Review Article A new ray of hope for uncomplicated falciparum malaria in India - A critical review

Krishna K*, Panda B K**, Dua P***

Background and Introduction the implementation of these policies has lagged behind due to factors such as high cost.4 The cost of other anti- ccording to WHO report 2011, 4.3 million malaria malarial combination kits like and lumefan- cases were reported in the year 2010, of which 2.4 trine is approx. 200 INR, artesunate and is Amillion were parasitologically confirmed. Three around 500 INR, artesunate and sulphadoxine is approx. countries accounted for 94% of the confirmed cases: India 220 INR, whereas, arterolane maleate and (66%), Myanmar (18%) and Indonesia (10%) in the South 1 phosphate combination kit cost around 130 INR which is East Asia region. Malaria is a major public health prob- comparatively less than the other combination kits. ACT lem in India, accounting for sizeable morbidity, mortality is generally priced almost 10 to 20 times higher than con- and economic loss. In the past, was effective ventional therapies. has been conventionally for treating nearly all cases of malaria. In recent stud- derived from a plant source and this makes it expensive. ies, chloroquine-resistant P. falciparum malaria has been are used in combination with different part- observed with increasing frequency across the country. ner drugs, however, because they are plant derivatives, The continued treatment of such cases with chloroquine there is potential for mismatch in demand and supply. is probably one of the factors responsible for increased 2 Therefore, there was an urgent need for development of proportion of P. falciparum relative to P. vivax. novel synthetic anti-malarial drugs with similar anti-ma- Artemisinin-based combination treatments (ACTs) larial activity.5,6 are now generally accepted as the best treatment for un- 3 Arterolane maleate is a new, fully synthetic 1,2,4-tri- complicated falciparum malaria. Since the publication oxolane with a peroxidic pharmacophore. It is a rapidly of the first edition of the guidelines in 2006, most of the acting oral anti-malarial drug, which has been launched countries where P. falciparum is endemic have progres- as a maleate salt with piperaquine as per WHO guide- sively updated treatment policies from the failing chlo- lines of Malaria treatment.7 Various in-vitro studies have roquine (CQ) and sulphadoxine- (SP) to proven its potency over chloroquine. Even, in-vivo stud- the recommended ACTs; this is the best current treatment ies against plasmodium have been shown to be effective.8 for uncomplicated falciparum malaria. Unfortunately, Pharmacokinetic (PK) studies indicate that arterolane is

*M.D, DNB, Professor, Department of Medicine, Bharati Vidyapeeth Deemed University Medical College and Hospital, Pune, Maharashtra 411043 **M.Pharm (Clinical Pharmacy & Pharmacy Practice), Assistant Professor, Pharm D Programme, Bharati Vidyapeeth Deemed University, Poona College of Pharmacy, Pune, Maharashtra 411043 ***Post Baccalaureate student, PharmD Programme, Bharati Vidyapeeth Deemed University, Poona College of Pharmacy, Pune, Maharashtra 411043 Correspondence to: Kavita Krishna, Bungalow no 23. Sopan Baug Coop Hsg Society, Pune 411001, Maharashtra, India Ph. no.: +91- 942-201-2160 Email id: [email protected]

490 The Indian Practitioner q Vol.67 No.8. August 2014 Review Article highly protein bound and has a high clearance (CL) with a large volume of distribution (Vd) in experimental animals. The elimi- nation half-life (t1/2) varies from 1 to 3 hours across the species. The bioavailability of the drug was found to be less at lower doses as compared to higher doses. The compound was well tolerated during rising single and multiple dose studies in healthy subjects without clinically significant side effects. Food marginally in- creased the systemic availability of arterolane: however, gender and age have no apparent effect on it.9 The arterolane maleate and piperaquine phosphate combina- tion was launched on 25th April 2012 - World Malaria Day. This critical review was un- dertaken to reveal the clinical ef- Fig. 1 Search strategy adopted for the review ficacy of this drug for uncomplicated falciparum malaria by analysing the various study reports available in the scientific database. Results Material and Methods Literature search Search strategy: Related studies were searched in Only, two randomised controlled trials (RCTs) having PubMed (updated October 2012) and Cochrane, by one follow-up data were included. There was no disagree- of the investigator by using the term ‘Arterolane’ OR ment between the reviewers regarding inclusion of trials. ‘Arterolane Maleate’ AND ‘Uncomplicated Malaria’ by Both the trials were multi-centric and randomised, out of initiating limits to only randomized controlled trials. which one trial was a Phase II double-blinded trial. Fig. This search strategy was developed according to Biondi- 1 briefly mentions the search strategy through the data- Zoccai.10 The language restriction was enforced to English base. and the search strategy was set to an end in the month of October, 2012. Study characteristics and outcome assessment Inclusion Criteria: Study design criteria for in- The characteristics and outcome measures of the two clusion in this review were: Case Reports, Clinical published RCTs are shown in Table 1 and Table 2 respec- Trials, Comparative Studies, Controlled Clinical Trials, tively. Out of the two trials, only one was double-blind- ed.12 The other was a comparative clinical trial study but Evaluation Studies, Multicenter Studies, and Randomized 12 Controlled Trials. was open labeled. The criteria for the population se- lection was almost same as shown in Table 1 where the Data Extraction and Analysis: All titles and abstracts study group was limited to P. falciparum mono- were screened independently by the reviewers and irrel- with plasma density ranging from 1000 to 100,000 asexual evant studies were discarded. The abstract and text of the parasites/µL of blood. The follow-up of the patients in the remaining studies were assessed to determine if the inclu- trial was restricted to 28 days. sion criteria were met. The included studies were assessed for trial characteristics and outcome, by the reviewers, The efficacy was measured in terms of parasite clear- ance (PC , PC ), Polymerase chain reaction-adequate without blinding to author or source. Any discrepancies 50 90 in outcome assessment were resolved in discussion clinical and parasitological response (cure rate) on day 28 and fever clearance time (FCT). The safety outcome was predicted in terms of adverse events reported during a stringent follow up.

