Drugs

, Volume 72, Issue 7, pp 937–961 | Cite as

Dihydroartemisinin/Piperaquine

A Review of its Use in the Treatment of Uncomplicated Plasmodium falciparum Malaria
Adis Drug Evaluation

Abstract

Artemisinin-based combination regimens are recommended by WHO for the treatment of uncomplicated Plasmodium falciparum malaria. One such combination comprises the artemisinin derivative dihydroartemisinin and the bisquinolone piperaquine. Eurartesim® is the only dihydroartemisinin/piperaquine formulation that meets international good manufacturing practice standards. This article reviews the pharmacological properties of dihydroartemisinin and piperaquine, and the therapeutic efficacy and tolerability of dihydroartemisinin/piperaquine in the treatment of uncomplicated P. falciparum malaria.

A number of trials have shown dihydroartemisinin/piperaquine to be highly effective in the treatment of uncomplicated P. falciparum malaria. Two pivotal, randomized, open-label, multicentre trials demonstrated the Eurartesim® formulation of dihydroartemisinin/piperaquine to be noninferior to artesunate plus mefloquine in children and adults in Asia and noninferior to artemether/lumefantrine in children in Africa, in terms of polymerase chain reaction-corrected cure rates. In both trials, dihydroartemisinin/piperaquine recipients were significantly less likely than artesunate plus mefloquine recipients or artemether/lumefantrine recipients to experience reinfection. Gametocyte carriage was greater in patients receiving dihydroartemisinin/piperaquine than in those receiving comparator antimalarial regimens.

The Eurartesim® formulation of dihydroartemisinin/piperaquine was generally well tolerated in the treatment of uncomplicated P. falciparum malaria, and was associated with significantly less nausea, vomiting and dizziness than artesunate plus mefloquine. Although prolongation of the corrected QT interval has been reported in patients receiving dihydroartemisinin/piperaquine, there are currently no clinical data signalling that it is associated with clinically significant arrhythmias.

In conclusion, dihydroartemisinin/piperaquine is a valuable option for use in the first-line treatment of uncomplicated P. falciparum malaria.

