Pharmacokinetics and Drug Interactions

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Antiviral Therapy 13:1–13 Review Darunavir: pharmacokinetics and drug interactions

David Back1*, Vanitha Sekar2 and Richard MW Hoetelmans3

1Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK 2Tibotec Inc., Yardley, PA, USA 3Tibotec BVBA, Mechelen, Belgium

*Corresponding author: E-mail: [email protected]

Darunavir (TMC114) is a new HIV protease inhibitor that been undertaken, covering a wide range of therapeutic has demonstrated substantial antiretroviral activity areas. Studies conducted in HIV-negative healthy volun- against wild-type HIV-1 virus and multidrug-resistant teers and in HIV-infected patients show that the strains. Darunavir inhibits and is primarily metabolized potential for interactions is well characterized and the by cytochrome P450 3A (CYP3A) isoenzymes and is co- interactions are manageable. For most drugs investi- administered with low-dose ritonavir (darunavir/r); gated, no dose adjustments of darunavir/r or the ritonavir is an inhibitor of CYP3A isoenzymes and phar- co-administered drug are required. This article reviews macologically enhances darunavir, resulting in increased all the pharmacokinetic and drug–drug interaction plasma concentrations and allowing for a lower daily studies conducted to date for darunavir/r, providing

dose. The t1/2 (terminal elimination half-life) of guidance on how to co-administer darunavir/r with many darunavir is 15 h in the presence of ritonavir. An exten- other antiretroviral or non-antiretroviral medications sive darunavir/r drug–drug interaction programme has commonly used in HIV-infected individuals.

Introduction

The aim of antiretroviral therapy is to maximally and POWER 1, 2 (TMC114-C213, TMC114-C202) and durably suppress levels of HIV-1 RNA, while restoring 3 (TMC114-C215/C208) Phase IIb studies [5–7]. All and preserving immunological function [1]. Failure to patients in the POWER studies received treatment respond to treatment is often related to the develop- with an investigator-selected optimized background ment of viral drug resistance, occurring as a result of regimen plus either darunavir/r or (in POWER 1 and mutations in the viral genome. An understanding of 2) an investigator-selected control PI. In a pooled resistance mechanisms is important for the design of analysis of the randomized, controlled, POWER 1 new agents, particularly for the management of treat- and 2 trials, treatment with darunavir/r 600/100 mg ment-experienced patients who have usually failed to twice daily resulted in greater virological and respond to multiple prior regimens and often devel- immunological responses than treatment with control oped mutations that confer resistance to most of the PIs (CPIs). At week 24, 45% of patients receiving current antiretroviral drugs. darunavir/r 600/100 mg twice daily achieved unde- Darunavir (TMC114) is a new protease inhibitor tectable viral load (HIV-1 RNA <50 copies/ml) (PI) that has been designed to have a high genetic compared with 12% of CPI patients. Furthermore, barrier to the development of resistance [2]. Studies viral suppression was sustained to week 48, with the have demonstrated that darunavir has activity against same proportion of darunavir/r patients achieving wild-type HIV-1 virus and a wide range of PI-resistant this undetectable level (compared with 11% of CPI viruses [2,3]. Co-administration of darunavir is with patients at this time point) [8]. These results were low-dose ritonavir (darunavir/r); the 600/100 mg twice corroborated by those from the larger POWER 3 daily dose has now been approved in many countries analysis, which was performed on data from two for treatment-experienced adult patients, such as those non-randomized, open-label trials that were with HIV-1 strains resistant to more than one PI [4]. conducted to provide additional efficacy and safety The efficacy and safety of darunavir/r in treatment- data on darunavir/r in treatment-experienced experienced patients have been demonstrated in the patients; 40% of POWER 3 patients achieved HIV-1

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RNA reductions to <50 copies/ml at week 24 [7]. In Figure 1. The chemical structure of darunavir ethanolate all three Phase IIb studies darunavir/r was generally safe and well tolerated [5–7]. This review summarizes the chemical and physical properties of darunavir, and discusses in detail the H O O pharmacokinetic data from studies of darunavir/r that O have been conducted as part of the extensive, ongoing H O O S clinical trial programme. Specifically, pharmaco- O N N H H kinetic studies conducted in vitro, in animals, in H H OH H3C HIV-negative healthy volunteers and HIV-infected NH 2 C H OH patients are described, along with those from patients CH 3 2 5 of different baseline subgroups, such as men and women, and patients with or without hepatitis B or C coinfection. In addition, given the need for HIV- infected patients to use other concomitant medications, it is important that any potential darunavir/r drug–drug interactions are identified and Absorption understood; thus, results from these studies are also Darunavir has an intermediate-to-high absorptive discussed here. permeability in Caco-2 monolayers, indicating that darunavir would exhibit sufficient membrane perme- Chemical and physical properties ability to obtain adequate intestinal absorption. The ratio of secretory/absorptive transport decreases with Darunavir (molecular weight 593.73) is a darunavir concentration, which is indicative of satura- peptidomimetic PI that contains a bis-tetrahydro- tion of an active transport process (for example, furanyl (bis-THF) moiety and sulfonamide isostere; P-glycoprotein [P-gp] or another efflux protein) the drug is administered as its ethanolate salt (Figure (unpublished data). Inhibition of transepithelial 1). Darunavir is structurally similar to another PI, permeation of P-gp substrates by darunavir could not amprenavir; however, whereas amprenavir has one be excluded, but findings from a study that assessed THF ring, darunavir has two THF rings that are fused the potential interaction between darunavir/r and to each other. This bis-THF moiety reverses the stere- digoxin support P-gp inhibition with darunavir/r in ochemistry at the bond that links it to the rest of the the clinic [12]. molecule and has a profound influence on the antiretroviral activity of darunavir; it allows additional Distribution interactions of darunavir with a key amino acid of the Darunavir is highly protein-bound. The binding of HIV protease, Asp29 [9,10]. As a result, darunavir darunavir to human plasma protein (albumin and α1- binds with the HIV protease >100 times more tightly acid glycoprotein [AAG]) was determined in vitro by than amprenavir does [11]. High-resolution X-ray equilibrium dialysis of plasma samples from healthy crystallography revealed the occurrence of at least six male volunteers using 14C-labelled darunavir. hydrogen bonds between darunavir and wild-type Darunavir was 95% bound to AAG and was also protease, with most of these interactions involving shown to be bound to albumin, but to a lesser extent main-chain atoms at the bottom of the protease than to AAG [13]. These findings are consistent with binding site [11]. Darunavir also fits closely within data obtained for almost all of the other available the substrate envelope; the protrusion of some atoms HIV-1 PIs [14]. outside this envelope allows darunavir to form the network of hydrogen bonds. Together, these proper- Metabolism ties could help explain why resistance to darunavir Results from an in vitro study of human liver micro- develops more slowly than to other available PIs, such somes indicate that darunavir primarily undergoes as nelfinavir, amprenavir and lopinavir [2]. oxidative metabolism [13] and is extensively metabolized by cytochrome P450 (CYP450) enzymes, mainly Pharmacokinetics CYP3A [4]. This is consistent with the metabolic pathways of other available PIs [15]. At least three oxidative Preclinical studies metabolites of darunavir have been identified in human The following section describes in detail the liver microsomes. All these metabolites showed activity pharmacokinetic studies of darunavir conducted against wild-type virus, but their activity was at least in vitro and in animals. 10-fold less than that of darunavir [4].

