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

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 AUC 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.

Dose Optimization of Chloroquine by Pharmacokinetic Modeling During Pregnancy for the Treatment of Zika Virus Infection

“…In non-Caucasian subjects, physiological parameters, such as body weight, vary significantly from typical Caucasian subjects, and these differences may alter the PK of the drugs. 46 We have previously demonstrated the impact of this in population groups of Thailand, 67,68 Sudan and Papua New Guinea, 68 Uganda, 69 and Malaysia, 70 and these alterations were made to the Simcyp HV population groups (Supplementary Materials: Section B). Following these revision, in all single-dose and multidose simulations involving Caucasians and non-Caucasian subjects, plasma concentrationetime profiles and the resultant PK parameters were well predicted ( Fig.…”

The impact of CYP2B6 polymorphisms on the interactions of efavirenz with lumefantrine: Implications for paediatric antimalarial therapy

“…The Ugandan population group was developed from reported age-weight relationships for Ugandan males and females (Hayes et al, 2015), and are detailed in the supplementary materials. A similar approach was reported and applied in PBPK modelling by our group (Olafuyi et al, 2017a). In the absence of literature reported abundance of CYP2B6 in Ugandan subjects, we fixed *1/*1 and *6/*6 genotype abundances to 6.9 and 2.4 pmol/mg protein, respectively, based upon adaptations found in a South African population group developed by Simcyp as part of the Critical Path to TB Drug Regimens (CPTR) (Critical Path to TB Drug Regimens, 2016) and which is available from population library repository of Simcyp.…”

“…Due to the complexity and ethical issues of recruitment of paediatrics into complex DDI studies in HIV-infected malaria subjects, population-based physiologically-based pharmacokinetic (PBPK) modelling can be used to explore the potential risk of DDIs in adults (Feng and Varma, 2016;Johansson et al, 2016;Olafuyi et al, 2017a) and paediatric populations (Johnson et al, 2014;Olafuyi et al, 2017b;Salem et al, 2013a;Salem et al, 2013b). The benefit of this approach is both the ability to model population variability in physiology (Jamei et al, 2009a;Jamei et al, 2009b;Jamei et al, 2009c;Olafuyi et al, 2017a, b), but to also specifically develop a modelling approach that is tailored towards a specific geographical population group of interest rather than a standard healthy (Caucasian) adult male.…”

“…Pharmacokinetics assessment of drug therapy in paediatric population groups is often neglected due to ethical complications and the sparse plasma sample collections inherent in such population groups. However, PBPK represents a novel modelling strategy that has gained regulatory acceptance (Wagner et al, 2015) in its applications in the paediatric population and has been used previously to model malaria pharmacokinetic in special population groups such as paediatrics (Olafuyi et al, 2017b) and pregnancy populations (Olafuyi et al, 2017a).…”

The Role of Clinical Pharmacology in Chemotherapy of Multidrug‐Resistant Plasmodium falciparum

“…Efavirenz or nevirapine increases metabolism and reduces the plasma concentration of piperaquine and thus the clinical efficacy of dihydroartemisinin‐piperaquine. PBPK modeling demonstrates consistent and relatively unchanged PK of dihydroartemisinin‐piperaquine in pregnancy, including the significant impact of antiretroviral therapy–mediated drug‐drug interactions 181 . Adaptation of the model incorporating relevant physiological and biochemical alterations in HIV/malaria patients may enhance the clinical application of the proposed model.…”