References

  1. 1.
    World Health Organization. Guidelines for the treatment of malaria: second edition [online]. Available from URL: http://whqlibdoc.who.int/publications/2010/9789241547925_eng.pdf [Accessed 2012 Jan 12]
  2. 2.
    German PI, Aweeka FT. Clinical pharmacology of artemisinin-based combination therapies. Clin Pharmacokinet 2008; 47 (2): 91–102PubMedCrossRefGoogle Scholar
  3. 3.
    World Health Organization. World malaria report 2011 [online]. Available from URL: http://www.who.int/malaria/world_malaria_report_2011/WMR2011_noprofiles_lowres.pdf [Accessed 2012 Feb 14]
  4. 4.
    Dondorp AM, Yeung S, White L, et al. Artemisinin resistance: current status and scenarios for containment. Nat Rev Microbiol 2010 Apr; 8 (4): 272–80PubMedGoogle Scholar
  5. 5.
    European Medicines Agency. Eurartesim (dihydroartemisinin/piperaquine phosphate): EU public assessment report [online]. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001199/WC500118116.pdf [Accessed 2012 Jan 10]
  6. 6.
    Mayxay M, Keomany S, Khanthavong M, et al. A phase III, randomized, non-inferiority trial to assess the efficacy and safety of dihydroartemisinin-piperaquine in comparison with artesunate-mefloquine in patients with uncomplicated Plasmodium falciparum malaria in southern Laos. Am J Trop Med Hyg 2010; 83 (6): 1221–9PubMedCrossRefGoogle Scholar
  7. 7.
    European Medicines Agency. Eurartesim (dihydroartemisinin/piperaquine) 20mg/160mg and 40mg/320 mg film-coated tablets: EU summary of product characteristics [online]. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001199/WC500118113.pdf [Accessed 2012 Jan 10]
  8. 8.
    Li W, Mo W, Shen D, et al. Yeast model uncovers dual roles of mitochondria in action of artemisinin. PLoS Genet 2005 Sep; 1 (3): e36Google Scholar
  9. 9.
    Eckstein-Ludwig U, Webb RJ, van Goethem IDA, et al. Artemisinins target the SERCA of Plasmodium falciparum. Nature 2003 Aug 21; 424 (6951): 957–61PubMedCrossRefGoogle Scholar
  10. 10.
    Davis TME, Hung T-Y, Sim I-K, et al. Piperaquine: a resurgent antimalarial drug. Drugs 2005; 65 (1): 75–87PubMedCrossRefGoogle Scholar
  11. 11.
    Nsobya SL, Kiggundu M, Nanyunja S, et al. In vitro sensitivities of Plasmodium falciparum to different antimalarial drugs in Uganda. Antimicrob Agents Chemother 2010 Mar; 54 (3): 1200–6PubMedCrossRefGoogle Scholar
  12. 12.
    Borrmann S, Sasi P, Mwai L, et al. Declining responsiveness of Plasmodium falciparum infections to artemisinin-based combination treatments on the Kenyan coast. PLoS One 2011 Nov; 6 (11): e26005Google Scholar
  13. 13.
    Briolant S, Henry M, Oeuvray C, et al. Absence of association between piperaquine in vitro responses and polymorphisms in the pfcrt, pfmdr1, pfmrp, and pfnhe genes in Plasmodium falciparum. Antimicrob Agents Chemother 2010 Sep; 54 (9): 3537–44PubMedCrossRefGoogle Scholar
  14. 14.
    Muangnoicharoen S, Johnson DJ, Looareesuwan S, et al. Role of known molecular markers of resistance in the antimalarial potency of piperaquine and dihydroartemisinin in vitro. Antimicrob Agents Chemother 2009 Apr; 53 (4): 1362–6PubMedCrossRefGoogle Scholar
  15. 15.
    Mwai L, Kiara SM, Abdirahman A, et al. In vitro activities of piperaquine, lumefantrine, and dihydroartemisinin in Kenyan Plasmodium falciparum isolates and polymorphisms in pfcrt and pfmdr1. Antimicrob Agents Chemother 2009 Dec; 53 (12): 5069–73PubMedCrossRefGoogle Scholar
  16. 16.
    Gargano N, Cenci F, Bassat Q. Antimalarial efficacy of piperaquine-based antimalarial combination therapies: facts and uncertainties. Trop Med Int Health 2011 Dec; 16 (12): 1466–73PubMedCrossRefGoogle Scholar
  17. 17.
    Dondorp AM, Nosten F, Yi P, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 2009 Jul 30; 361 (5): 455–67PubMedCrossRefGoogle Scholar
  18. 18.