Darunavir: pharmacokinetics and drug interactions

Figure 2. Mean plasma concentration–time profiles of absence or presence of ritonavir (either 100 mg once darunavir over 24 h following administration of darunavir (oral daily, 100 mg twice daily or 200 mg once daily). The or intravenous) with or without co-administration of ritonavir use of ritonavir at the higher dose of 200 mg twice daily with darunavir 600 mg once daily did not result Darunavir 150 mg single dose (intravenous infusion) in any relevant increase in plasma concentrations of Darunavir 600 mg single dose (oral) darunavir compared with that of ritonavir 100 mg Darunavir 150 mg single dose (intravenous infusion) twice daily, indicating that maximum pharmaco- + ritonavir 100 mg twice daily (oral) kinetic enhancement was achieved with the lower Darunavir 600 mg single dose (oral) ritonavir dose [13]. Consequently, darunavir 600 mg + ritonavir 100 mg twice daily (oral) should only be administered when combined with 100 mg of ritonavir [4]. 6,000 Absorption and bioavailability: the effect of food 5,000 The presence of food in the stomach affects darunavir absorption and bioavailability. An open-label, 4,000 randomized, two-panel, crossover study determined the effect of various meal types, or fasting, on 3,000 darunavir bioavailability. When darunavir was given as a 400 mg single dose in the presence of low-dose 2,000 ritonavir (100 mg) to HIV-negative, healthy volunteers immediately after intake of a standard meal, the 1,000 plasma concentration of darunavir was increased by 30% compared with administration under fasted Darunavir plasma concentration, ng/ml 0 conditions (Figure 3) [17]. Furthermore, the plasma 0 4 8 12 16 20 24 concentration–time profile for darunavir was compa- Time, h rable for the different types of meals assessed: standard breakfast, high-fat breakfast, nutritional protein-rich drink or croissant with coffee. It is, there- Clinical studies fore, recommended that darunavir/r be given with food; however, there is no restriction on the type of Absorption and bioavailability: the effect of low-dose food consumed, as this does not affect the plasma ritonavir concentration–time profile for darunavir. These Darunavir is metabolized by and also inhibits results are consistent with those reported for several CYP3A. However, in combination with ritonavir, a other PIs where, compared with the fasted state, the more potent inhibitor of CYP3A, there is a marked AUC for nelfinavir, lopinavir and atazanavir in the increase in darunavir plasma concentrations. In a presence of food was increased by 200–300%, study of HIV-negative, healthy volunteers, absolute 48–97% and 35%, respectively [18]. bioavailability of darunavir (600 mg once daily) was increased to 82% in the presence of ritonavir (100 mg Distribution twice daily) compared with 37% when darunavir was The volume of distribution (Vd) was determined in a administered alone [16]. This pharmacokinetic trial conducted in eight HIV-negative healthy volun- enhancement caused by ritonavir suggests that first- teers; the mean Vd of darunavir alone was 88.1 l, while pass elimination of darunavir is almost completely it was increased to 130 l in the presence of ritonavir inhibited. When the effect of elimination was taken 100 mg twice daily [4].

into account, the overall increase in the AUClast (area under the plasma concentration–time curve) for Metabolism and elimination darunavir was 14-fold when taken with ritonavir In a darunavir mass balance study, healthy volunteers 100 mg twice daily versus administration alone received a single dose of darunavir (400 mg) radiola- (Figure 2). Darunavir/r 600/100 mg twice daily was belled with the isotope 14C and low-dose ritonavir absorbed following oral administration with a time to (100 mg). After 48 h the metabolism of [14C]darunavir

maximum darunavir plasma concentration (Tmax) of was found to be extensive when darunavir was admin- approximately 2.5 to 4 h [4]. In a second, dose-esca- istered alone, but was markedly reduced when lation study, 32 HIV-negative, healthy volunteers co-administered with ritonavir; the proportion of received darunavir (200 mg once daily, 300 mg twice unchanged drug eliminated was 8% (6.8% in faeces daily, 400 mg, 600 mg or 1,200 mg once daily) in the and 1.2% in urine) and 49% (41.2% in faeces and

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Figure 3. Mean plasma concentration–time profiles of Age darunavir after a single oral dose of darunavir (400 mg) with Population pharmacokinetic analyses showed that ritonavir (100 mg twice daily): effect of various meal types compared with fasting there was no marked difference in the AUC24h for darunavir between the different age categories of 18–40, 40–50 and >50 years in HIV-infected patients Standard breakfast (n=23) from POWER 1 and 2, suggesting no dose modifica- 6,000 Fasted conditions (n=12) tions are required in older patients; however, there High-fat breakfast (n=12) was a low number of patients aged >65 years in this 5,000 Nutritional protein-rich analysis [4]. In general, caution should be exercised drink (n=10) in the administration of darunavir/r to elderly 4,000 Croissant with coffee (n=11) patients, reflecting the greater frequency of reduced hepatic function and of concomitant disease or other 3,000 drug therapy. The pharmacokinetic profile of darunavir in combi- 2,000 nation with low-dose ritonavir has not been established in paediatric patients; this is currently 1,000 under evaluation [4].

Darunavir plasma concentration, ng/ml 0 Co-infection with hepatitis B or C virus 0 4 8 12 16 20 24 Analysis of 24-week data from the POWER 1 study in Time, h 31 HIV-infected patients indicated that hepatitis B and/or C virus coinfection status had no apparent

effect on the AUC24h for darunavir [4].

7.7% in urine) in the absence and presence of ritonavir, Hepatic impairment respectively [4,13]. Results at 168 h after administra- As darunavir is primarily metabolized and eliminated tion showed that [14C]darunavir or metabolites of by the liver, patients with hepatic impairment might [14C]darunavir were excreted mainly in the faeces be at risk of increased plasma concentrations of

(80%) and to a lesser extent in urine (14%) [4]. The t1/2 darunavir/r. The results of a multiple-dose study (terminal elimination half-life) of darunavir when demonstrated that patients with mild or moderate combined with ritonavir (1,200/100 mg once daily) in hepatic impairment have an AUC for darunavir a dose-ranging study of healthy volunteers was found similar to that obtained for patients without hepatic to be 15 h [4,13]. Following intravenous administra- impairment (unpublished data). Dose adjustments tion of darunavir (150 mg; single 1 h infusion) alone or are not necessary in individuals with mild or darunavir in the presence of low-dose ritonavir moderate liver impairment, and usual clinical moni- (100 mg twice daily) in HIV-negative, healthy volun- toring of these individuals receiving darunavir/r is teers, the mean systemic clearance was 32.8 l/h and considered adequate. This recommendation is consis- 5.9 l/h, respectively [16]. tent with recommendations for other PIs, as they are also metabolized by hepatic cytochrome CYP3A Effect of demographic characteristics on darunavir isoenzymes [18]. The effect of severe hepatic impair- pharmacokinetics ment on the pharmacokinetics of darunavir has not Gender been studied. Population pharmacokinetic analysis showed that HIV-infected female patients from the POWER 1 and Renal impairment

2 studies (n=68) had a slightly higher mean AUC24h for Moderate renal impairment is not expected to have a darunavir (16.8%) compared with that observed in major effect on plasma concentration–time profiles for males. However, this difference was not considered to darunavir, as results from a mass balance study indi- be clinically relevant [4]. cate that following darunavir/r administration only 7.7% of darunavir is recovered unchanged in urine Race [13]. A population pharmacokinetic analysis of 20

There was no difference in the AUC24h for darunavir HIV-infected patients with mild/moderate impaired between people of different ethnic origins (Caucasian, renal function (creatinine clearance 30–60 ml/min) Black, Hispanic, other) in a population pharmaco- showed that the AUC for darunavir was not signifi- kinetic analysis of HIV-infected patients from POWER cantly affected. There are no pharmacokinetic data 1 and 2 [4]. available in HIV-infected patients with severe renal

