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Eur J Clin Pharmacol. 2006 May;62(5):335-41. Epub 2006 Mar 29.

Pharmacokinetics of piperaquine after repeated oral administration of the antimalarial combination CV8 in 12 healthy male subjects.

Author information

1
Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.

Abstract

OBJECTIVE:

To investigate the pharmacokinetic properties of piperaquine after repeated oral administration of the antimalarial combination CV8 in healthy subjects.

METHODS:

Twelve healthy fasted Vietnamese males were administered four tablets CV8 (320 mg piperaquine phosphate, 32 mg dihydroartemisinin, 5 mg primaquine phosphate, 90 mg trimethoprim) on day 1, followed by two tablets every 24th hour, for a total of 3 days. Blood samples were frequently drawn on days 1 and 3 and sparsely drawn until day 29. Samples were analyzed for piperaquine using solid phase extraction followed by high-performance liquid chromatography. Population pharmacokinetic parameter estimates were obtained by nonlinear mixed effects modeling of the observed data using NONMEM.

RESULTS:

A two-compartment disposition model with an absorption lag time described the observed piperaquine concentrations. Absorption profiles were found to be irregular with double or multiple peaks. A dual pathway first-order absorption model improved the goodness of fit. Piperaquine pharmacokinetics were characterized by a large volume of distribution and a terminal half-life of several days. Estimates [95% confidence interval (CI)] of CL/F, V(ss)/F and t(1/2)(z) were found to be 56.4 (29-84) l/h, 6,000 (3,500-8,500) l and 11.7 (8.3-15.7) days, respectively.

CONCLUSION:

Piperaquine pharmacokinetics after repeated oral doses were characterized by multiple concentration peaks and multiphasic disposition, resulting in a long terminal half-life. Sustained exposure to the drug after treatment should be taken into account when designing future clinical studies, e.g. duration of follow-up, and may also drive resistance development in areas of high malaria transmission.

PMID:
16570188
DOI:
10.1007/s00228-005-0084-9
[Indexed for MEDLINE]

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