Physiologically based pharmacokinetic modelling of antimalarial agents

Abstract

The usefulness of physiologically based pharmacokinetic (PBPK) modelling in antimalarial drug research is evolving. Antimalarial agents are subject to drug-drug interactions (DDIs) and the resultant pharmacokinetics in special population groups is not well understood. To optimise antimalarial dosing in special population groups, the application of PBPK modelling has significant advantages towards improving clinical efficacy. This thesis addresses some of the drug therapy issues associated with antimalarial treatment in special populations using PBPK modelling. Firstly, it addresses the problem of the impact of DDI interaction between artemether and lumefantrine and rifampicin based anti-tuberculosis agent in children, then the effect of DDI perpetrated by efavirenz and ritonavir on the pharmacokinetics of piperaquine during pregnancy was evaluated. Finally, PBPK modelling was used to optimise the dose of chloroquine for the treatment of ZIKV disease during pregnancy.The fixed dosed combination of artemether and lumefantrine (AL) is widely used for the treatment of malaria in adults and children in sub-Sahara Africa, with lumefantrine day 7 concentrations being widely used as a marker for clinical efficacy. Both are substrates for CYP3A4 and susceptible to drug-drug interactions (DDIs) but the knowledge of the impact of DDIs is currently sparse in paediatric population groups therefore complicating the treatment of malaria in patients co-infected with other infectious diseases like tuberculosis. The concomitant treatment of AL with tuberculosis chemotherapy, which includes the CYP3A4 inducer rifampicin, increases the risk of parasite recrudescence and malaria treatment failure. This study developed a population-based PBPK model for AL in adults capable of predicting the pharmacokinetics of AL under non-DDI and DDI conditions, as well as predicting AL pharmacokinetics in paediatrics of 2–12 years of age. The validated model was utilised to assess the concomitant treatment of rifampicin and lumefantrine under standard body-weight based treatment regimens for 2–5 year olds, and demonstrated that no subjects attained the target day 7 concentration (Cd7) of 280 ng/mL, highlighting the importance of this DDI and the potential risk of malaria-TB based DDIs. An adapted 7-day treatment regimen was simulated and resulted in 63% and 74.5% of subjects attaining the target Cd7 for 1-tablet and 2-tablet regimens respectively. Antimalarial therapy during pregnancy poses important safety concerns due to potential teratogenicity and the impact of 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 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.The treatment of tropical diseases is often faced with the problem of appropriate drug therapy. While researchers work to isolate new molecules that might be used to treat them, the benefits of using PBPK modelling for repurposing molecules with potentially efficacious and safe profiles against these diseases is yet to be explored. The insidious nature of Zika virus (ZIKV) infections can have a devastating consequence for foetal development. Recent reports have highlighted that chloroquine (CQ) is capable of inhibiting ZIKV endocytosis in brain cells. We applied pharmacokinetic modelling to develop a predictive model for CQ exposure to identify an optimal maternal/foetal dosing regimen to prevent ZIKV endocytosis in brain cells. Model validation used 13 non-pregnancy and 3 pregnancy clinical studies, and a therapeutic CQ plasma window of 0.3-2 μM was derived. Dosing regimens used in rheumatoid arthritis, systemic lupus erythematosus, and malaria were assessed for their ability to target this window. Dosing regimen identified that weekly doses used in malaria were not sufficient to reach the lower therapeutic window, however daily doses of 150 mg achieved this therapeutic window. The impact of gestational age was further assessed and culminated in a final proposed regimen of 600 mg on day 1, 300 mg on day 2 and 3, and 150 mg thereafter until the end of trimester 2, which resulted in maintaining 65% and 94% of subjects with a trough plasma concentration above the lower therapeutic window on day 6 and at term, respectively.