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Table 1 Characteristics of the studies using Arterolane in uncomplicated falciparum malaria Ref Study Population No. of Drug and Doses given to respective Follow Patients groups up (n) 12V. Neena et al. 13 to 65 years of Age; Body weight = 30 230 50 mg ( n = 78) 28 days Multi-centric, kilograms; P.falciparum mono-infection; Initial parasite densities ranging from 1000 to 100 mg ( n = 76) 100,000 asexual parasites/µL of blood; Febrile patients with axillary temperature = 37.5°C or 200 mg ( n = 75) oral or rectal temperature = 38°C 11Gautam et al. 13 to 65 years of Ag; Body weight = 30 230 50 mg ( n = 78) 28 days Multi-centric kilograms; P.falciparum mono-infection; Initial parasite densities ranging from 1000 to 100 mg ( n = 76) 100,000 asexual parasites/µL of blood; Febrile patients with axillary temperature = 37.5°C or 200 mg ( n = 75) oral or rectal temperature = 38°C

13V. Neena et al. P.falciparum mono-infection 240 160 patients received arterolane maleate 28 days Multi-centric Initial parasite densities ranging from 1000 to + piperaquine phosphate (AM+PQP) 100,000 asexual parasites/µL of blood 80 patients received -

Another published work was based on pharmacody- Discussion namic (PD) modeling which reports the relationship be- tween pharmacokinetic (PK) parameter (AUC (0-8 h) on Arterolane maleate, a novel new synthetic non-arte- day 0/day 6 and indices of PD response - 50% parasite misinin drug has proven efficacy over chloroquine as an clearance [PC (50)], 90% parasite clearance [PC (90)], par- anti-malarial. It is cytotoxic to all parasite stages of P. fal- asite clearance time [PCT], recrudescence from a phase II, ciparum and is well distributed in infected RBCs. double-blind, multicentre, randomised, parallel-group, Clinical Efficacy: A phase II study12 was performed to dose-ranging trial. Patients with acute uncomplicated compare the efficacy of 3 dose levels (50, 100 and 200 mg) P. falciparum malaria were randomised to 1 of 3 artero- administered orally for consecutive days on time, lead- lane maleate (50, 100, and 200 mg) doses for 7 consecu- ing to 90% parasite clearance in patients at 4 multi-centric tive days. The study recommended a minimum 150-mg sites. The aim was to optimise the dose of the novel agent dose arterolane maleate to optimise the probability of that could be considered for combination therapy with a maximum therapeutic benefits for an adult. This study selected partner drug. The various doses were adminis- emphasised the need of combining short and long-acting tered for 7 continuous days and the follow-up of patients drugs to prevent resistance development and minimise was for at least 28 days following the first dose of the recrudescence.11 study . The results showed no significant dif- A comparative randomised Phase III trial13 assessed ference in PC and PC (< 24h) between 100 mg and 200 50 90 the antimalarial efficacy and safety of arterolane male- mg dose groups. The parasitological response (cure rate) ate-piperaquine phosphate (AM-PQP) with artemether- was higher and comparable in the high dose groups. The lumefantrine (Coartem). It was a double blind, multicen- median PCT (parasite clearance time) was < 32 h for high tric and randomised and allocated in (2:1) ratio. The cure dose groups (100 & 200 mg). The findings were compara- rates were 94.4% and 96.3% for the AM-PQP and Coartem ble to the findings after mono-therapies with different ar- 14 group, which is non-significant and comparable. No dif- temisinin derivatives (~ 43 h; range 38-104 h). Arterolane ference was observed in the median PCT (30 h) or FCT maleate (AM), as a monotherapy claimed recrudescence (24 h) for both the treatments. Earlier trials with Coartem rate between 28% and 37% whereas the reported treat- showed median PCT from 24-48 h.18 The novel drug com- ment failures after artemisinin mono-therapy vary from bination provides a better antimalarial activity at differ- 3% to 50%, depending on the duration of treatment in 15-17 ent time windows as AM is a rapid and short acting drug studies. These studies, however, did not differentiate effective at all stages of parasite while PQP is a slow, long recrudescence from repeat infection. acting that kills the residual parasite.

