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, Vss/F and t½z 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.
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Acknowledgements
This study was supported by the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). The authors would gratefully like to thank Dr. Ulrika Wählby for her helpful comments.
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Appendix
Appendix
The differential equations describing the pharmacokinetic model in Fig. 2 are:
where
and A1 is the amount of piperaquine base administered, A2 is the amount in the central compartment and A3 and A4 are the amounts in the peripheral compartments.
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Röshammar, D., Hai, T.N., Friberg Hietala, S. et al. Pharmacokinetics of piperaquine after repeated oral administration of the antimalarial combination CV8 in 12 healthy male subjects. Eur J Clin Pharmacol 62, 335–341 (2006). https://doi.org/10.1007/s00228-005-0084-9
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DOI: https://doi.org/10.1007/s00228-005-0084-9