Darunavir: pharmacokinetics and drug interactions

impairment or end-stage renal disease. However, as In all the drug interaction studies to date, both the renal clearance of darunavir is limited (7.7% ritonavir and darunavir concentrations were excreted unchanged in urine), a decrease in total body measured and results are reported in each of the cited clearance is not expected in these patients. Given that publications; however, no formal cross-study darunavir and ritonavir are highly bound to plasma comparison of ritonavir concentrations have been proteins, it is unlikely they will be removed by made. It is worth noting that doses of ritonavir haemodialysis or peritoneal dialysis [4]. higher than 100 mg do not further increase darunavir concentrations [13] and, consequently, any increase Drug interaction studies in ritonavir concentrations due to the co-administered drug would not be expected to affect The treatment of HIV-infected individuals with highly darunavir/r concentrations. Thus, it is predicted that active antiretroviral therapy (HAART) requires long- any changes in darunavir concentrations represent a term administration of combinations of multiple direct effect of the co-administered drug on antiretroviral drugs [1]. In addition, these patients darunavir disposition. Doses lower than 100 mg frequently need to co-administer other medications, ritonavir have not been studied with darunavir and it such as those used to prevent or treat opportunistic therefore cannot be excluded that if the co-adminis- infections, those to treat other concomitant illnesses or tered drug decreases ritonavir it might also effect drugs to manage antiretroviral side effects. Given this darunavir pharmacokinetics. unavoidable multidrug therapy, there is a potential for complex and difficult-to-predict drug interactions, Drug interactions with antiretrovirals: PIs some of which may be clinically significant [19]. As Both darunavir and ritonavir are inhibitors of and many of the drugs used by HIV-infected individuals substrates for CYP3A [4] and, as all of the other have similar metabolic pathways, and also inhibit or currently available PIs act as substrates or inhibitors induce enzymes used in these pathways, knowledge of and/or inducers of the CYP3A isoenzymes [42], there drug interactions is essential. Although most is the potential that they will affect the plasma pharmacokinetic interactions pose challenging clinical concentrations of each other when used in combina- problems and therefore can be difficult to manage tion. In addition, PIs are substrates for, and [15], not all drug–drug interactions are undesirable: modulators of, P-gp and other transport proteins; the well-established pharmacokinetic enhancement therefore, further drug–drug interactions are possible effect of PIs by ritonavir illustrates how a drug–drug [43]. It is important to be able to predict drug inter- interaction can be beneficial. The potential for actions of darunavir/r with other PIs, as future drug–drug interactions with darunavir/r has been therapies could potentially include double ritonavir- investigated in numerous studies conducted in healthy enhanced PI regimens. However, data from recent volunteers and HIV-infected patients [20]. Results clinical trials have shown no benefit of double riton- from these studies are described in the sections below avir-enhanced over single ritonavir-enhanced PIs and and summarized in Table 1 [4,12,21–40]). in vitro studies have also shown varying types of Although many of the studies described below were interaction [44,45]. Several studies have examined conducted using lower doses of darunavir/r than darunavir/r drug interactions with PIs in healthy those currently used in clinical practice, there has volunteers and HIV-infected patients; those in the been extensive pharmacokinetic/pharmacodynamic former provide an insight into the possibility of inter- (PK/PD) analysis of darunavir/r at doses of 400/100 actions among HIV-infected individuals. mg once daily, 800/100 mg once daily, 400/100 mg twice daily and 600/100 mg twice daily in 468 Atazanavir POWER 1 and 2 treatment-experienced patients. The potential interaction between atazanavir/r

These studies found that darunavir AUC and C0h (300/100 mg once daily) and darunavir/r (trough concentration) values increased less than dose (400/100 mg twice daily) has been evaluated in HIV- proportionally [41]. The PK/PD studies supported the negative, healthy individuals [21]. The AUC for selection of darunavir/r 600/100 mg twice daily for darunavir was not affected when co-administered the treatment of HIV-1 infected treatment-experi- with atazanavir, and vice versa. Thus, dosage adjust- enced patients. Where a lower dose was used in an ments of either drug in patients receiving darunavir/r interaction study it is possible that the magnitude of and atazanavir are not considered necessary. In the interaction may be slightly different with the contrast, it might be necessary to make alterations to licensed dose, but currently there is no evidence to the drug dosage or timing of administration for other suggest any substantive difference and consequently ritonavir-enhanced PIs when used in combination we would predict similar results. with atazanavir.

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Table 1. Summary of drug interaction studies of darunavir with low-dose ritonavir (darunavir/r) Co-administered drug Dose/schedule Number of AUC, LSM (90% CI)* [reference] Co-administered drug Darunavir/r individuals Co-administered drug Darunavir Guidance

Protease inhibitors Atazanavir [21] 300 mg qd (+ritonavir 400/100 mg bid 13 No clinically relevant 100 mg qd in combination) 1.08 1.03 interaction (0.94–1.24) (0.94–1.12) Indinavir [22] 800 mg bid 400/100 mg bid 9 Indinavir dose 1.23 1.24 reduction from 800 to (1.06–1.42) (1.09–1.42) 600 mg bid in case of intolerance Lopinavir [23] 400 mg bid (+ritonavir 1,200/100 or 29 Combination not 100 mg bid) 600/100 mg bid 1.09 0.62 recommended (0.86–1.37) (0.53–0.73) Saquinavir [24] 1,000 mg bid (+ritonavir 400/100 mg bid 14 Combination not 100 mg bid in combination) 0.94 0.74 recommended (0.76–1.17) (0.63–0.86) NRTIs Tenofovir [4,25] 300 mg qd 300/100 mg bid 12 No clinically relevant 1.22 1.21 interaction anticipated (1.10–1.35) (0.95–1.54) but monitor renal function Didanosine [26] 400 mg qd 600/100 mg bid 17 No clinically relevant 0.91 1.01 interaction (0.75–1.10) (0.95–1.07) NNRTIs Efavirenz [27] 600 mg qd 300/100 mg bid 12 No clinically relevant 1.21 0.87 interaction anticipated (1.08–1.36) (0.75–1.01) but monitor for CNS toxicity Etravirine [29] 100 mg bid 600/100 mg bid 32 No clinically relevant 0.63 1.06 interaction anticipated (0.54–0.73) (1.00–1.13) Nevirapine [28] 200 mg bid 400/100 mg bid 8† No clinically relevant 1.27 1.24 interaction anticipated (1.12–1.44) (0.97–1.57) Fusion inhibitor Enfuvirtide [30] 90 mg (1 ml) bid 600/100 mg bid 292† ND No clinically relevant (subcutaneous injection) interaction Integrase inhibitor Elvitegravir [31] 125 mg qd (+ritonavir 600/100 mg bid 20 No clinically relevant 100 mg qd in combination) 111‡ 88.7‡ interaction (99.1–122) (82.3–95.6) HMG-CoA reductase inhibitors Atorvastatin [32] 40 mg qd alone and 10 mg 300/100 mg bid 15 Marked increase§ ND Atorvastatin starting qd in combination 0.85§ dose 10 mg qd (0.76–0.97) titrated to clinical response Pravastatin [33] 40 mg qd 600/100 mg bid 14 ND Start at lowest dose 1.81 and titrate to (1.23–2.66) clinical response Gastric pH modifiers Omeprazole [34] 20 mg qd 400/100 mg bid 16 ND No clinically relevant 1.04 interaction (0.96–1.13)

