1921
Volume 99, Issue 1
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645

Abstract

Abstract.

The pharmacokinetics (PK) and ex vivo activity (pharmacodynamics [PD]) of two artemisinin combination therapies (ACTs) (artemisinin–piperaquine [ARN–PPQ] [Artequick] and artesunate–amodiaquine [ARS–AQ] [Coarsucam]) in healthy Vietnamese volunteers were compared following 3-day courses of the ACTs for the preselection of the drugs for falciparum malaria therapy. For PK analysis, serial plasma samples were collected from two separate groups of 22 volunteers after ACT administration. Of these volunteers, ex vivo activity was assessed in plasma samples from seven volunteers who received both ACTs. The area under the concentration–time curve (AUC) was 3.6-fold higher for dihydroartemisinin (active metabolite of ARS) than that for ARN, whereas the AUC of desethylamodiaquine (active metabolite of AQ) was 2.0-fold lower than that of PPQ. Based on the 50% inhibitory dilution values of the volunteers’ plasma samples collected from 0.25 to 3 hours after the last dose, the ex vivo activity of ARS–AQ was 2.9- to 16.2-fold more potent than that of ARN–PPQ against the drug-sensitive D6 line. In addition, at 1.5, 4.0, and 24 hours after the last dose, the ex vivo activity of ARS–AQ was 20.8-, 3.5-, and 8.5-fold more potent than that of ARN–PPQ against the ARN-sensitive MRA1239 line. By contrast, at 1.5 hours, the ex vivo activity of ARS–AQ was 5.4-fold more active than that of ARN–PPQ but had similar activities at 4 and 24 hours against the ARN-resistant MRA1240 line. The PK–PD data suggest that ARS–AQ possesses superior antimalarial activity than that of ARN–PPQ and would be the preferred ACT for further in vivo efficacy testing in multidrug-resistant falciparum malaria areas.

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References

  1. World Health Organization, 2015. World Malaria Report 2015. Geneva, Switzerland: WHO. Available at: http://www.who.int/malaria/publications/world-malaria-report-2015/report/en/. Accessed April 23, 2018.
  2. Bhatt S, 2015. The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015. Nature 526: 207211. [Google Scholar]
  3. World Health Organization, 2018. Malaria. Geneva, Switzerland: WHO. Available at: http://www.who.int/mediacentre/factsheets/fs094/en/. Accessed April 23, 2018.
  4. World Health Organization, 2015. Guidelines for the Treatment of Malaria, 3rd edition. Geneva, Switzerland: WHO. Available at: http://www.who.int/malaria/publications/atoz/9789241549127/en/. Accessed April 23, 2018.
  5. Krudsood S, Tangpukdee N, Thanchatwet V, Wilairatana P, Srivilairit S, Pothipak N, Jianping S, Guoqiao L, Brittenham GM, Looareesuwan S, , 2007. Dose ranging studies of new artemisinin-piperaquine fixed combinations compared to standard regimens of artemisisnin combination therapies for acute uncomplicated falciparum malaria. Southeast Asian J Trop Med Public Health 38: 971978. [Google Scholar]
  6. Nguyen TX, Trieu TN, Nguyen PC, Huynh QH, Bui D, Shanks GD, Chavchich M, Edstein MD, , 2012. The efficacy and tolerability of artemisinin-piperaquine (Artequick®) versus artesunate-amodiaquine (Coarsucam) for the treatment of uncomplicated Plasmodium falciparum malaria in south–central Vietnam. Malar J 11: 217. [Google Scholar]