    Noedl H, Se Y, Schaecher K, et al. Evidence of artemisinin-resistant malaria in western Cambodia [letter]. N Engl J Med 2008 Dec 11; 359 (24): 2619–20PubMedCrossRefGoogle Scholar
  19. 19.
    Jambou R, Legrand E, Niang M, et al. Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6. Lancet 2005 Dec 3; 366 (9501): 1960–3PubMedCrossRefGoogle Scholar
  20. 20.
    Basco LK, Ringwald P. In vitro activities of piperaquine and other 4-aminoquinolines against clinical isolates of Plasmodium falciparum in Cameroon. Antimicrob Agents Chemother 2003 Apr; 47 (4): 1391–4PubMedCrossRefGoogle Scholar
  21. 21.
    Some AF, Sere YY, Dokomajilar C, et al. Selection of known Plasmodium falciparum resistance-mediating polymorphisms by artemether-lumefantrine and amodia-quine-sulfadoxine-pyrimethamine but not dihydroartemisinin-piperaquine in Burkina Faso. Antimicrob Agents Chemother 2010 May; 54 (5): 1949–54PubMedCrossRefGoogle Scholar
  22. 22.
    Fivelman QL, Adagu IS, Warhurst DC. Effects of piperaquine, chloroquine, and amodiaquine on drug uptake and of these in combination with dihydroartemisinin against drug-sensitive and -resistant Plasmodium falciparum strains. Antimicrob Agents Chemother 2007 Jun; 51 (6): 2265–7PubMedCrossRefGoogle Scholar
  23. 23.
    Davis TME, Hamzah J, Ilett KF, et al. In vitro interactions between piperaquine, dihydroartemisinin, and other conventional and novel antimalarial drugs. Antimicrob Agents Chemother 2006 Aug; 50 (8): 2883–5PubMedCrossRefGoogle Scholar
  24. 24.
    Valecha N, Phyo AP, Mayxay M, et al. An open-label, randomised study of dihydroartemisinin-piperaquine versus artesunate-mefloquine for falciparum malaria in Asia. PLoS One 2010 Jul; 5 (7): e11880Google Scholar
  25. 25.
    Bassat Q, Mulenga M, Tinto H, et al. Dihydroartemisinin-piperaquine and artemether-lumefantrine for treating uncomplicated malaria in African children: a randomised, non-inferiority trial. PLoS One 2009 Nov 17; 4 (11): e7871Google Scholar
  26. 26.
    Mytton OT, Ashley EA, Peto L, et al. Electrocardiographic safety evaluation of dihydroartemisinin-piperaquine in the treatment of uncomplicated falciparum malaria. Am J Trop Med Hyg 2007 Sep; 77 (3): 447–50PubMedGoogle Scholar
  27. 27.
    Karunajeewa H, Lim C, Hung T-Y, et al. Safety evaluation of fixed combination piperaquine plus dihydroartemisinin (Artekin®) in Cambodian children and adults with malaria. Br J Clin Pharmacol 2004 Jan; 57 (1): 93–9PubMedCrossRefGoogle Scholar
  28. 28.
    Ashley EA, Krudsood S, Phaiphun L, et al. Randomized, controlled dose-optimization studies of dihydroartemisinin-piperaquine for the treatment of uncomplicated multidrug-resistant falciparum malaria in Thailand. J Infect Dis 2004 Nov 15; 190 (10): 1773–82PubMedCrossRefGoogle Scholar
  29. 29.
    Ashley EA, McGready R, Hutagalung R, et al. A randomized, controlled study of a simple, once-daily regimen of dihydroartemisinin-piperaquine for the treatment of uncomplicated, multidrug-resistant falciparum malaria. Clin Infect Dis 2005 Aug 15; 41 (4): 425–32PubMedCrossRefGoogle Scholar
  30. 30.
    Borsini F, Crumb W, Pace S, et al. In vitro cardiovascular effects of dihydroartemisin-piperaquine combination: comparison with other antimalarials. Antimicrob Agents Chemother. Epub 2012 Mar 5Google Scholar
  31. 31.
    White NJ. Cardiotoxicity of antimalarial drugs. Lancet Infect Dis 2007 Aug; 7 (8): 549–58PubMedCrossRefGoogle Scholar
  32. 32.
    Nguyen DVH, Nguyen QP, Nguyen ND, et al. Pharmacokinetics and ex vivo pharmacodynamic antimalarial activity of dihydroartemisinin-piperaquine in patients with uncomplicated falciparum malaria in Vietnam. Antimicrob Agents Chemother 2009 Aug; 53 (8): 3534–7PubMedCrossRefGoogle Scholar
  33. 33.