Darunavir: pharmacokinetics and drug interactions

Table 1. continued. Co-administered drug Dose/schedule Number of AUC, LSM (90% CI)* [reference] Co-administered drug Darunavir/r individuals Co-administered drug Darunavir Guidance

Ranitidine [34] 150 mg bid 400/100 mg bid 16 ND No clinically relevant 0.95 interaction (0.90–1.01) Narcotic analgesic R-methadone [35] 55–150 mg qd 600/100 mg bid 16 ND No clinically relevant 0.84¶ interaction (0.78–0.91) Oral contraceptives Ethinyl estradiol [36] 35 μg (with 1 mg 600/100 mg bid 11 ND Additional norethindrone) 0.56 contraception should (0.50–0.63) be used by women taking ethinyl estradiol/norethindrone Norethindrone [36] 1 mg (with 35 μg 600/100mg bid 11 ND Additional ethinyl estradiol) 0.86 contraception should (0.75–0.98) be used by women taking ethinyl estradiol/norethindrone PDE-5 inhibitors Sildenafil [37] 100 mg qd alone and 400/100 mg bid 16 Marked increase ND No more than sildenafil 25 mg qd in combination 0.97# 25 mg recommended (0.86–1.09) over 48 h Mood-disorder drugs Paroxetine [38] 20 mg qd 400/100 mg bid 16 If clinically indicated 0.61 1.02 may be co- (0.56–0.66) (0.95–1.10) administered but monitor paroxetine and titrate if necessary Sertraline [38] 50 mg qd 400/100 mg bid 13 If clinically indicated 0.51 0.98 may be co- (0.46–0.58) (0.84–1.14) administered but monitor sertraline and titrate if necessary Anti-infective and antifungal agents Clarithromycin [39] 500 mg bid 400/100 mg bid 17 Reduce clarithromycin 1.57 0.87 dose by 50% and 75% (1.35–1.84) (0.75–1.01) for patients with creatinine clearance 30–60 and <30 ml/min, respectively Ketoconazole [40] 200 mg bid 400/100 mg bid 15 Maximum ketoconazole 3.12 1.42 dose 200 mg qd and no (2.65–3.68) (1.23–1.65) dose adjustment for darunavir/r is Cardiac glycosides recommended Digoxin [12] 0.4 mg qd 600/100 mg bid 14 ND Prescribe lowest 1.35 possible digoxin dose; (1.00–1.82) titrate and monitor digoxin concentrations

*Based on least squares mean (LSM) ratio of area under the plasma concentration–time curve (AUC) values. †HIV-1-infected patients. ‡Determined by geometric mean ratio. §The mean AUC for atorvastatin at 40 mg alone was similar to that of 10 mg when combined with darunavir/r. ¶(R)-isomer. #The mean AUC for sildenafil at 100 mg alone was similar to that of 25 mg when combined with darunavir/r. bid, twice daily; CI, confidence interval; CNS, central nervous system; ND, not determined; NNRTI, non- nucleoside reverse transcriptase inhibitor; NRTI, nucleoside/tide reverse transcriptase inhibitor; PI, protease inhibitor; qd, once daily. , no change; , increase; , decrease.

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Indinavir Tipranavir The co-administration of indinavir (800 mg twice No formal study on the interaction of darunavir/r and daily) and darunavir/r (400/100 mg twice daily) was tipranavir has been conducted. However, as tipranavir investigated in HIV-negative healthy volunteers [22]. markedly affects the AUC for other PIs, possibly The mean AUC for darunavir and indinavir was through multiple mechanisms, it is likely to have an increased by 24% and 23%, respectively, when these unfavourable interaction with darunavir/r and use of drugs were combined. These increases are deemed not the combination is not recommended [47]. to be clinically significant, and both can be co-administered without dose adjustments. Dose reductions of Drug interactions with antiretrovirals: NRTIs indinavir from 800/100 mg twice daily to 600/100 mg Very few clinically significant drug–drug interactions twice daily may be warranted, however, if the known have been documented with nucleoside(tide) reverse indinavir side effect of gastrointestinal intolerance transcriptase inhibitors (NRTIs). However, occurs [46]. This result is consistent with those from co-administration of the NRTI tenofovir disoproxil studies of the combined use of indinavir and currently fumarate (an ester prodrug of tenofovir) with PIs has available ritonavir-enhanced PIs. resulted in increased concentrations of tenofovir [48–50]. As tenofovir is renally excreted and is not a Lopinavir substrate, inducer or inhibitor of any CYP enzyme, Lopinavir/r (400/100 mg twice daily) was administered the mechanism is likely to involve drug-transporter in combination with darunavir/r (1,200/100 mg or proteins [51]. The two-way pharmacokinetic interac- 600/100 mg twice daily) in a study in HIV-infected tion between darunavir/r (300/100 mg twice daily) patients [23]. Despite a twofold increase in darunavir and tenofovir disoproxil fumarate (300 mg once dose, from 600 mg to 1,200 mg twice daily, mean values daily) was investigated in HIV-negative, healthy

of AUC12h, Cmax (maximum plasma concentration), volunteers [25]. Co-administration of these drugs led

Ctrough (trough plasma concentration) and Cmin to a 21% and 22% increase in the mean AUC for (minimum plasma concentration) for darunavir were darunavir and tenofovir, respectively. These increases

considerably reduced (by ~40% for AUC12h compared are similar to those seen for tenofovir combined with with 600 mg twice daily) by co-administration of other PIs and no dose adjustment is needed. lopinavir/r 400/100 mg twice daily. In contrast, The combined use of darunavir/r (600/100 mg

lopinavir AUC12h, Cmin, Cmax and C0h were unaltered or twice daily) and didanosine (400 mg once daily) was slightly increased when lopinavir/r 400/100 mg twice investigated in a clinical trial of HIV-negative, daily was co-administered with darunavir/r healthy volunteers [26]. The mean AUC for 1,200/100 mg twice daily. Given the substantial reduc- darunavir was unchanged in the presence of didano- tion in pharmacokinetic parameters for darunavir, sine, while the mean AUC for didanosine was co-administration of darunavir/r and lopinavir/r is not decreased by 9%. This decrease for didanosine was recommended. The combined use of other ritonavir- not considered to be clinically relevant and no dose enhanced PIs and lopinavir/r requires close monitoring, adjustment for either drug is recommended when altering of drug dosage or timing of administration. they are co-administered. The use of didanosine with other ritonavir-enhanced PIs is permitted; however, Saquinavir close monitoring, altering of drug dosage or timing The potential interaction of saquinavir/r with of administration might be required. darunavir/r has been studied in healthy volunteers [24].