  7. Salman S, Page-Sharp M, Batty KT, Kose K, Griffin S, Siba PM, Ilett KF, Mueller I, Davis TM, , 2012. Pharmacokinetic comparison of two piperaquine-containing artemisinin combination therapies in Papua New Guinean children with uncomplicated malaria. Antimicrob Agents Chemother 56: 32883297. [Google Scholar]
  8. Rogers WO, Sem R, Tero T, Chim P, Lim P, Muth S, Socheat D, Ariey F, Wongsrichanalai C, , 2009. Failure of artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria in southern Cambodia. Malar J 8: 10. [Google Scholar]
  9. Saunders DL, Vanachayangkul P, Lon C, , 2014. Dihydroartemisinin-piperaquine failure in Cambodia. N Engl J Med 371: 484485. [Google Scholar]
  10. Na-Bangchang K, Ruengweerayut R, Mahamad P, Ruengweerayut K, Chaijaroenkul W, , 2010. Declining in efficacy of a three-day combination regimen of mefloquine-artesunate in a multi-drug resistance area along the Thai-Myanmar border. Malar J 9: 273. [Google Scholar]
  11. Hien TT, 2012. In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam. Malar J 11: 355. [Google Scholar]
  12. Thriemer K, 2014. Delayed parasite clearance after treatment with dihydroartemisinin-piperaquine in Plasmodium falciparum malaria patients in central Vietnam. Antimicrob Agents Chemother 58: 70497055. [Google Scholar]
  13. Thanh NV, 2017. Rapid decline in the susceptibility of Plasmodium falciparum to dihydroartemisinin-piperaquine in the south of Vietnam. Malar J 16: 27. [Google Scholar]
  14. Edstein MD, Yeo AE, Kyle DE, Looareesuwan S, Wilairatana P, Rieckmann KH, , 1996. Proguanil polymorphism does not affect the antimalarial activity of proguanil combined with atovaquone in vitro. Trans R Soc Trop Med Hyg 90: 418421. [Google Scholar]
  15. Na-Bangchang K, Tippawangkosol P, Thanavibul A, Ubalee R, Karbwang J, , 1999. Pharmacokinetic and pharmacodynamic interactions of mefloquine and dihydroartemisinin. Int J Clin Pharmacol Res 19: 917. [Google Scholar]
  16. Kongthaisong M, Na-Bangchang K, Mungthin M, Sinchaipanid N, Tan-Ariya P, , 2004. Comparison of the bioequivalence of three oral formulations of dihydroartemisinin based on ex vivo blood schizontocidal activities against Plasmodium falciparum. Am J Trop Med Hyg 71: 703710. [Google Scholar]
  17. Teja-Isavadharm P, Peggins JO, Brewer TG, White NJ, Webster HK, Kyle DE, , 2004. Plasmodium falciparum-based bioassay for measurement of artemisinin derivatives in plasma or serum. Antimicrob Agents Chemother 48: 954960. [Google Scholar]
  18. Nguyen DV, Nguyen QP, Nguyen ND, Le TT, Nguyen TD, Dinh DN, Nguyen TX, Bui D, Chavchich M, Edstein MD, , 2009. Pharmacokinetics and ex vivo pharmacodynamic antimalarial activity of dihydroartemisinin-piperaquine in patients with uncomplicated falciparum malaria in Vietnam. Antimicrob Agents Chemother 53: 35343537. [Google Scholar]
  19. Chavchich M, Birrell GW, Ager AL, MacKenzie DO, Heffernan GD, Schiehser GA, Jacobus LR, Shanks DG, Jacobus DP, Edstein MD, , 2016. Lead selection of the new aminomethylphenol, JPC-3210 for malaria treatment and prevention. Antimicrob Agents Chemother 60: 31153118. [Google Scholar]
  20. WHO, 2016. WHO Plans for Reviewing the Cardiotoxicity of Antimalarial Medicines. Salle A, ed. Malaria Policy Advisory Committee (MPAC) Meeting, September 14–16, 2016. Geneva, Switzerland: World Health Organization. Available at: http://www.who.int/malaria/mpac/mpac-sep2016-cardiotoxicity-of-antimalarials.pdf?ua=1. Accessed April 23, 2018.
