The application of physiologically based pharmacokinetic modelling to assess the impact of antiretroviral ‐mediated drug–drug interactions on piperaquine antimalarial therapy 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 AUCratio in 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.
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL PAPER Source Type: research