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Table 2 Quality assessment and outcome measures of trials for Arterolane in uncomplicated falciparum malaria Ref Study Randomisation Blinding? Study Groups Measurement of Outcomes Type Outcomes 12 V. Neena, Stated Double- Phase II 50 mg ( n = 78), Primary End point: Significant PC90 values K.Srivicha, blind PC90 (12.8 h & 12.6 h) for Randomised, Secondary End point: 100 mg & 200 mg multi-centric, 100 mg ( n = 76) PC50, 100% PCT, PCR respectively. parallel group corrected ACPR on day PCT shorter in 200 mg clinical trial, 28, FCT dose group. 200 mg ( n = 75) 2010 PCR corrected ACPR on day 28 was higher in 100 mg & 200 mg dose group. 11Gautam et al, Stated Double- 50 mg ( n = 78), PK parameter: mean Phase II, blind Pharmaco- t1/2, AUC Re–stresses on multicentre, dynamic 100 mg ( n = 76) combining short and Modelling Randomised, PD parameter: PC50, long–acting drugs to (PD) study 200 mg ( n = 75) parallel-group, PC90, PCT, PCR- prevent resistance 2011 corrected ACPR on day development and 28 (cure rate) minimise recrudescence. 13V. Neena, Stated Double- Phase III Arterolane maleate- Primary End point: 94.4% and 96.3 % cure K.Srivicha, blind Piperaquine phosphate PCR-corrected ACPR rate for AM-PQP and Randomised, (AM,150mg+PQP,750 on day 28 (cure rate) CoartemR respectively, multi-centric, mg): n=160 Secondary End point: non significant and parallel group Median PCT and comparable. Artemether- clinical trial, median FCT, lumefantrine: No difference in median 2012 R Gametocyte Carriage Coartem : n= 80 PCT (30 hrs) or FCT (24hrs)

98% zero gametocyte count in both groups.

PCR (Polymerase chain reaction) adjusted ACPR- Adequate Clinical and Parasitological Response, PCT-Parasite Clearance Time, FCT-Fever Clearance Time, PC50-Parasite Clearance 50%, PC90-Parasite Clearance 90%

Safety and tolerability: The safety and tolerabil- ponatraemia were also observed. Hyperbilirubinaemia, ity were also assessed through ECG and laboratory tests hypoglycaemia, increase in liver enzymes and hypoalbu- (haematology, biochemistry and urinalysis) were per- minaemia were other treatment emergent AEs. The vari- formed at the time of screening, on day 6, day 28, and on ous other studies on Coartem treatment for malaria also any other day, if a patient spontaneously returned with documented anaemia and thrombocytopenia frequently. fever. None of the patients died or experienced any seri- All the recorded blood abnormalities improved consid- ous adverse events during the study. Only mild clinical erably with the resolution of the disease. The gastroin- adverse events were reported after the initiation of the testinal AEs like dyspepsia, nausea, vomiting, upper ab- treatment. The complaints did not exceed 10% in any of dominal pain and dizziness were comparable in both the the groups and were transient. They included headache, treatment groups.13 vomiting, abdominal pain, diarrhoea and vertigo. There Advantages of Arterolane Maleate (AM) combina- was no significant difference between the dose groups. tions: It is a synthetic drug and hence easier to manufac- There was no documented evidence of any toxic reactions ture with better predictability and reliability of supplies. to the treatments.12 Further as the drug is being developed as a once-a-day The novel drug combination (AM-PQP) showed a therapy for three days, this would improve patient com- majority of adverse events (AEs) related to the blood and pliance, besides being safe and efficacious. The avail- lymphatic system. Eosinophilia (35.5%) was most com- able therapy requires an adult to consume 24 tablets of mon followed by neutropenia (31.3%), thrombocytopenia, Coartem® (Artemether, 20 mg + Lumefantrine 120 mg) lymphocytosis and leucopenia. Hyperkalaemia and hy- over three days whereas AM-PQP dosage is 1 tablet per