Although the mean AUC12h for saquinavir Drug interactions with antiretrovirals: NNRTIs (1,000/100 mg twice daily) was not affected by Efavirenz, nevirapine and etravirine are all non- concomitant darunavir/r use, the mean AUC for nucleoside reverse transcriptase inhibitors (NNRTIs) darunavir (darunavir/r 400/100 mg twice daily) was that are substrates for and inducers of CYP3A4 and,

reduced by 26% and the Cmin of darunavir was reduced consequently, combined use with darunavir/r could by 42% when co-administered in the presence of reduce darunavir concentrations. saquinavir/r. As reductions in plasma concentrations of darunavir in the presence of saquinavir/r were consid- Efavirenz ered to be of clinical relevance in treatment-experienced Darunavir/r (300/100 mg twice daily) and efavirenz patients, use of this combination is currently not recom- (600 mg once daily) were co-administered in a study mended. The use of saquinavir/r with other involving 12 HIV-negative, healthy volunteers [27]. ritonavir-enhanced PIs is permitted; however, close The mean AUC for efavirenz was increased by 21% in monitoring and alterations to the drug dosage or timing the presence of darunavir/r. Conversely, the AUC for of administration may be required. darunavir was decreased by 13% when given with

Darunavir: pharmacokinetics and drug interactions

efavirenz. These changes are unlikely to be of clinical administered with an antiretroviral regimen compared significance, however, until additional data are avail- with an antiretroviral drug alone [52], it is likely that able, combinations of darunavir/r and efavirenz should enfuvirtide will be combined with darunavir/r in the be used with caution. This result is consistent with treatment of HIV-infected highly treatment-experi- those from studies of the use of efavirenz co-adminis- enced patients. Enfuvirtide is not metabolized by tered with other currently available ritonavir-enhanced CYP450 enzymes, hence no drug–drug interaction PIs. The combination of efavirenz and darunavir/r is would be expected when it is co-administered with currently being evaluated further in patients who have darunavir/r or other agents that are metabolized by the efavirenz in their optimized background regimen in a CYP450 enzyme system. A possible pharmacokinetic Phase III clinical trial, TITAN. interaction was investigated by population pharmacokinetic analysis in 292 treatment-experienced, Etravirine (TMC125) HIV-infected patients from the POWER 3 analysis The pharmacokinetic interaction of the investigational [30]. The mean AUC for darunavir was unaffected NNRTI, etravirine (100 and 200 mg twice daily) and when darunavir/r (600/100 mg twice daily) was darunavir/r (600/100 mg twice daily) was evaluated in combined with enfuvirtide; therefore, no dose adjust- a study of 32 healthy volunteers [29]. With darunavir/r ment is needed. With the exception of tipranavir

co-administration, the mean AUC12h for etravirine (which is given with 200 mg of ritonavir and where given as 100 mg twice daily was decreased by 37%; monitoring, altering of drug dosage or timing of

Cmax and Cmin were decreased by 32% and 49%, respec- administration may be required), the same findings tively. For etravirine 200 mg twice daily were reported with the use of other ritonavir-enhanced

co-administered with darunavir/r, the mean AUC12h, PIs and enfuvirtide.

Cmax and Cmin of etravirine were 80%, 81% and 67% greater, respectively, than etravirine 100 mg given alone Drug interactions with antiretrovirals: integrase twice daily. Darunavir pharmacokinetics were unchanged inhibitors

except a 15% increase in mean AUC12h was observed The combined use of darunavir/r and the integrase when darunavir/r was given with etravirine 200 mg twice inhibitor elvitegravir/r was assessed in a study of 20 daily. The magnitude of this interaction is comparable to healthy volunteers who received elvitegravir/r (125/100 etravirine interactions with other ritonavir-enhanced PIs mg once daily) and darunavir/r (600/100 mg twice daily) observed in Phase IIb trials in HIV-1-infected patients. [31]. The mean AUC for darunavir was not affected Darunavir/r can be co-administered with etravirine when co-administered with elvitegravir/r, and vice versa. without dose adjustments. Thus, if clinically warranted, and when elvitegravir is licensed, dosage adjustments of either drug when Nevirapine combined in patients would be not considered necessary. The two-way pharmacokinetic interaction between darunavir/r (400/100 mg twice daily) and nevirapine Drug interactions with other drugs commonly used (200 mg twice daily) was investigated in HIV-infected in HIV-infected patients patients who were on stable nevirapine therapy and Patients with HIV receiving darunavir/r are likely to taking ≥2 NRTIs [28]. Co-administration of nevirapine receive drugs for other co-morbidities, especially given with darunavir/r caused a 24% increase in the mean their vulnerability to opportunistic infections, thus it is AUC for darunavir compared with historical data for important to investigate how such drugs interact with darunavir/r alone, and the mean AUC for nevirapine darunavir/r and to determine if therapeutic drug levels was increased by 27% when combined with are compromised. darunavir/r. These mean AUC changes for nevirapine and darunavir are unlikely to be of clinical significance, HMG-CoA reductase inhibitors and darunavir/r and nevirapine may be co-adminis- HMG-CoA reductase inhibitors are drugs used to tered with no dose adjustment. This finding is contrary lower cholesterol. A study of the interaction between to those from other studies on the use of ritonavir- darunavir/r (300/100 mg twice daily) and the HMG- enhanced PIs with nevirapine, where altering the drug CoA reductase inhibitor atorvastatin (10 mg or 40 mg dosage or timing of administration may be required. once daily) in healthy volunteers indicated that low- dose atorvastatin plus darunavir/r gives an atorvastatin Drug interactions with antiretrovirals: entry inhibitors AUC that is 15% lower than atorvastatin 40 mg once Enfuvirtide is an antiretroviral drug from the fourth daily alone [32]. As atorvastatin metabolism is and newest licensed class of drugs available for HIV CYP3A4-mediated, this result is expected and is treatment, the entry inhibitors. Given the additional presumably driven by the ritonavir component of efficacy benefits observed when enfuvirtide is co- darunavir/r. When these drugs are combined, the

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recommended starting dose of atorvastatin is 10 mg no prior dose adjustment of methadone is required once daily, with a gradual dose increase tailored to when methadone and darunavir/r are combined; response [32]. This observation and recommendation is however, patients should be monitored for opiate absti- consistent with those from studies of other ritonavir- nence syndrome [54]. The observations and enhanced PIs with atorvastatin. recommendations in this study are consistent with those Co-administration of pravastatin in HIV-negative, for use of methadone with other ritonavir-enhanced PIs. healthy volunteers as 40 mg once daily with darunavir/r (600/100 mg twice daily) caused the mean AUC for Oral contraceptives/oestrogens pravastatin to be increased by 81% [33]. Furthermore, The possibility of contraceptive failure is a general there was a high degree of variability between individ- concern for HIV-infected women being treated with uals. The mechanism of this interaction requires further HAART who are also receiving oestrogen and progestin investigation; pravastatin is not significantly metabo- (a synthetic progestogen). The effect of darunavir/r lized by CYP enzymes and therefore a likely mechanism (600/100 mg twice daily) on the pharmacokinetics of the is an interaction with a transporter. On the basis of combined oral contraceptive, ethinyl estradiol/norethin- these data, initiation with the lowest dose of pravastatin drone (0.035/1 mg once daily) was investigated in 19 is recommended when co-administered with HIV-negative healthy volunteers [36]. The mean AUC for darunavir/r. With the exception of saquinavir/r, drug ethinyl estradiol was decreased by 44% when combined interaction studies with pravastatin and other ritonavir- with darunavir/r compared with ethinyl estradiol alone. enhanced PIs have revealed that no clinically significant Thus, it is recommended that alternative or additional interaction would be expected. The darunavir/r–pravas- contraceptive measures are used when darunavir/r and tatin interaction study is currently being repeated and the above oral contraceptives are combined. Ethinyl includes a pharmacogenetic component. In addition, a estradiol is metabolized by CYP3A and glucuronyl trans- darunavir/r–rosuvastatin interaction study is also being ferase; hence, this finding is consistent with other drugs performed. The results of these two studies should be (such as PIs) that affect these enzymes and lead to loss of available in the near future. ethinyl estradiol effectiveness [55,56].

