Abstract

Dihydroartemisinin-piperaquine (DHA-PQ) provides highly effective therapy and chemoprevention for malaria in pregnant African women. PQ concentrations >10.3 ng/mL have been associated with reduced maternal parasitemia, placental malaria and improved birth outcomes. We characterized the population pharmacokinetics (PK) of PQ in a post-hoc analysis of human immunodeficiency virus (HIV)-infected and -uninfected pregnant women receiving DHA-PQ as chemoprevention every 4 or 8 weeks. The effects of covariates such as pregnancy, nutritional status (body mass index, BMI) and efavirenz (EFV)-based antiretroviral therapy were investigated. PQ concentrations from two chemoprevention trials were pooled to create a population PK database from 274 women and 2218 PK observations. A three-compartment model with an absorption lag best fit the data. Consistent with our prior intensive PK evaluation, pregnancy and EFV use resulted in a 72% and 61% increased PQ clearance, compared to post-partum 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. The reduced piperaquine exposure in women with low BMI as well as during EFV co-administration, compared to pregnant women with higher BMIs and not taking EFV, suggests that these populations could benefit from weekly instead of monthly dosing for prevention of malaria parasitemia. Simulations indicated that because of the BMI-clearance relationship, weight-based regimens would not improve protection compared to a 2880 mg fixed-dose regimen when provided monthly.

View details for DOI 10.1128/AAC.01013-20

View details for PubMedID 33020153