The Indian Practitioner q Vol.67 No.8. August 2014 493 Review Article day for three days, thereby resulting in lesser pill burden 8. Maerki S, Brun R, Charman SA, Dorn A, Matile H, for the patients and reduced cost. Wittlin S.In vitro assessment of the pharmacodynamic properties and the partitioning of OZ277/RBx-11160 Limitations: The review was restricted to only two in cultures of plasmodium falciparum. Journal of major scientific databases and taking this into consider- Antimicrobial Chemotherapy. 2006;58:52-8. ation that very few trials were published for wide access to medical professionals. There are evidences of Phase III 9. Paliwal J. Pharmacokinetics of RBx 11160 in healthy trials that were conducted but extensive search did not subjects and P. falciparum patients. Abstract present- reveal any published literatures. The published literature ed at: ASTMH 55th Annual Meeting; November 12-16, established the efficacy and safety of AM in uncomplicat- 2006; Atlanta, GA. ed falciparum malaria as mono-infection. So its effective- 10. Biondi-Zoccai GG, Agostoni P, Abbate A, Testa L, ness in mixed infection is questionable and unverified. Burzotta F. A simple hint to improve Robinson and- There are no head to head trials conducted to verify its Dickersin’s highly sensitive PubMed search strategy effectiveness with other WHO recognised artemisinin for controlled clinical trials. International Journal of based combination therapy (ACT). Epidemiology. 2005;34:224-5. One Phase III trial has been registered and completed 11. Gautam et al. Pharmacokinetics and Pharmacodyna- in Indians addressing the efficacy of AM+PQP (fixed dose mics of Arterolane Maleate Following Multiple Oral combination) in uncomplicated P. Vivax malaria, but the Doses in Adult Patients with P. falciparum Malaria. publication is awaited. The unpublished data are on file Journal of Clinical Pharmacology. 2011;51:1519-28. with the sponsor. 12. Valecha N. et al. Arterolane maleate and Piperaquine Conclusion phosphate combination for the treatment of uncom- Arterolane in fixed dose combinations can be con- plicated Plasmodium falciparum malaria: a compara- sidered for the treatment of uncomplicated P. falciparum tive, multicentre randomized clinical trial. CID. 2010; monoinfection. The novel drug effectiveness remains 51:684-91. unverified in mixed which may limit its use in 13. Valecha N, et al. Arterolane maleate and Piperaquine clinical practice. There are no other trials published tak- phosphate combination for the treatment of uncom- ing other artemisinin combinations as an active control to plicated Plasmodium falciparum malaria: a compara- confirm its effectiveness. tive, multicentre randomized clinical trial. CID. 2012; 55(5):663-71. References 14. Giao PT, Binh TQ, Kager PA, et al. Artemisinin for 1. Switzerland. World Health Organization Global treatment of uncomplicated falciparum malaria: is Malaria Program. World Malaria Report. 2011: 66. there a place for monotherapy? Am J Trop Med Hyg. 2. India. Naional Institute of Malaria research and 2001; 65: 690-5. National Vector Borne disease Control Programme; 15. Meshnick SR, Taylot TE, Kamchonwongpaisan S. Guidelines for Diagnosis and Treatment of Malaria in Artemisinin and the antimalarial endoperoxides: from India. 2011: 1. herbal remedy to targeted chemotherapy. Microbiol 3. Nicholas J. White. Artemisinin based combination Rev. 1996; 60: 301-15. treatment of falciparum Malaria; American Society of 16. McIntosh HM, Olliaro P. Artemisinin derivatives for Tropical Medicine and Hygiene. 2007; 77: 181–92. treating severe malaria. Cochrane Database Syst Rev. 4. Switzerland. World Health Organization; Guidelines 2000; 2: CD000527. for the treatment of malaria. Second edition; 2010:1. 17. Price RN, Nosten F, Luxemberger C, et al. Effects of 5. Ridley RG. Medical need, Scientific opportunity artemisinin derivatives on malarial transmissibility. and the drive for anti-malarial drugs. Nature. 2002; Lancet. 1996; 347: 1654-8. 415:686–93. 18. Falade C, Manyando C. Safety profile of Coartem: 6. Shanks GD. Treatment of falciparum malaria in the age the evidence base. Malar J. 2009; 8 (suppl). Available of drug resistance. Journal of Postgraduate Medical. at: http://www.malarialjournal.com/content/8/S1/S6. 2006; 52:277–80. Accessed 20 June 2012. 7. Vennerstrom JL, Arbe-Barnes S, Brun R, et al. Identification of an anti-malarial synthetic trioxolane X drug development candidate. Nature. 2004; 430:900–4.

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