Palang Chotsiri (1), Julie R. Gutman (2), Rukhsana Ahmed (3,4), Jeanne Rini Poespoprodjo (5,6,7), Din Syafruddin (4), Carole Khairallah (3), Puji BS Asih (4), Anne L’lanziva (8), Kephas Otieno (9), Simon Kariuki (9), Peter Ouma (9), Vincent Were (9), Abraham Katana (10), Ric N. Price (1,11,12), Meghna Desai (2), Feiko O. ter Kuile (3), Joel Tarning (1,12)
(1) Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand (2) Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA (3) Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK (4) Malaria and Vector Resistance Laboratory, Eijkman Institute for Molecular Biology, Jakarta, Indonesia (5) Mimika District Health Authority, District Government Building, Jl. Cendrawasih, Timika, 99910, Papua, Indonesia (6) Timika Malaria Research Programme, Papuan Health and Community Development Foundation, Jl. SP2-SP5, RSMM Area, Timika, 99910, Papua, Indonesia (7) Centre for Child Health and Department of Child Health, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Jl. Kesehatan no 1, Sekip, Yogyakarta, 55284, Indonesia (8) Centers for Diseases Control and Prevention (CDC), Kisumu, Kenya (9) Kenya Medical Research Institute, Centre for Global Health Research, Kisumu, Kenya (10) Centers for Diseases Control and Prevention (CDC), Nairobi, Kenya (11) Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia (12) Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, Oxford University, Oxford, UK
Objective: Pregnant women are at higher risk of Plasmodium falciparum infection and pregnancy-specific adverse effects. The parasites can sequester in the placenta vasculature which cause placental malaria and affects both the mother and the infant. Therefore, WHO suggests that intermittent preventive therapy in pregnancy (IPTp) starts in the second or third trimester and continues until delivery. Dihydroartemisinin-piperaquine (DP) is a long-acting artemisinin combination treatment that provides effective chemoprevention and has been proposed as an alternative antimalarial drug for IPTp. Several pharmacokinetic studies have shown that dose adjustment may not be needed for the treatment of malaria in pregnancy with DP. However, there are limited data on the optimal dosing for IPTp. This study aimed to evaluate the population pharmacokinetics of piperaquine given as IPTp in pregnant women.
Methods: Pregnant women were enrolled in clinical trials conducted in Kenya and Indonesia [1, 2] and treated with standard 3-day courses of DP, administered in 4-8 weeks intervals from the second trimester until delivery. Pharmacokinetic blood samples were collected sparsely for piperaquine drug quantification before each treatment round, at the time of breakthrough symptomatic malaria, and at delivery. Piperaquine population pharmacokinetic properties were investigated using nonlinear mixed-effects modelling. The $PRIOR functionality in NONMEM was used to stabilise the model performance. A previously published population pharmacokinetic model, describing DP in the treatment of uncomplicated falciparum malaria in pregnant women in Thailand, was used as the prior model [3].
Results: In total, data from 366 Kenyan and 101 Indonesian pregnant women were analysed. The pharmacokinetic properties of piperaquine were adequately described using a flexible transit absorption (n=5) followed by a three-compartment disposition model. Allometric scaled bodyweight was implemented according to the prior model. Gestational age and other pregnancy-related parameters did not affect the pharmacokinetic parameters of piperaquine. After three rounds of monthly IPTp, 9.45% (95% CI: 1.8-26.5) of pregnant women had trough piperaquine concentrations below the suggested target concentration, i.e., at 10.3 ng/mL [4]. This study observed that only 0.9% (3/350) and 1.14% (4/350) of Kenyan women and 0% (0/89) and 2.25% (2/89) of Indonesian women presented with acute and chronic placenta malaria, respectively. These small numbers of observed active placental malaria were not sufficient to undertake statistical analysis or pharmacodynamic modelling. Translational simulation suggested that more than 90.3% of pregnant women who receive three monthly courses of IPTp achieved piperaquine exposures associated with protection against acquired malaria infections. Predicted peak concentrations did not accumulate with repeated dosing courses, suggesting that IPTp with DP is not likely to increase the risk for QT-prolongation associated with piperaquine exposure but further cardiac safety data is still needed. The PK/PD analysis presented here suggested that monthly IPTp with DP is likely to be highly protective against placental malaria.
Conclusions: Monthly administration of a DP has the potential to offer optimal prevention of malaria during pregnancy.
References:
[1] Desai M, Gutman J, L’Lanziva A, Otieno K, Juma E, Kariuki S, Ouma P, Were V, Laserson K, Katana A, Williamson J, ter Kuile FO. 2015. Intermittent screening and treatment or intermittent preventive treatment with dihydroartemisinin-piperaquine versus intermittent preventive treatment with sulfadoxine-pyrimethamine for the control of malaria during pregnancy in western Kenya: an open-label, three-group, randomised controlled superiority trial. Lancet 386:2507-19.
[2] Ahmed R, Poespoprodjo JR, Syafruddin D, Khairallah C, Pace C, Lukito T, Maratina SS, Asih PBS, Santana-Morales MA, Adams ER, Unwin VT, Williams CT, Chen T, Smedley J, Wang D, Faragher B, Price RN, Ter Kuile FO. 2019. Efficacy and safety of intermittent preventive treatment and intermittent screening and treatment versus single screening and treatment with dihydroartemisinin-piperaquine for the control of malaria in pregnancy in Indonesia: a cluster-randomised, open-label, superiority trial. Lancet Infect Dis doi:10.1016/S1473-3099(19)30156-2.
[3] Tarning J, Rijken MJ, McGready R, Phyo AP, Hanpithakpong W, Day NP, White NJ, Nosten F, Lindegardh N. 2012. Population pharmacokinetics of dihydroartemisinin and piperaquine in pregnant and nonpregnant women with uncomplicated malaria. Antimicrob Agents Chemother 56:1997-2007.
[4] Savic RM, Jagannathan P, Kajubi R, Huang L, Zhang N, Were M, Kakuru A, Muhindo MK, Mwebaza N, Wallender E, Clark TD, Opira B, Kamya M, Havlir DV, Rosenthal PJ, Dorsey G, Aweeka FT. 2018. Intermittent Preventive Treatment for Malaria in Pregnancy: Optimization of Target Concentrations of Dihydroartemisinin-Piperaquine. Clin Infect Dis 67:1079-1088.
Reference: PAGE 29 (2021) Abstr 9720 [www.page-meeting.org/?abstract=9720]
Poster: Drug/Disease Modelling - Infection