UCSF

Malaria is a significant contributor to maternal and childhood morbidity and mortality. While precise numbers are lacking, it is estimated that these infections are responsible for 10-20% of maternal deaths in endemic regions or 30,000 mortalities annually. Additionally, malaria during pregnancy is a known risk factor for adverse birth outcomes including stillbirth, pre-term birth and low birthweight deliveries resulting in 100,000 infant mortalities each year. Safe and effective treatment and prevention regimens are needed to reduce the burden of malaria. However, current therapeutic guidelines do not account for the effects of pregnancy, co-morbidities or concomitant medications on drug concentrations and efficacy. The aims of this work were to characterize antimalarial drug exposure, safety, and efficacy to optimize dosing regimens in pregnant women with an emphasis on malaria prevention. Human immunodeficiency virus (HIV) infection and malaria are endemic in sub-Saharan Africa resulting in a large population of HIV-infected individuals receiving malaria treatment. Both antiretroviral and antimalarial therapies are metabolized by cytochrome P450 enzymes which could lead to drug-drug interactions altering antimalarial exposure and clinical response. In a prospective clinical pharmacokinetic (PK) study, the effects of efavirenz on artemether-lumefantrine (AL), the most commonly prescribed artemisinin-based combination therapy (ACT) for uncomplicated malaria, were investigated. Specifically, the exposure of the artemisinins, artemether and it’s active metabolite dihydroartemisinin (DHA) and long-acting lumefantrine were characterized in HIV-infected and uninfected pregnant Ugandan women. Relative to HIV-uninfected women, concomitant efavirenz therapy significantly lowered peak DHA concentrations as well as the terminal artemether and lumefantrine concentrations. In addition, there were nonsignificant reductions in DHA and lumefantrine area under the concentration–time curve with efavirenz therapy. These results suggest that pregnant women receiving efavirenz may require higher or additional doses of AL to improve drug exposure. Dihydroartemisinin-piperaquine (DHA-PQ), also considered a first line ACT for uncomplicated malaria, provides highly effective therapy and is being evaluated for malaria chemoprevention in pregnant African women. However, few prevention studies have included a pharmacokinetic component to define the longitudinal PK of PQ during pregnancy. To address this need we pooled data from two large clinical trials to perform a post hoc analysis with 274 women and 2,218 PK observations. We included HIV-infected and -uninfected pregnant Ugandan women throughout the second and third trimesters, as well as postpartum women. Pregnancy and efavirenz use resulted in a 72% and 61% increase in PQ clearance, compared to postpartum and HIV-uninfected pregnant women, respectively. Low BMI at 28 weeks gestation was associated with increased clearance (2% increase per unit decrease in BMI). Low-BMI women given DHA-PQ every 8 weeks had a higher prevalence of parasitemia, malaria infection, and placental malaria compared to women with higher BMIs. Simulations indicated women taking efavirenz and/or with a low BMI could benefit from more frequent dosing such as weekly instead of monthly DHA-PQ. Piperaquine prolongs the corrected QT interval (QTc), and repeated monthly dosing, as required for prevention, could lead to progressive QTc prolongation. Characterization of the relationship between piperaquine concentration and QTc interval throughout pregnancy is needed to inform prevention guidelines. Data from a randomized controlled trial, where pregnant Ugandan women received monthly DHA-PQ or sulfadoxine-pyrimethamine (SP) were used to establish the piperaquine – QTc relationship and trends in longitudinal QTc for the SP arm. A positive linear relationship between piperaquine concentration and Fridericia corrected QTc interval was identified. Interestingly, the slope of this relationship progressively decreased from a 4.42 to 2.13 millisecond increase per 100 ng/mL increase in piperaquine concentration at 20 and 36 weeks gestation, respectively. SP was not associated with any change in QTc. These results indicate that monthly dosing of DHA-PQ in pregnant women carries minimal risk of QTc prolongation and this risk diminishes with repeat doses over the course of pregnancy. The PK/PD relationship between piperaquine concentrations and malaria parasitemia is not well defined in the context of malaria prevention in pregnant women. A robust PK/PD relationship is required to determine optimal dosing strategies for prevention. This analysis included monthly piperaquine trough concentrations and parasite densities collected from a large prevention trial in Ugandan pregnant women. These data were used to define the PK/PD relationship for piperaquine and parasitemia (binary outcome) in pregnant women. The piperaquine drug effect was best captured by an Emax relationship. Primigravida was identified as a risk factor for being parasite positive. In comparison to a previous study, 10.3 ng/mL was 70 and 80% protective for primigravida and multigravida women, respectively. To better compare results between the two studies, women with parasite densities below 1,000 parasites/mL were considered negative (this was done to adjust to differences in assay sensitivity) in a sensitivity analysis. This led to 10.3 ng/mL being 95 and 97.5% protective for primigravida and multigravida women, respectively. While increasing piperaquine concentrations led to a decreased probability of parasitemia, the Emax relationship was such that concentrations above 10.3 ng/mL did not lead to a significant reduction in parasitemia. Therefore, simulations were preformed to maximize the number of women maintaining 10.3 ng/mL. These simulations suggested that women, particularly primigravida, could benefit from more frequent dosing. Collectively, this dissertation research demonstrates that pregnant women are a unique population who warrant dedicated clinical trials with consideration of PK/PD to evaluate treatment and prevention regimens. Our findings provide dosing recommendations for the next generation of antimalarial treatment and prevention studies in pregnant women.