    Annerberg A, Lwin KM, Lindegardh N, et al. A small amount of fat does not affect piperaquine exposure in patients with malaria. Antimicrob Agents Chemother 2011 Sep; 55 (9): 3971–6PubMedCrossRefGoogle Scholar
  34. 34.
    Sim I-K, Davis TME, Ilett KF. Effects of a high-fat meal on the relative oral bioavailability of piperaquine. Antimicrob Agents Chemother 2005 Jun; 49 (6): 2407–11PubMedCrossRefGoogle Scholar
  35. 35.
    Chinh NT, Quang NN, Thanh NX, et al. Pharmacokinetics of the antimalarial drug piperaquine in healthy Vietnamese subjects. Am J Trop Med Hyg 2008 Oct; 79 (4): 620–3Google Scholar
  36. 36.
    Hai TN, Hietala SF, Van Huong N, et al. The influence of food on the pharmacokinetics of piperaquine in healthy Vietnamese volunteers. Acta Trop 2008 Aug; 107 (2): 145–9PubMedCrossRefGoogle Scholar
  37. 37.
    Hung TY, Davis TME, Ilett KF. Measurement of piperaquine in plasma by liquid chromatography with ultraviolet absorbance detection. J Chrom B Anal Tech Biomed Life Sci 2003 Jul 5; 791 (1-2): 93-101Google Scholar
  38. 38.
    Tarning J, Ashley EA, Lindegardh N, et al. Population pharmacokinetics of piperaquine after two different treatment regimens with dihydroartemisinin-piperaquine in patients with Plasmodium falciparum malaria in Thailand. Antimicrob Agents Chemother 2008 Mar; 52 (3): 1052–61PubMedCrossRefGoogle Scholar
  39. 39.
    Tarning J, Lindegardh N, Sandberg S, et al. Pharmacokinetics and metabolism of the antimalarial piperaquine after intravenous and oral single doses to the rat. J Pharm Sci 2008 Aug; 97 (8): 3400–10PubMedCrossRefGoogle Scholar
  40. 40.
    Grande T, Bernasconi A, Erhart A, et al. A randomised controlled trial to assess the efficacy of dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Peru. PLoS One 2007 Oct; 2 (10): e1101Google Scholar
  41. 41.
    Hien TT, Dolecek C, Mai PP, et al. Dihydroartemisinin-piperaquine against multidrug-resistant Plasmodium falciparum malaria in Vietnam: randomised clinical trial. Lancet 2004 Jan 3; 363 (9402): 18–22CrossRefGoogle Scholar
  42. 42.
    Janssens B, van Herp M, Goubert L, et al. A randomized open study to assess the efficacy and tolerability of dihy-droartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Cambodia. Trop Med Int Health 2007 Feb; 12 (2): 251–9PubMedCrossRefGoogle Scholar
  43. 43.
    Mayxay M, Thongpraseuth V, Khanthavong M, et al. An open, randomized comparison of artesunate plus mefloquine vs. dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in the Lao People’s Democratic Republic (Laos). Trop Med Int Health 2006 Aug; 11 (8): 1157–65PubMedGoogle Scholar
  44. 44.
    Tangpukdee N, Krudsood S, Thanachartwet W, et al. An open randomized clinical trial of Artekin® vs artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria. Southeast Asian J Trop Med Public Health 2005 Sep; 36 (5): 1085–91PubMedGoogle Scholar
  45. 45.
    Nambozi M, van Gerrtruyden J-P, Hachizovu S, et al. Safety and efficacy of dihydroartemisinin-piperaquine versus artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Zambian children. Malar J 2011 Feb 28; 10: 50Google Scholar
  46. 46.
    The 4ABC Study Group. A head-to-head comparison of four artemisinin-based combinations for treating uncomplicated malaria in African children: a randomized trial. PLoS Med 2011 Nov; 8 (11): e1001119Google Scholar
  47. 47.
    Mens PF, Sawa P, van Amsterdam SM, et al. A randomized trial to monitor the efficacy and effectiveness by QT-NASBA of artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment and transmission control of uncomplicated Plasmodium falciparum malaria in western Kenya. Malar J 2008 Nov 18; 7: 237Google Scholar
  48. 48.
    Adam I, Salah MT, Eltahir HG, et al. Dihydroartemisinin-piperaquine versus artemether-lumefantrine, in the treatment of uncomplicated Plasmodium falciparum malaria in central Sudan. Ann Trop Med Parasitol 2010; 104 (4): 319–26PubMedCrossRefGoogle Scholar
