Wendy Chu1,2, Wietse M. Schouten2, Hypolite Muhindo Mavoko3, Doudou Yobi3, Japhet Kabalu Tshiongo3, Freddy-Arnold Kabasele3, Esperança Sevene4,5, Anifa Vala4, Alwin D.R. Huitema2,6,7, Kassoum Kayentao8, Thomas P.C. Dorlo1
1Department of Pharmacy, Uppsala University, 2Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, 3Department of Tropical Medicine, University of Kinshasa, 4Centro de Investigação em Saúde de Manhiça, 5Universidade Eduardo Mondlane, 6Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, 7Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht University, 8Malaria Research and Training Center, University of Sciences Techniques and Technologies of Bamako
Introduction Pregnant women are highly vulnerable to malaria, yet concerns over safety often exclude them from clinical trials, limiting treatment options. A recent clinical trial evaluated the efficacy and safety of pyronaridine-artesunate (Pyramax®) in pregnancy (1). Pyronaridine is a lipophilic, basic compound that accumulates in red blood cells as well as the malaria parasite food vacuoles. Substantial PK differences between healthy individuals and patients suggest that physiological and disease-related changes, likely due to hematological alterations, influence its volume of distribution in whole blood (VWB) (2). Objectives This study characterized the population whole blood PK of pyronaridine in pregnant and non-pregnant women, including those with HIV co-infection. The objectives were to assess the impact of pregnancy, malaria, and HIV co-infection on the PK of pyronaridine. Methods PK data were collected as part of the PYRAPREG study (PACTR202011812241529) (1) in the Democratic Republic of the Congo and Mozambique, including non-pregnant and pregnant women (2nd/3rd trimester) with malaria, with and without HIV co-infection. Participants received Pyramax® tablets orally once daily for three days based on body weight. Each tablet contained 180 mg pyronaridine tetraphosphate (equivalent to 100 mg pyronaridine) and 60 mg artesunate. Whole blood samples were analyzed for pyronaridine using UPLC-MS/MS (range: 0.5-500 µg/L) (3). Population PK analysis was conducted using NONMEM. Malaria infection causes erythrocyte destruction, leading to hemoglobin (Hb) reduction, while Hb is also affected by pregnancy-related anemia, particularly in the 2nd trimester (4). To evaluate the impact of pregnancy and malaria on PK, baseline Hb, parasitemia and pregnancy status were tested as covariates. Besides, to distinguish malaria-induced Hb decline from pregnancy-related changes, a reference Hb level normalized to estimated gestational age (HbEGA) was established (5). The malaria-induced Hb reduction (?Hbmalaria) was calculated as the difference between HbEGA and the observed Hb and was tested as a covariate. Model-based whole blood pyronaridine exposure over 42 days (AUC0-42d) was derived. Predicted concentrations were compared to the in vitro EC50 (4.67 µg/L) against clinical Plasmodium falciparum isolates to evaluate PK target attainment (6). Results Data were available from 112 female malaria patients, of which 55 were pregnant and 48 HIV co-infected. Median estimated gestational age was 24 weeks, with 58.2% in 2nd and 41.8% in 3rd trimester. Median Hb levels were below normal across all subgroups, with pregnant women exhibiting levels around 1.5 g/dL lower than non-pregnant women. Anemia prevalence was high, affecting 64.9% of non-pregnant and 83.6% of pregnant women. Pyronaridine PK was best described by a three-compartment model with first-order absorption and elimination. The estimated typical absorption rate constant was 0.161 1/h (95%CI 0.144-0.182), clearance was 43.5 L/h (40.3-46.6), and VWB was 157 L (107-221). Intercompartmental clearances were estimated at 147 L/h (131-165) and 13.2 L/h (10.9-16.0), with peripheral volumes of distribution of 6390 L (5650-7210) and 5320 L (4650-6330). Relative oral bioavailability was 56.5% (26.6-92.2) higher in the 3rd trimester compared to non-pregnant women, while HIV co-infection reduced VWB by 30.6% (7.80-51.0). Total Hb level and parasitemia were not identified as covariates. However, one-unit increase in ?Hbmalaria was associated with a 32.6 % (13.8-60.8) increase in VWB. Median AUC0-42d was 22% higher in pregnant women compared to non-pregnant women. On day 28, pyronaridine concentrations remained above the in vitro EC50 in >75% of patients in all subgroups, while on day 42, this proportion was 14.8% in non-pregnant and 33.3% in pregnant women. Conclusions Pyronaridine exposure was unexpectedly higher in pregnant women compared to non-pregnant women, with prolonged concentrations exceeding the EC50. Variability in absorption was notably high, especially among pregnant women co-infected with HIV. This analysis revealed a complex interplay between Hb levels, malaria and HIV co-infection influencing pyronaridine distribution. Whether dose adjustment in pregnancy is necessary remains uncertain based on this analysis. Further PK-PD studies are required to assess the efficacy (e.g., parasite recrudescence) and safety (e.g., liver injury) profiles associated with increased pyronaridine exposure during pregnancy.
1. Djimde M, Tshiongo JK, Muhindo HM, Tinto H, Sevene E, Traore M, et al. Efficacy and safety of pyronaridine-artesunate (PYRAMAX) for the treatment of P. falciparum uncomplicated malaria in African pregnant women (PYRAPREG): study protocol for a phase 3, non-inferiority, randomised open-label clinical trial. BMJ Open. 2023 Oct 9;13(10). 2. Chu WY, Dorlo TPC. Pyronaridine: a review of its clinical pharmacology in the treatment of malaria. Journal of Antimicrobial Chemotherapy. 2023 Oct 1;78(10):2406. 3. Schouten WM, Roseboom IC, Lucas L, Kabalu Tshiongo J, Muhindo Mavoko H, Kayentao K, et al. Development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry method for the quantification of the antimalarial drug pyronaridine in human whole blood. J Pharm Biomed Anal. 2024 Aug 1;245:116154. 4. Sifakis S, Pharmakides G. Anemia in Pregnancy. Ann N Y Acad Sci. 2000 Apr 1;900(1):125–36. 5. Yefet E, Yossef A, Nachum Z. Prediction of anemia at delivery. Scientific Reports 2021 11:1. 2021 Mar 18;11(1):1–7. 6. Pascual A, Madamet M, Briolant S, Gaillard T, Amalvict R, Benoit N, et al. Multinormal in vitro distribution of Plasmodium falciparum susceptibility to piperaquine and pyronaridine. Malar J. 2015 Feb 5;14(1):1–8.
Reference: PAGE 33 (2025) Abstr 11376 [www.page-meeting.org/?abstract=11376]
Poster: Drug/Disease Modelling - Infection