  21. Lindegardh N, 2008. Major pitfalls in the measurement of artemisinin derivatives in plasma in clinical studies. J Chromatogr B Analyt Technol Biomed Life Sci 876: 5460. [Google Scholar]
  22. Lourens C, Lindegardh N, Barnes KI, Guerin PJ, Sibley CH, White NJ, Tarning J, , 2014. Benefits of a pharmacology antimalarial reference standard and proficiency testing program provided by the worldwide antimalarial resistance network (WWARN). Antimicrob Agents Chemother 58: 38893894. [Google Scholar]
  23. Desjardins RE, Canfield CJ, Haynes JD, Chulay JD, , 1979. Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob Agents Chemother 16: 710718. [Google Scholar]
  24. Ovenden SP, Cobbe M, Kissell R, Birrell GW, Chavchich M, Edstein MD, , 2011. Three novel phenolic glycosides with antimalarial activity from Grevillea “Poorinda Queen.” J Nat Prod 74: 7478. [Google Scholar]
  25. Nagelschmitz J, Voith B, Wensing G, Roemer A, Fugmann B, Haynes RK, Kotecka BM, Rieckmann KH, Edstein MD, , 2008. First-time-in-humans safety, tolerability, pharmacokinetics and ex vivo pharmacodynamic antimalarial activity of the new artemisinin derivative, artemisone. Antimicrob Agents Chemother 52: 30853091. [Google Scholar]
  26. Morris CA, Duparc S, Borghini-Fuhrer I, Jung D, Shin C-S, Fleckenstein L, , 2011. Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration. Malar J 10: 263. [Google Scholar]
  27. Davis TM, Phuong HL, Ilett KF, Hung NC, Batty KT, Phuong VDB, Powell SM, Thien HV, Binh TQ, , 2001. Pharmacokinetics and pharmacodynamics of intravenous artesunate in severe falciparum malaria. Antimicrob Agents Chemother 45: 181186. [Google Scholar]
  28. Parikh S, Ouedraogo JB, Goldstein JA, Rosenthal PJ, Kroetz DL, , 2007. Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa. Clin Pharmacol Ther 82: 197203. [Google Scholar]
  29. Li XQ, Björkman A, Andersson TB, Ridderström M, Masimirembwa CM, , 2002. Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. J Pharmacol Exp Ther 300: 399407. [Google Scholar]
  30. Straimer J, 2015. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science 347: 428431. [Google Scholar]
  31. Ashton M, Gordi T, Hai TN, Huong NV, Sy ND, Nieu NT, Huong DX, Johansson M, Cong DL, , 1998. Artemisinin pharmacokinetics in healthy adults after 250, 500, and 1000 mg single oral doses. Biopharm Drug Dispos 19: 245250. [Google Scholar]
  32. Ashton M, Hai TN, Sy ND, Huong DX, Huong NV, Niêu NT, Công LD, , 1998. Artemisinin pharmacokinetics is time-dependent during repeated oral administration in healthy male adults. Drug Metab Dispos 26: 2527. [Google Scholar]
  33. Sim IK, Davis TME, Ilett KF, , 2005. Effects of a high-fat meal on the relative oral bioavailability of piperaquine. Antimicrob Agents Chemother 49: 24072411. [Google Scholar]
  34. Ahmed T, Sharma P, Gautam A, Varshney B, Kothari M, Ganguly S, Moehrle JJ, Paliwal J, Saha N, Batra V, , 2008. Safety, tolerability, and single- and multiple-dose pharmacokinetics of piperaquine phosphate in healthy subjects. J Clin Pharmacol 48: 166175. [Google Scholar]
  35. Nguyen TC, Nguyen NQ, Nguyen XT, Bui D, Travers T, Edstein MD, , 2008. Pharmacokinetics of the antimalarial drug piperaquine in healthy Vietnamese subjects. Am J Trop Med Hyg 79: 620623. [Google Scholar]
  36. Reuter SE, Evans AM, Shakib S, Lungershausen Y, Francis B, Valentini G, Bacchieri A, Ubben D, Pace S, , 2015. Effect of food on the pharmacokinetics of piperaquine and dihydroartemisinin. Clin Drug Investig 35: 559567. [Google Scholar]
  37. Hai TN, Hietala SF, Huong NV, Ashton M, , 2008. The influence of food on the pharmacokinetics of piperaquine in healthy Vietnamese volunteers. Acta Trop 107: 145149. [Google Scholar]
  38. Chinh NT, Quang NN, Thanh NX, Dai B, Travers T, Edstein MD, , 2009. Pharmacokinetics and bioequivalence evaluation of two fixed tablet formulations of dihydroartemisinin and piperaquine in Vietnamese subjects. Antimicrob Agents Chemother 53: 828831. [Google Scholar]
  39. Pécoul B, Sevcsik A-M, Amuasi J, Diap G, Kiechel JR, , 2008. The story of ASAQ: the first antimalarial product development partnership success. Health Partnerships Review. Geneva, Switzerland: Global Forum for Health Research, 77–83. Available at: https://www.dndi.org/2008/media-centre/scientific-articles/scientific-articles-malaria/the-story-of-asaq-the-first-antimalarial-product-development-partnership-success/. Accessed April 23, 2018.
