Intermittent Preventive Treatment for Malaria in Pregnancy: Optimization of Target Concentrations of Dihydroartemisinin-Piperaquine

Abstract

Background: Dihydroartemisinin-piperaquine (DHA-PQ) is highly efficacious as intermittent preventive therapy for malaria during pregnancy (IPTp). Determining associations between piperaquine (PQ) exposure, malaria risk, and adverse birth outcomes informs optimal dosing strategies.

Methods: Human immunodeficiency virus-uninfected pregnant women (n = 300) were enrolled in a placebo-controlled trial of IPTp at 12-20 weeks' gestation and randomized to sulfadoxine-pyrimethamine every 8 weeks, DHA-PQ every 8 weeks, or DHA-PQ every 4 weeks during pregnancy. Pharmacokinetic sampling for PQ was performed every 4 weeks, and an intensive pharmacokinetic substudy was performed in 30 women at 28 weeks' gestation. Concentration-effect relationships were assessed between exposure to PQ; the prevalence of Plasmodium falciparum infection during pregnancy; outcomes at delivery including placental malaria, low birth weight, and preterm birth; and risks for toxicity. Simulations of new dosing scenarios were performed.

Results: Model-defined PQ target venous plasma concentrations of 13.9 ng/mL provided 99% protection from P. falciparum infection during pregnancy. Each 10-day increase in time above target PQ concentrations was associated with reduced odds of placental parasitemia, preterm birth, and low birth weight, though increases in PQ concentrations were associated with QT interval prolongation. Modeling suggests that daily or weekly administration of lower dosages of PQ, compared to standard dosing, will maintain PQ trough levels above target concentrations with reduced PQ peak levels, potentially limiting toxicity.

Conclusions: The protective efficacy of IPTp with DHA-PQ was strongly associated with higher drug exposure. Studies of the efficacy and safety of alternative DHA-PQ IPTp dosing strategies are warranted.

Clinical trials registration: NCT02163447.

Figures

Figure 1.

Trial profile and derivation of population pharmacokinetics (PK) model. A, Trial profile showing women enrolled, randomized, and sampled for piperaquine during pregnancy; infants delivered; and outcomes assessed. Numbers below population PK sampling show samples analyzed/collected at each timepoint. B–E, Raw and modeled PK data between dihydroartemisinin-piperaquine dosing every 4 weeks (B and C) and every 8 weeks (D and E). Abbreviations: BLQ, below the limit of quantitation; cPK, capillary sample; D, active drug; DHA-PQ, dihydroartemisinin-piperaquine; iPK, intensive PK study; P, placebo; q4wk, every 4 weeks; q8wk, every 8 weeks; SP, sulfadoxine-pyrimethamine; vPK, venous sample.

Figure 2.

Derivation of target concentration to prevent parasitemia during pregnancy. A, Raw population piperaquine (PQ) levels at loop-mediated isothermal amplification (LAMP)–positive or LAMP-negative visits. B, Increasing raw population PQ levels (stratified into 5 categories) associated with lower probability of LAMP positivity during pregnancy. Marginal estimates were derived using mixed-effects logistic regression, accounting for repeated observations within individuals (below the limit of quantitation [BLQ] of 0.5 ng/mL). C and D, Modeled trough PQ levels of 10.3 and 13.9 define upper bounds of uncertainty for 95% and 99% protection from malaria infection during pregnancy, respectively. Abbreviations: LAMP, loop-mediated isothermal amplification; PQ, piperaquine.

Figure 3.

Increasing piperaquine (PQ) exposure associated with improved outcomes at birth. A, Days above target PQ concentration among women randomized to dihydroartemisinin-piperaquine every 4 weeks vs every 8 weeks. Probability of placental malaria (B and C), preterm birth (D), and low birth weight (E) modeled over time above target PQ concentration. Red line represents probability of outcome at delivery among women randomized to intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine. Similar results obtained with cumulative area under the curve (AUC) and cumulative AUC above target. Abbreviations: LAMP, loop-mediated isothermal amplification; q4week, every 4 weeks; q8week, every 8 weeks.

Figure 4.

Simulated piperaquine (PQ) concentrations for dihydroartemisinin-piperaquine dosing with or without an initial loading dose for chemoprevention during pregnancy. A, Modeled PQ concentrations over weeks of pregnancy for 8 different dosing strategies. All simulations used 5000 virtual subjects, with chemoprevention initiation at 20 weeks, and continuing through 40 weeks of gestation. Regimens indicate PQ dosing in mg. For regimens with loading dose, daily regimens begin either 3 days (D3) or 4 weeks (W24) following loading dose, and weekly regimens begin either 1 week (W21) or 4 weeks (W24) following loading dose. The horizontal dotted line represents a target PQ concentration of 10.3 ng/mL. B, Percentage of women predicted to have >95% of duration of pregnancy above target concentration for each dosing regimen. C, Model-predicted probabilities of parasitemia during pregnancy with different dosing regimens. Abbreviations: LAMP, loop-mediated isothermal amplification; Q4W, every 4 weeks; QD, once daily; QW, once weekly.