  49. 49.
    Kamya MR, Yeka A, Bukirwa H, et al. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment of malaria: a randomized trial. PLoS Clin Trials 2007 May; 2 (5): e20Google Scholar
  50. 50.
    Yavo W, Faye B, Kuete T, et al. Multicentric assessment of the efficacy and tolerability of dihydroartemisinin-piperaquine compared to artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in sub-Saharan Africa. Malaria J 2011 Jul 20; 10: 198Google Scholar
  51. 51.
    Yeka A, Dorsey G, Kamya MR, et al. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treating uncomplicated malaria: a randomized trial to guide policy in Uganda. PLoS One 2008 Jun; 3 (6): e2390Google Scholar
  52. 52.
    Zongo I, Dorsey G, Rouamba N, et al. Randomized comparison of amodiaquine plus sulfadoxine-pyrimethamine, artemether-lumefantrine, and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in Burkina Faso. Clin Infect Dis 2007 Dec 1; 45 (11): 1453–61PubMedCrossRefGoogle Scholar
  53. 53.
    Arinaitwe E, Sandison TG, Wanzira H, et al. Artemether-lumefantrine versus dihydroartemisinin-piperaquine for falciparum malaria: a longitudinal, randomized trial in young Ugandan children. Clin Infect Dis 2009; 49 (11): 1629–37PubMedCrossRefGoogle Scholar
  54. 54.
    Song J, Socheat D, Tan B, et al. Randomized trials of artemisinin-piperaquine, dihydroartemisinin-piperaquine phosphate and artemether-lumefantrine for the treatment of multi-drug resistant falciparum malaria in Cambodia-Thailand border area. Malaria J 2011 Aug 10; 10: 231Google Scholar
  55. 55.
    Karema C, Fanello CI, Van Overmeir C, et al. Safety and efficacy of dihydroartemisinin/piperaquine (Artekin®) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan children. Trans R Soc Trop Med Hyg 2006 Dec; 100 (12): 1105–11PubMedCrossRefGoogle Scholar
  56. 56.
    Thanh NX, Trung TN, Phong NC, et al. Open label randomized comparison of dihydroartemisinin-piperaquine and artesunate-amodiaquine for the treatment of uncomplicated Plasmodium falciparum malaria in central Vietnam. Trop Med Int Health 2009 May; 14 (5): 504–511PubMedCrossRefGoogle Scholar
  57. 57.
    Trung TN, Tan B, Van Phuc D, et al. A randomized, controlled trial of artemisinin-piperaquine vs dihydroartemisinin-piperaquine phosphate in treatment of falciparum malaria. Chin J Integr Med 2009 Jun; 15 (3): 189–92PubMedCrossRefGoogle Scholar
  58. 58.
    Carrara VI, Zwang J, Ashley EA, et al. Changes in the treatment responses to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment. PLoS One 2009 Feb; 4 (2): e4551PubMedCrossRefGoogle Scholar
  59. 59.
    Rogers WO, Sem R, Tero T, et al. Failure of artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria in southern Cambodia. Malar J 2009 Jan 12; 8: 10PubMedCrossRefGoogle Scholar
  60. 60.
    Karunajeewa HA, Mueller I, Senn M, et al. A trial of combination antimalarial therapies in children from Papua New Guinea. N Engl J Med 2008 Dec 11; 359 (24): 2545–57PubMedCrossRefGoogle Scholar
  61. 61.
    Tarning J, Zongo I, Some FA, et al. Population pharmacokinetics and pharmacodynamics of piperaquine in children with uncomplicated falciparum malaria. Clin Pharmacol Ther 2012 Mar; 91 (3): 497–505PubMedCrossRefGoogle Scholar
  62. 62.
    Novartis Pharmaceuticals UK Ltd. Riamet (artemether/lumefantrine) 20mg/120mg tablets: UK summary of product characteristics [online]. Available from URL: http://www.medicines.org.uk/EMC/medicine/9196/SPC/Riamet+20+120mg+tablets/ [Accessed 2012 Feb 14]
  63. 63.
    Douglas NM, Anstey NM, Angus BJ, et al. Artemisinin combination therapy for vivax malaria. Lancet Infect Dis 2010 Jun; 10 (6): 405–16PubMedCrossRefGoogle Scholar
  64. 64.
    Myint HY, Ashley EA, Day NP, et al. Efficacy and safety of dihydroartemisinin-piperaquine. Trans R Soc Trop Med Hyg 2007 Sep; 101 (9): 858–66PubMedCrossRefGoogle Scholar