Gastric pH modifiers Phosphodiesterase type-5 inhibitors The pharmacokinetic interaction between darunavir/r Sildenafil is a phosphodiesterase type-5 (PDE-5) (400/100 mg twice daily) and the gastric pH modifiers inhibitor used for the treatment of erectile dysfunction. omeprazole (20 mg once daily) or ranitidine (150 mg It is converted to its primary metabolite, N-desmethyl- twice daily) was investigated in HIV-negative, healthy sildenafil, primarily by the isoenzyme CYP3A4. As volunteers [34]. There was no effect on mean darunavir ritonavir is a potent inhibitor of this isoenzyme, AUC when co-administered with either omeprazole or combined use of darunavir/r and sildenafil may reduce ranitidine, and therefore pre-emptive dose adjustment of the metabolism of sildenafil and could cause an increase either agent is not required. Knowledge of the interaction in concentration. Indeed, when these three drugs were between PIs and gastric pH modifiers is important as, at taken concomitantly by 16 HIV-negative healthy male least for atazanavir/r, co-administration with proton volunteers, the mean AUC for sildenafil was increased pump inhibitors is not recommended and with H2 by fourfold compared with sildenafil alone [37]. Thus, receptor antagonists timing of administration is crucial. when co-administered with darunavir/r, the recommended dose of sildenafil is 25 mg over a 48-h period Narcotic analgesics (instead of 100 mg). These findings are consistent with The oral synthetic opioid methadone is given as a racemic those found with other PIs [57] and can be used to mixture of (R)- and (S)-isomers, although only the former provide dosing recommendations for other PDE-5 is the active isomer. As ritonavir is a known inducer of the inhibitors that are also CYP3A substrates (vardenafil metabolism of methadone, a decrease in the AUC for [2.5 mg once daily in 72 h] and tadalafil [10 mg once methadone is expected when methadone and darunavir/r daily in 72 h] when co-administered with darunavir/r). are combined [53]. The effect of darunavir/r (600/100 mg twice daily) on the pharmacokinetics of methadone was Mood-disorder drugs investigated in 16 HIV-negative opioid-dependent volun- Co-administration of the selective serotonin re-uptake teers, receiving once daily methadone maintenance inhibitors (SSRIs) or other mood-disorder drugs with therapy at a stable individualized dose of 55–200 mg ritonavir is known to affect plasma concentrations of [35]. The mean AUC for (R)-methadone was decreased the former [58]. The two-way pharmacokinetic interac- by 16% when combined with darunavir/r, as tion between darunavir/r (400/100 mg twice daily) and compared with (R)-methadone alone. No methadone two SSRIs, sertraline (50 mg once daily) and paroxe- dose adjustment was required in this study. Therefore, tine (20 mg once daily), was therefore investigated in

Darunavir: pharmacokinetics and drug interactions

HIV-negative healthy volunteers [38]. The mean AUC glycoside digoxin (0.4 mg once daily) was investigated for sertraline and paroxetine was reduced by 49% and in HIV-negative healthy volunteers [12]. When these 39%, respectively, when co-administered in the pres- two drugs were combined the mean AUC for digoxin ence of darunavir/r, without affecting the AUC for was increased by 77%, with substantial interindividual darunavir. If clinically indicated, sertraline or paroxe- variability. As a consequence of this interaction, it is tine can be co-administered with darunavir/r. Although recommended that the lowest possible dose of digoxin previous studies failed to show a correlation between should initially be used, with careful titration of dose SSRI concentrations and mood-disorder response and monitoring of digoxin concentrations. [59,60], clinical monitoring and, if needed, dose titration of the SSRI is recommended. These findings are Other commonly prescribed medications similar to those found for fosamprenavir/r. As described above, darunavir and ritonavir are both inhibitors of the CYP3A subfamily. Therefore, co- Anti-infectives and antifungals administration of darunavir/r with drugs metabolized Clarithromycin and ketoconazole are frequently primarily by CYP3A may increase plasma concentra- prescribed for prophylaxis and the treatment of bacte- tions of such drugs, thus increasing and/or prolonging rial and fungal infections, respectively, which are their therapeutic effect and adverse events. common opportunistic infections in HIV-infected Consequently, drugs highly dependent on CYP3A for patients. Both drugs inhibit CYP3A4 and, therefore, clearance are contraindicated for use with darunavir/r; are associated with a number of drug interactions. these include the antihistamines astemizole and terfe- A study of the interaction between darunavir/r nadine, the ergot derivatives dihydroergotamine, (400/100 mg twice daily) and clarithromycin (500 mg ergonavine, ergotamine and methylergonovine, certain twice daily) in HIV-negative healthy volunteers indi- gastrointestinal motility agents, for example, cisapride, cates that there is a 57% increase in the AUC for certain neuroleptics, pimozide, and the sedative/ clarithromycin [39]. Conversely, the AUC for hypnotics midazolam and triazolam [4]. darunavir was decreased by 13% when given with clar- As darunavir and ritonavir are both metabolized by ithromycin. Plasma concentrations of the active CYP3A, co-administration of darunavir/r with drugs metabolite, 14-hydroxy-clarithromycin, were reduced that induce CYP3A could increase clearance of to undetectable levels when clarithromycin was darunavir and ritonavir, and decrease their plasma combined with darunavir/r, probably due to the inhibi- concentrations and therapeutic effect. Therefore, tion of CYP3A by darunavir/r. No dose adjustments several drugs should not be co-administered with are necessary for patients with normal renal function; darunavir/r: the anticonvulsants carbamazepine, however, patients with renal impairment should have phenobarbitone and phenytoin; rifampin and St. John’s their dose adjusted to that recommended for patients Wort. In addition, we consider that systemic dexam- taking clarithromycin alone [61]. The dose of clar- ethasone should be started at the lowest possible dose, ithromycin should be reduced by 50% for patients with as it induces CYP3A and can thereby potentially creatinine clearance of 30–60 ml/min, and by 75% for decrease darunavir plasma concentrations [4]. patients with creatinine clearance of <30 ml/min [61]. This finding is generally similar to those in studies of Conclusions other ritonavir-enhanced PIs and clarithromycin. When ketoconazole (200 mg twice daily) and Darunavir is a new PI that represents a substantial darunavir/r (400/100 mg twice daily) were co-adminis- advancement in the treatment of treatment-experienced tered in HIV-negative healthy volunteers, the mean AUC HIV-infected patients. The pharmacokinetics of for ketoconazole was increased by 212% compared with darunavir/r have been extensively studied in numerous administration of ketoconazole alone; the mean AUC for Phase I studies as part of the clinical development darunavir was increased by 42% versus darunavir/r programme of darunavir. In addition, the potential for alone [40]. The increase in darunavir AUC was not interactions of darunavir/r with other drugs are well considered to be clinically relevant; nonetheless, given characterized and results from the studies outlined in the changes in the AUC for ketoconazole, the maximum this article can be used as guidance for the use of daily dose of ketoconazole should be 200 mg when these darunavir/r with other agents. drugs are combined. This recommendation is similar to that for other ritonavir-enhanced PIs and ketoconazole. Acknowledgements

Cardiac glycosides The authors wish to thank Catherine M Bragg of The two-way pharmacokinetic interaction between Gardiner-Caldwell Communications for editorial darunavir/r (600/100 mg twice daily) and the cardiac support and Tibotec for funding support.

