The application of physiologically based pharmacokinetic modelling to assess the impact of antiretroviral-mediated drug-drug interactions on piperaquine antimalarial therapy during pregnancy

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Abstract

Antimalarial therapy during pregnancy poses important safety concerns due to potential teratogenicity and maternal physiological and biochemical changes during gestation. Piperaquine (PQ) has gained interest for use in pregnancy in response to increasing resistance towards sulfadoxine-pyrimethamine in sub-Saharan Africa. Coinfection with HIV is common in many developing countries, however, little is known about the impact of antiretroviral (ARV) mediated drug-drug interaction (DDI) on piperaquine pharmacokinetics during pregnancy. This study applied mechanistic pharmacokinetic modelling to predict pharmacokinetics in non-pregnant and pregnant patients, which was validated in distinct customised population groups from Thailand, Sudan and Papua New Guinea. In each population group, no significant differences in day 7 concentrations were observed during different gestational weeks (GW) (weeks 10-40), supporting the notion that piperaquine is safe throughout pregnancy with consistent pharmacokinetics, although possible teratogenicity may limit this. Antiretroviral-mediated DDIs (efavirenz and ritonavir) had moderate effects on piperaquine during different gestational weeks with a predicted AUCratioin the range 0.56-0.8 and 1.64-1.79 for efavirenz and ritonavir, respectively, over GW 10-40, with a reduction in circulating human serum albumin significantly reducing the number of subjects attaining the day 7 (post-dose) therapeutic efficacy concentrations under both efavirenz and ritonavir DDIs. This present model successfully mechanistically predicted the pharmacokinetics of piperaquine in pregnancy to be unchanged with respect to non-pregnant women, in the light of factors such as malaria/HIV co-infection. However, antiretroviral-mediated DDIs could significantly alter piperaquine pharmacokinetics. Further model refinement will include collation of relevant physiological and biochemical alterations common to HIV/malaria patients.

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Original languageEnglish
Pages (from-to)464-478
Number of pages15
JournalBiopharmaceutics and Drug Disposition
Volume38
Issue number8
Early online date29 Sep 2017
DOIs
Publication statusE-pub ahead of print - 29 Sep 2017

Bibliographic note

Copyright © 2017 by John Wiley & Sons. This is the peer reviewed version of the following article: The application of physiologically based pharmacokinetic modelling to assess the impact of antiretroviral-mediated drug-drug interactions on piperaquine antimalarial therapy during pregnancy Olafuyi, O., Coleman, M. & Badhan, R. K. S. 29 Sep 2017 In : Biopharmaceutics and Drug Disposition. 38, 8, p. 464-478 15 p., which has been published in final form at http://doi.org/10.1002/bdd.2087. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.

    Keywords

  • anti‐retroviral, drug–drug interaction, malaria, physiologically based pharmacokinetics, pregnancy

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