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Pharmacokinetics and pharmacodynamics of oral artesunate monotherapy in patients with uncomplicated Plasmodium falciparum malaria in western Cambodia.

Abstract
Artemisinin-resistant malaria along the Thailand-Cambodian border is an important public health concern, yet mechanisms of drug action and their contributions to the development of resistance are poorly understood. The pharmacokinetics and pharmacodynamics of oral artesunate monotherapy were explored in a dose-ranging trial in an area of emerging artesunate resistance in western Cambodia. We enrolled 143 evaluable subjects with uncomplicated Plasmodium falciparum malaria in an open label study of directly observed artesunate monotherapy at 3 dose levels (2, 4, and 6 mg/kg of body weight/day) for 7 days at Tasanh Health Center, Tasanh, Cambodia. Clinical outcomes were similar among the 3 groups. Wide variability in artesunate and dihydroartemisinin concentrations in plasma was observed. No significant dose-effect or concentration-effect relationships between pharmacokinetic (PK) and parasite clearance parameters were observed, though baseline parasitemia was modestly correlated with increased parasite clearance times. The overall parasite clearance times were prolonged compared with the clearance times in a previous study at this site in 2006 to 2007, but this did not persist when the evaluation was limited to subjects with a comparable artesunate dose (4 mg/kg/day) and baseline parasitemia from the two studies. Reduced plasma drug levels with higher presentation parasitemias, previously hypothesized to result from partitioning into infected red blood cells, was not observed in this population with uncomplicated malaria. Neither in vitro parasite susceptibility nor plasma drug concentrations appeared to have a direct relationship with the pharmacodynamic (PD) effects of oral artesunate on malaria parasites. While direct concentration-effect relationships were not found, it remains possible that a population PK modeling approach that allows modeling of greater dose separation might discern more-subtle relationships.
AuthorsDavid Saunders, Phisit Khemawoot, Pattaraporn Vanachayangkul, Raveewan Siripokasupkul, Delia Bethell, Stuart Tyner, Youry Se, Wiriya Rutvisuttinunt, Sabaithip Sriwichai, Lon Chanthap, Jessica Lin, Ans Timmermans, Doung Socheat, Pascal Ringwald, Harald Noedl, Bryan Smith, Mark Fukuda, Paktiya Teja-Isavadharm
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 56 Issue 11 Pg. 5484-93 (Nov 2012) ISSN: 1098-6596 [Electronic] United States
PMID22869581 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antimalarials
  • Artemisinins
  • artesunate
  • dihydroartemisinin
Topics
  • Administration, Oral
  • Adult
  • Antimalarials (blood, pharmacokinetics, pharmacology)
  • Artemisinins (blood, pharmacokinetics, pharmacology)
  • Cambodia
  • Drug Administration Schedule
  • Female
  • Humans
  • Malaria, Falciparum (blood, drug therapy, parasitology)
  • Male
  • Parasitemia (blood, drug therapy)
  • Plasmodium falciparum (drug effects, growth & development)
  • Severity of Illness Index

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