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Disclosure statement 13. Sekar V, Spinosa-Guzman S, Lefebvre E, Hoetelmans R. Clinical pharmacology of TMC114 – a new HIV protease inhibitor. The 16th International AIDS Conference. Vanitha Sekar and Richard Hoetelmans are employees 13–18 August 2006, Toronto, Canada. Abstract TUPE0083. of Tibotec. David Back is on the advisory boards for 14. Schon A, del Mar Ingaramo M, Freire E. The binding of Bristol Myers Squibb, Boehringer Ingelheim, Tibotec, HIV-1 protease inhibitors to human serum proteins. Pfizer, GlaxoSmithKline, and Delphic Diagnostics Ltd. Biophys Chem 2003; 105:221–230. He is also on the speakers bureau for Abbott 15. Winston A, Boffito M. The management of HIV-1 protease inhibitor pharmacokinetic interactions. Laboratories, Bristol Myers Squibb, Boehringer J Antimicrob Chemother 2005; 56:1–5. Ingelheim, Tibotec, Gilead and GlaxoSmithKline. 16. Sekar V, Guzman S, Stevens T, et al. Absolute Unrestricted educational grants have been provided by bioavailability of TMC114, administered in the absence and presence of low-dose ritonavir. The 7th International Abbott Laboratories, Bristol Myers Squibb, Boehringer Workshop on Clinical Pharmacology of HIV Therapy. Ingelheim, GlaxoSmithKline, Roche, Tibotec, Gilead, 20–22 April 2006, Lisbon, Portugal. Abstract P86. Merck Sharp & Dohme and Pfizer. 17. Sekar V, Kestens D, Spinosa-Guzman S, et al. The effect of different meal types on the pharmacokinetics of darunavir (TMC114)/ritonavir in HIV-negative healthy References volunteers. J Clin Pharmacol 2007; 47:479–484. 18. Boffito M, Acosta E, Burger D, et al. Current status and 1. US Department of Health and Human Services (DHHS). future prospects of therapeutic drug monitoring and Guidelines for the Use of Antiretroviral Agents in HIV-1- applied clinical pharmacology in antiretroviral therapy. Infected Adults and Adolescents. October 2006. [Updated Antivir Ther 2005; 10:375–392. Dec 2006; accessed 19 Jan 2007]. Available from: http://aidsinfo.nih.gov/ContentFiles/ 19. Furler MD, Einarson TR, Walmsley S, Millson M, AdultandAdolescentGL.pdf. Bendayan R. Polypharmacy in HIV: impact of data source and gender on reported drug utilization. AIDS Patient 2. De Meyer S, Azijn H, Surleraux D, et al. TMC114, a novel Care STDS 2004; 18:568–586. human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including 20. Back D, Sekar V, Lefebvre E, et al. Use of darunavir a broad range of clinical isolates. Antimicrob Agents (TMC114) in combination with other drugs: guidance Chemother 2005; 49:2314–2321. from pharmacokinetic studies. 8th International Congress on Drug Therapy in HIV Infection. 12–16 November 3. Koh Y, Nakata H, Maeda K, et al. Novel bis- 2006, Glasgow, UK. Abstract PL5.1. tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI) UIC-94017 (TMC114) with potent activity 21. Sekar VJ, Lefebvre E, De MT, et al. Pharmacokinetics of against multi-PI-resistant human immunodeficiency virus darunavir (TMC114) and atazanavir during in vitro. Antimicrob Agents Chemother 2003; coadministration in HIV-negative, healthy volunteers. 47:3123–3129. Drugs R D 2007; 8:241–248. 4. Tibotec Inc. PREZISTA™ (darunavir) Prescribing 22. Sekar V, Lefebvre E, De Marez T, et al. Pharmacokinetic Information. June 2006. Available from: interaction between the HIV protease inhibitors TMC114 http://www.tibotectherapeutics.com/PREZISTA_pi.pdf. and indinavir in the presence of low-dose ritonavir. The International Symposium on HIV and Emerging 5. Haubrich RH, Berger D, Chiliade P, et al. Week 24 efficacy Infectious Diseases. June 21–23 2006, Toulon, France. and safety of TMC114/ritonavir in treatment-experienced Abstract PP4.15. HIV patients. AIDS 2007; 21:F11–F18. 23. Sekar V, Lefebvre E, Spinosa-Guzman S, et al. 6. Katlama C, Esposito R, Gatell JM, et al. Efficacy and safety Pharmacokinetic interaction between the protease of TMC114/ritonavir in treatment-experienced HIV inhibitors TMC114 and lopinavir/ritonavir. 46th patients: 24-week results of POWER 1. AIDS 2007; Interscience Conference on Antimicrobial Agents and 21:395–402. Chemotherapy. 27–30 September 2006, San Francisco, 7. Molina J, Cohen C, Katlama C, et al. Safety and efficacy of CA, USA. Abstract A-0367. darunavir (TMC114) with low-dose ritonavir in treatment- 24. Sekar V, Lefebvre E, Marien K, et al. Pharmacokinetic experienced patients: 24-week results of POWER 3. interaction between the HIV protease inhibitors TMC114 J Acquir Immune Defic Syndr 2007; 46:24–31. and saquinavir, in the presence of low-dose ritonavir. 44th 8. Clotet B, Bellos N, Molina JM, et al. Efficacy and safety of Annual Meeting of the Infectious Diseases Society of darunavir-ritonavir at week 48 in treatment-experienced America. 12–15 October 2006, Toronto, Ontario, patients with HIV-1 infection in POWER 1 and 2: a pooled Canada. Abstract 959. subgroup analysis of data from two randomized trials. 25. Hoetelmans R, Marien K, De Pauw M, et al. Lancet 2007; 369:1169–1178. Pharmacokinetic interaction between TMC114/ritonavir 9. Surleraux DL, Tahri A, Verschueren WG, et al. Discovery and tenofovir disoproxil fumarate in healthy volunteers. and selection of TMC114, a next generation HIV-1 protease Br J Clin Pharmacol 2007; 64:665–661. inhibitor. J Med Chem 2005; 48:1813–1822. 26. Sekar VJ, Spinosa-Guzman S, De Paepe E, et al. 10. Tie Y, Boross PI, Wang YF, et al. High resolution crystal Pharmacokinetic interaction trial between darunavir in structures of HIV-1 protease with a potent non-peptide combination with low-dose ritonavir and didanosine. 4th inhibitor (UIC-94017) active against multi-drug-resistant IAS Confernce on HIV Pathogenesis, Treatment and clinical strains. J Mol Biol 2004; 338:341–352. Prevention. Sydney, Australia. 22–25 July 2007. Poster WEPEB012. 11. King NM, Prabu-Jeyabalan M, Nalivaika EA, et al. Structural and thermodynamic basis for the binding of 27. Sekar V, De Pauw M, Marien K, et al. Pharmacokinetic TMC114, a next-generation human immunodeficiency virus interaction between TMC114/r and efavirenz in healthy type 1 protease inhibitor. J Virol 2004; 78:12012–12021. volunteers. Antivir Ther 2007; 12:509–514. 12. Sekar V, El Malt M, De Paepe E, et al. Effect of the HIV 28. Sekar V, Lefebvre E, Marien K, et al. Pharmacokinetic protease inhibitor darunavir (TMC114), coadministered interaction between the antiretroviral agents TMC114 with low-dose ritonavir, on the pharmacokinetics of digoxin and nevirapine, in the presence of low-dose ritonavir. 44th in healthy volunteers. The Annual Meeting of the American Annual Meeting of the Infectious Diseases Society of Society for Clinical Pharmacology and Therapeutics. March America. 12–15 October 2006, Toronto, Ontario, 21–24 2007, Anaheim, CA, USA. Abstract PII-104. Canada. Poster 956.

