PT-007 - VALIDATING THE PROTECTIVE CONCENTRATION OF PIPERAQUINE FOR MALARIA PREVENTION IN PREGNANT UGANDAN WOMEN.

E. Hughes¹, E. Wallender¹, R. Kajubi², P. Jagannathan³, A. Kakuru², M. Kamya^2,4, P. Rosenthal¹, G. Dorsey¹, F. Aweeka¹, R. Savic¹; ¹University of California, San Francisco, San Francisco, CA, USA, ²Infectious Disease Research Collaboration, Kampala, Uganda, ³Stanford University, Stanford, CA, USA, ⁴Makerere University College of Health Sciences, Mulago, Uganda.

Background: Malaria during pregnancy poses serious health risks to both the mother and fetus. Dihydroartemisinin-piperaquine (DHA-PQ) is currently under study in pregnant women as an alternative option for malaria prevention. A prior analysis indicated 10.3 ng/mL PQ protects 95% of women against parasitemia measured by loop-mediated isothermal amplification (LAMP). To ensure efficacy and propose optimized dosing regimens, we explored protection using a larger clinical trial with more sensitive parasite detection.

Methods: A randomized controlled trial enrolled 373 healthy pregnant Ugandan women. Beginning at 16 or 20 weeks gestation until delivery, women received monthly tablets of 120/960mg DHA/PQ for 3 days. Each month, a 28-day plasma PQ level (n=1,226) and qPCR parasite density (p/mL) (n=2456) was measured. A PK-logit PD model was built using a sequential approach. To facilitate comparisons between the studies, LAMP and qPCR have different detection limits (LLOQ: 1,000 vs. 1 p/mL respectively), a sensitivity analysis was performed. Data were analyzed using nonlinear mixed-effects modeling.

Results: An Emax model best fit the PK/PD data with an EC50 of 3.9 ng/mL (2.4-6.2; 95% CI). Primigravida women had a 10% increased probability of being parasitemic compared to multigravida women. The prior protective concentration of 10.3 ng/mL was 70 and 80% protective for primigravida and multigravida women, respectively. When using LAMP’s LLOQ, the EC50 decreased to 2.1 ng/mL (0.6-4.2; 95% CI) and 10.3 ng/mL was 95% protective for all women. Once weekly dosing was predicted to protect 30% more women compared to monthly.

Conclusion: In pregnant women, 10.3 ng/mL PQ was 95% protective against parasite densities using LAMP’s LLOQ, but not using qPCR’s LLOQ. Simulations indicted that weekly dosing could protect more women than monthly dosing.

1. Kajubi R, Ochieng T, Kakuru A, et al. Monthly sulfadoxine-pyrimethamine versus dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in pregnancy: a double-blind, randomised, controlled, superiority trial. Lancet 2019; 393(10179): 1428-39.
2. Savic RM, Jagannathan P, Kajubi R, et al. Intermittent Preventive Treatment for Malaria in Pregnancy: Optimization of Target Concentrations of Dihydroartemisinin-Piperaquine. Clin Infect Dis 2018; 67(7): 1079-88.
3. World Health Organization. World malaria report 2020. Geneva, Switzerland, 2020.