and tmax vary Piperaquine has a very long t1/2 of about within and between individuals, primarily due to 2–3 weeks and consequently could be expected fat-dependent absorption. Furthermore, there is a to provide a long period of posttreatment nonlinear absorption of lumefantrine which is sat- prophylaxis. urated at the currently recommended doses. Both the mechanisms of action and of resistance Plasma protein binding is high (99.7%). of piperaquine have not been well characterized but Lumefantrine is extensively metabolized in the are likely to be similar to chloroquine. Mutation of liver, primarily by the CYP3A4, to the active pfcrt (P. falciparum chloroquine-resistant trans- metabolite desbutyllumefantrine. T1/2 is about porter) as well as increase in plasmepsin II/III copy 3 days. number has been implicated in piperaquine-resistant P. falciparum. Cross-resistance between piperaquine and chloroquine has been reported. Pharmacology of Antimalarial Drugs, Current Anti-malarials 51

the terminal elimination phase in children than in adults. This low plasma piperaquine concentra- tion on day 7 has been shown to be associated with treatment failure. There are no clinically important differences in the pharmacokinetics of dihydroartemisinin or piperaquine between preg- nant and nonpregnant women. Plasma concentration of piperaquine and poten- Pharmacology of Antimalarial Drugs, Current Anti- tial toxicity are increased when piperaquine is malarials, Fig. 12 Chemical structure of piperaquine given with verapamil, indinavir, lopinavir/ritona- vir, HMG-CoA reductase inhibitors (statins), and cyclosporine. Co-administration of piperaquine However, piperaquine has also been shown to be with barbiturates, chronic alcohol use, rifampicin, active against highly chloroquine-resistant efavirenz, nevirapine, phenytoin, or carbamazepine P. falciparum. Resistance to both artemisinin and increases metabolism of piperaquine and therefore piperaquine is now prevalent in Cambodia, as dem- reduces plasma concentration of piperaquine with onstrated by the increase in the number of cases of reduced effectiveness. dihydroartemisinin-piperaquine treatment failure. Co-administration with drugs that prolong QTc interval increases piperaquine risk of Adverse Reactions and Toxicity cardiotoxicity. The symptomatic adverse reactions produced by piperaquine are more or less tolerable. These Pyronaridine include dizziness, headache, nausea, vomiting, anorexia, myalgia, cough, asthenia, arthralgia, Antimalarial Activities and Therapeutic Indications abdominal distress, pyrexia, eosinophilia, and for Malaria QTc prolongation. Pyronaridine is (Fig. 13), a Mannich base 1-aza-acridine structurally related to mepacrine. Pharmacokinetics It is a benzonaphthyridine derivative which was Piperaquine pharmacokinetic properties are similar first synthesized in 1970 at the Institute of Chinese to those of chloroquine. The kinetics of piperaquine Parasitic Disease, Chinese Academy of Preven- in adult patients is described by a three- tive Medicine. It was used in China for the treat- compartment model with first-order elimination ment of malaria as a single agent for the past and two first-order absorption processes. 30 years. Pyronaridine-artesunate has been devel- Piperaquine is highly lipid soluble, and its oral oped by the Medicines for Malaria Venture bioavailability may be lower when given without (MMV) and Shin Poong Pharm Co Ltd any food. A large quantity of co-administered fat (Republic of Korea) for the treatment of acute enhances absorption significantly. uncomplicated P. falciparum and blood stage Piperaquine is highly bound to plasma proteins P. vivax malaria with a fixed-dose combination (>98%), with a very large Vd/F (>100 l/kg), a tablet and granule formulation for pediatric low CL/F (1–2 l/h/kg), and a consequently long administration (as a potential ACT). It is on the t1/2 (13–28 days). World Health Organization’s List of Essential Medicines, the most effective and safe medicines Factors Associated with Altered Drug Exposure needed in a health system. and/or Treatment Response Pyronaridine exhibits high efficacy, including The pharmacokinetic properties of piperaquine against chloroquine- and amodiaquine-resistant are affected by body weight and age. Concentra- strains, and the reassurance of many years of tions of piperaquine, when co-administered with successful use in China as monotherapy and in dihydroartemisinin, are lower at the beginning of combination with other antimalarials, without the 52 Pharmacology of Antimalarial Drugs, Current Anti-malarials

unknown but may be due to a direct effect on the pyronaridine mechanism of action.

Adverse Reactions and Toxicity Pyronaridine also appears to be well tolerated in clinical studies. Overall, the acute and subacute toxicity of pyronaridine is generally less than that of chloroquine in all animal species tested. Adverse reactions are mild and are usually resolved within 2 days of starting therapy. The Pharmacology of Antimalarial Drugs, Current Anti- most common adverse events after oral malarials, Fig. 13 Chemical structure of pyronaridine pyronaridine therapy in many cases are similar to the symptoms of malaria, i.e., dizziness, nau- development of widespread drug resistance. sea, vomiting, and abdominal discomfort. The Pyronaridine has potent in vitro activity against incidence of cardiovascular toxicity is also less P. falciparum strains and clinical isolates includ- than that of chloroquine. There are no unexpected ing those that are resistant to other antimalarials. findings that would be a particular cause for con- In vivo animal models indicate a synergistic effect cern at therapeutic levels in human subjects. The between pyronaridine and artemisinins against concern of liver toxicity which led to a restriction parasites resistant to one or both components, of pyronaridine use has now been resolved. How- restoring efficacy against these strains. Conse- ever, evidence of embryotoxicity in rodents sug- quently, pyronaridine represents an ideal candi- gests that pyronaridine should be used with date for combination therapy with artemisinin caution during pregnancy. There are also some derivatives, such as artesunate. reports of palpitations and allergic skin reaction. Almost all published clinical trials to date used Similarly to chloroquine, pruritus may also rarely the Chinese enteric-coated tablet formulation with occur in African patients. 175 mg of the tetraphosphate, equal to 100 mg base, with dosages lipophilic at pH 7.4 (logD 0.34); lipophilicity was reduced at pH 5. The base Pharmacokinetics is more liposoluble than the salt. Clinical studies of Oral bioavailability of pyronaridine is relatively the combination of pyronaridine tetraphosphate low. The relative bioavailability of enteric-coated and artesunate are encouraging and show it to be tablets and capsules are about 20% and 32%, a promising new artemisinin combination therapy respectively. In vitro studies using human for the treatment of both P. falciparum and P. vivax CYP450 isoforms indicated that pyronaridine malaria in adult, children, and infant populations. could be metabolized by CYP1A2, CYP2D6, The drug is administered as pyronaridine tetra- and CYP3A4. Quinoneimine metabolites of phosphate (56.89% base), a yellow, odorless pow- aminoquinolines are thought to cause the toxicity der with a bitter taste. problems. Pyronaridine preferentially associates The mechanism(s) by which pyronaridine acts with blood cells with a blood/plasma distribution – as an antimalarial appears to be similar to chloro- of 1.2 1.7 in human. Plasma protein binding is – quine through inhibition of the production of, and high (92 96%). As pyronaridine concentrates in formation of complexes with, b-hematin to erythrocytes, plasma assays may underestimate enhance hematin-induced human blood cell pyronaridine concentrations. The drug is exten- lysis. Pyronaridine also inhibits glutathione- sively distributed to various body tissues. The t1/2 dependent heme degradation. The mechanism by of pyronaridine in healthy adult subjects and adult which resistance to pyronaridine develops is malaria subjects are estimated to be 11.3 and 13.2 days, respectively. The pharmacokinetics of pyronaridine appears to be altered in patients with Pharmacology of Antimalarial Drugs, Current Anti-malarials 53

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