Darunavir: pharmacokinetics and drug interactions

29. Schöller-Gyüre M, Kakuda T, Sekar V, et al. 43. Huang L, Wring SA, Woolley JL, et al. Induction of Pharmacokinetics of darunavir/ritonavir (DRV/r) and P`glycoprotein and cytochrome P450 3A by HIV protease TMC125 alone and co-administered in HIV-negative inhibitors. Drug Metab Dispos 2001; 29:754–760. volunteers. Antivir Ther 2007; 12:789–796. 44. Molla A, Mo H, Vasavanonda S, et al. In vitro antiviral 30. Sekar V, De Paepe E, Vangeneugden T, et al. Absence of an interaction of lopinavir with other protease inhibitors. interaction between the potent HIV protease inhibitor Antimicrob Agents Chemother 2002; 46:2249–2253. TMC114 and the fusion inhibitor enfuvirtide in the POWER 3 analysis. 7th International Workshop on Clinical 45. Boffito M, Moyle GJ. Pharmacokinetic considerations for Pharmacology of HIV Therapy. 20–22 April 2006, Lisbon, combining 2 protease inhibitors. The AIDS Reader 2004; Portugal. Abstract P54. 14:110–116. 46. Merck and Co.Inc. CRIXIVAN® (indinavir sulfate) 31. Mathias A, Shen G, Enejosa J, et al. Lack of pharmacokinetic Capsules Prescribing Information. 2006; Available from: interaction between ritonavir-boosted GS-9137 (elvitegravir) http://www.crixivan.com/crixivan/shared/documents/ppi.p and Darunavir/r. 4th IAS Confernce on HIV Pathogenesis, df. Issued April 2006. Treatment and Prevention. 22–25 July 2007, Sydney, Australia. Abstract TUPDB03. 47. Back DJ. Drug–drug interactions that matter. Topics in HIV medicine 2006; 14:88–92. 32. Hoetelmans R, Lasure A, Koester A, et al. The effect on TMC114, a potent next-generation HIV protease inhibitor, 48. Kruse G, Esser S, Stocker H, et al. The steady-state with low-dose ritonavir on atorvastatin pharmacokinetics. pharmacokinetics of nelfinavir in combination with 44th Interscience Conference on Antimicrobial Agents and tenofovir in HIV-infected patients. Antivir Ther 2005; Chemotherapy. October 30–November 2, 2004, Washington 10:349–355. DC, USA. Poster H-865. 49. Piketty C, Gerard L, Chazallon C, et al. Salvage therapy 33. Sekar VJ, Spinosa-Guzman S, Marien K, et al. with atazanavir/ritonavir combined to tenofovir in HIV- Pharmacokinetic drug–drug interaction between the new HIV infected patients with multiple treatment failures: protease inhibitor darunavir (TMC114) and the lipid- randomized ANRS 107 trial. Antivir Ther 2006; lowering agent pravastatin. 8th International Workshop on 11:213–221. Clinical Pharmacology of HIV Therapy. 16–18 April, 2007, 50. Kearney BP, Mathias A, Mittan A, et al. Pharmacokinetics Budapest, Hungary. Abstract 54. and safety of tenofovir disoproxil fumarate on 34. Sekar VJ, Lefebvre E, De PE, et al. Pharmacokinetic coadministration with lopinavir/ritonavir. J Acquir interaction between TMC114/r and omeprazole or ranitidine Immune Defic Syndr 2006; 43:278–283. in HIV-negative healthy volunteers. Antimicrob Agents Chemother 2007; 51:958–961. 51. Ray AS. Role of intestinal absorption in increased tenofovir exposure when tenofovir disoproxil fumarate is 35. Sekar V, El Malt M, De Paepe E, et al. Pharmacokinetic co-administered with atazanavir or lopinavir/ritonavir. 7th interaction between darunavir (TMC114), a new protease International Workshop on Clinical Pharmacology of inhibitor, and methadone. 8th International Congress on HIV Therapy. 20-22 April 2006, Lisbon, Portugal. Drug Therapy in HIV Infection. 12–16 November 2006, Abstract 49. Glasgow, UK. Abstract P294. 52. Trottier B, Walmsley S, Reynes J, et al. Safety of 36. Sekar V, Lefebvre E, Spinosa-Guzman S, et al. enfuvirtide in combination with an optimized background Pharmacokinetic interaction between ethinyl estradiol, of antiretrovirals in treatment-experienced HIV-1-infected norethindrone and TMC114, a new protease inhibitor. 46th adults over 48 weeks. J Acquir Immune Defic Syndr Interscience Conference on Antimicrobial Agents and 2005; 40:413–421. Chemotherapy. September 27–30, 2006, San Francisco, CA, USA. Abstract A-0368. 53. McCance-Katz EF, Rainey PM, Friedland G, Jatlow P. The protease inhibitor lopinavir-ritonavir may produce opiate 37. Sekar V, Lefebvre E, De Marez T, et al. Pharmacokinetic withdrawal in methadone-maintained patients. Clin Infect interaction between TMC114, a new protease inhibitor and Dis 2003; 37:476–482. sildenafil. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 27–30, 2006, San 54. Antoniou T, Tseng AL. Interactions between recreational Francisco, CA, USA. Abstract A-0369. drugs and antiretroviral agents. Ann Pharmacother 2002; 36:1598–1613. 38. Sekar V, De Paepe E, De Marez T, et al. Pharmacokinetic interaction between darunavir (TMC114), a new protease 55. Boffito M, Maitland D, Pozniak A. Practical perspectives inhibitor, and the selective serotonin reuptake inhibitors on the use of tipranavir in combination with other (SSRIs), paroxetine and sertraline. 8th International Congress medications: lessons learned from pharmacokinetic on Drug Therapy in HIV Infection. 12–16 November 2006, studies. J Clin Pharmacol 2006; 46:130–139. Glasgow, UK. Abstract P295. 56. Roy P, Jakate AS, Patel A, et al. Effect of multiple-dose 39. Sekar VJ, Guzman S, De Pauw M, et al. The pharmacokinetic dexloxiglumide on the pharmacokinetics of oral interaction between clarithromycin and TMC114/ritonavir in contraceptives in healthy women. J Clin Pharmacol 2005; healthy subjects. The 2006 Annual Meeting of the American 45:329–336. Society for Clinical Pharmacology and Therapeutics. March 57. Highleyman L. Protease inhibitors and sildenafil (Viagra) 8–11 2006, Baltimore, MD, USA. Abstract PI-61. should not be combined. BETA 1999; 12:3 40. Sekar V, Lefebvre E, De Pauw M, Vangeneugden T, 58. Krikorian SA, Rudorf DC. Drug–drug interactions and Hoetelmans R. Pharmacokinetic interaction between HIV therapy: what should pharmacists know? J Pharm TMC114 and ketoconazole, in the absence and presence of Practice 2005; 18:278–294. low-dose ritonavir. 44th Annual Meeting of the Infectious Diseases Society of America. 12–15 October 2006, Toronto, 59. Tasker TC, Kaye CM, Zussman BD, Link CG. Paroxetine Ontario, Canada. Abstract P960. plasma levels: lack of correlation with efficacy or adverse events. Acta Psychiatr Scand Suppl 1989; 350:152–155. 41. Sekar V, De Meyer S, Vangeneugden T, et al. Pharmacokinetic/pharmacodynamic (PK/PD) analyses of 60. Preskorn SH, Harvey A. Biochemical and clinical dose- TMC114 in the POWER 1 and POWER 2 trials in response curves with sertraline. Clin Pharmacol Ther treatment-experienced HIV-infected patients. 13th Conference 1996; 59:180. on Retroviruses and Opportunistic Infections. February 5–8 61. Abbot Laboratories. Biaxin®XL (clarithromycin) Patient 2006, Denver, CO, USA. Abstract J-121. Information [cited 6 February 2007]. Available from: 42. Malaty LI, Kuper JJ. Drug interactions of HIV protease http://www.rxabbott.com/pdf/biapi.PDF. Revised August inhibitors. Drug Saf 1999; 20:147–169. 2006.

Accepted for publication 13 September 2007

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