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


CONCLUSIONS
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.
Röshammar
Daniel
D
Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
Hai
Trinh Ngoc
TN
Friberg Hietala
Sofia
S
Van Huong
Nguyen
N
Ashton
Michael
M
D000284:Administration, Oral; D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D037621:Artemisinins / Q000008:administration & dosage / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004338:Drug Combinations; D005215:Fasting; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011319:Primaquine / Q000008:administration & dosage / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000493:pharmacokinetics; D014295:Trimethoprim / Q000008:administration & dosage / Q000493:pharmacokinetics; D010879:Piperazines
D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D011319:Primaquine; D011804:Quinolines; D012717:Sesquiterpenes; D014295:Trimethoprim; C039060:artenimol; C034759:piperaquine; D010879:Piperazines