  40. Fitoussi S, Thang C, Lesauvage E, Barré J, Charron B, Filali-Ansary A, Lameyre V, , 2009. Bioavailability of a co-formulated combination of amodiaquine and artesunate under fed and fasted conditions. A randomised, open-label crossover study. Arzneimittelforschung 59: 370376. [Google Scholar]
  41. Teja-Isavadharm P, Watt G, Eamsila C, Jongsakul K, Li Q, Keeratithakul G, Sirisopana N, Luesutthiviboon L, Brewer TG, Kyle DE, , 2001. Comparative pharmacokinetics and effect kinetics of orally administered artesunate in healthy volunteers and patients with uncomplicated falciparum malaria. Am J Trop Med Hyg 65: 717721. [Google Scholar]
  42. Batty KT, Ilett KF, Powell SM, Martin J, Davis TM, , 2002. Relative bioavailability of artesunate and dihydroartemisinin: investigations in the isolated perfused rat liver and in healthy Caucasian volunteers. Am J Trop Med Hyg 66: 130136. [Google Scholar]
  43. Navaratnam V, Ramanathan S, Wahab MS, Siew Hua G, Mansor SM, Kiechel JR, Vaillant M, Taylor WR, Olliaro P, , 2009. Tolerability and pharmacokinetics of non-fixed and fixed combinations of artesunate and amodiaquine in Malaysian healthy normal volunteers. Eur J Clin Pharmacol 65: 809821. [Google Scholar]
  44. Orrell C, Little F, Smith P, Folb P, Taylor W, Olliaro P, Barnes KI, , 2008. Pharmacokinetics and tolerability of artesunate and amodiaquine alone and in combination in healthy volunteers. Eur J Clin Pharmacol 64: 683690. [Google Scholar]
  45. Chinh NT, Quang NN, Thanh NX, Dai B, Chavchich M, Birrell G, Edstein MD, , 2011. The pharmacokinetics and ex vivo antimalarial activity of artesunate plus azithromycin in healthy volunteers. Antimicrob Agents Chemother 55: 44124415. [Google Scholar]
  46. Food and Drug Administration, 2005. Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs. Rockville, MD: FDA.
  47. Darpo B, Ferber G, Siegl P, Laurijssens B, Macintyre F, Toovey S, Duparc S, , 2015. Evaluation of the QT effect of a combination of piperaquine and a novel anti-malarial drug candidate OZ439, for the treatment of uncomplicated malaria. Br J Clin Pharmacol 80: 706715. [Google Scholar]
  48. Eurartesim, 2011. EU Summary of Product Characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001199/WC500118113.pdf. Accessed April 23, 2018.
  49. Wongsrichanalai C, Meshnick SR, , 2008. Declining artesunate-mefloquine efficacy against falciparum malaria on the Cambodia–Thailand border. Emerg Infect Dis 14: 716719. [Google Scholar]
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  • Received : 03 Jun 2017
  • Accepted : 09 Mar 2018
  • Published online : 05 Jul 2018

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