Biopharmaceutics & drug disposition 2017 07 14() doi 10.1002/bdd.2087
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. Co-infection with HIV is common in many developing countries, however, little is known about the impact of anti-retroviral (ARV) mediated drug-drug interaction (DDI) on PQ 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 difference in day 7 concentrations were observed during different gestational weeks (GW) (weeks 10-40), supporting the notion that PQ is safe throughout pregnancy with consistent pharmacokinetics, although possible teratogenicity may limit this. Antiretroviral-mediated DDIs (efavirenz and ritonavir) had moderate effects on PQ during different gestational weeks with a predicted AUCratio ranging from 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 PQ in pregnancy to be unchanged with respect to non-pregnant women, in the light of factors such as malaria/HIV co-infection. However, ART-mediated DDIs could significantly alter PQ pharmacokinetics. Further model refinement will include collation of relevant physiological and biochemical alterations common to HIV/malaria patients.