  65. 65.
    Zwang J, Ashley EA, Karema C, et al. Safety and efficacy of dihydroartemisinin-piperaquine in falciparum malaria: a prospective multi-centre individual patient data analysis. PLoS One 2009 Jul; 4 (7): e6358PubMedCrossRefGoogle Scholar
  66. 66.
    World Health Organization. International travel and health 2011 [online]. Available from URL: http://www.who.int/ith/en/ [Accessed 2012 Jan 18]
  67. 67.
    Antinori S, Cigardi B, Galimberti L, et al. Diagnosis and therapy for hospitalized imported malaria in adults in Italy. J Travel Med 2011; 18 (6): 379–85PubMedCrossRefGoogle Scholar
  68. 68.
    Kelesidis T, Kelesidis I, Rafailidis PI, et al. Counterfeit or substandard antimicrobial drugs: a review of the scientific evidence. J Antimicrob Chemother 2007 Aug; 60 (2): 214–36PubMedCrossRefGoogle Scholar
  69. 69.
    World Health Organization. Survey of the quality of selected antimalarial medicines circulating in six countries of sub-Saharan Africa [online]. Available from URL: http://www.who.int/medicines/publications/WHO_QAMSA_report.pdf [Accessed 2012 Mar 19]
  70. 70.
    Nankabirwa J, Cundill B, Clarke S, et al. Efficacy, safety, and tolerability of three regimens for prevention of malaria: a randomized, placebo-controlled trial in Ugandan schoolchildren. PLoS One 2010 Oct; 5 (10): e13438Google Scholar
  71. 71.
    Cisse B, Cairns M, Faye E, et al. Randomized trial of piperaquine with sulfadoxine-pyrimethamine or dihydroartemisinin for malaria intermittent preventive treatment in children. PLoS One 2009 Sep; 4 (9): e7164Google Scholar
  72. 72.
    Bojang K, Akor F, Bittaye O, et al. A randomised trial to compare the safety, tolerability and efficacy of three drug combinations for intermittent preventive treatment in children. PLoS One 2010 Jun; 5 (6): e11225Google Scholar
  73. 73.
    Lwin KM, Phyo AP, Tarning J, et al. A randomised, doubleblind, placebo controlled trial of monthly versus second monthly dihydroartemisinin-piperaquine chemoprevention in adults at high risk of malaria. Antimicrob Agents Chemother 2012 Mar; 56 (3): 1571–7PubMedCrossRefGoogle Scholar
  74. 74.
    Phyo AP, Lwin KM, Price RN, et al. Dihydroartemisinin-piperaquine versus chloroquine in the treatment of Plasmodium vivax malaria in Thailand: a randomized controlled trial. Clin Infect Dis 2011 Nov 15; 53 (10): 977–84PubMedCrossRefGoogle Scholar
  75. 75.
    Awab GR, Pukrittayakamee S, Imwong M, et al. Dihydroartemisinin-piperaquine versus chloroquine to treat vivax malaria in Afghanistan: an open randomized, non-inferiority, trial. Malaria J 2010 Apr 21; 9: 105Google Scholar
  76. 76.
    Poespoprodjo JR, Fobia W, Kenangalem E, et al. Adverse pregnancy outcomes in an area where multidrug-resistant Plasmodium vivax and Plasmodium falciparum infections are endemic. Clin Infect Dis 2008 May 1; 46 (9): 1374–81PubMedCrossRefGoogle Scholar
  77. 77.
    Rijken MJ, McGready R, Boel ME, et al. Dihydroartemisinin-piperaquine rescue treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy: a preliminary report. Am J Trop Med Hyg 2008; 78 (4): 543–5PubMedGoogle Scholar
  78. 78.
    Rijken MJ, McGready R, Phyo AP, et al. Pharmacokinetics of dihydroartemisinin and piperaquine in pregnant and nonpregnant women with uncomplicated falciparum malaria. Antimicrob Agents Chemother 2011 Dec; 55 (12): 5500–6PubMedCrossRefGoogle Scholar
  79. 79.
    Tarning J, Rijken MJ, McGready R, et al. Population pharmacokinetics of dihydroartemisinin and piperaquine in pregnant and non-pregnant women with uncomplicated malaria. Antimicrob Agents Chemother 2012 Apr; 56 (4): 1997–2007PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG 2012

Authors and Affiliations

  1. 1.AdisAucklandNew Zealand

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