Importance of Lysosomal Trapping and Plasmodium Parasite Infection on the Pharmacokinetics of Pyronaridine: A Physiologically Based Pharmacokinetic Model-Based Study.
Wan-Yu Chu, Wietse M Schouten, Hypolite Muhindo Mavoko, Japhet Kabalu Tshiongo, Doudou Malekita Yobi, Freddy-Arnold Kabasele, Gustave Kasereka, Vivi Maketa, Esperança Sevene, Anifa Vala, Jangsik Shin, Umberto D'Alessandro, Kassoum Kayentao, Alwin D R Huitema, Thomas P C Dorlo
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Abstract
Background and objective: Pyronaridine is a blood schizonticide with a high blood-to-plasma ratio, effective against Plasmodium parasites. As a lipophilic, moderately strong base, it accumulates in low-pH compartments such as lysosomes and parasite food vacuoles, leading to tissue accumulation and differences in drug exposure between healthy individuals and patients with malaria. This study applied physiologically based pharmacokinetic (PBPK) modeling to evaluate the effects of lysosomal sequestration, red blood cell (RBC) accumulation, and parasitemia on pyronaridine pharmacokinetics.
Methods: Data were available from a phase I clinical trial and the PYRAPREG study. PBPK models were developed in PK-Sim® and MoBi®. A standard multicompartment structure was expanded by adding lysosome compartments to relevant organs. To account for malaria infection, Plasmodium parasite compartments were incorporated into RBCs, with volume scaled by parasitemia.
Results: Data from 52 healthy individuals and 25 patients with malaria were used for model optimization. Incorporating lysosomal sequestration was essential for capturing pyronaridine distribution. In patients with malaria, incorporating low hemoglobin (Hb) and drug accumulation in the parasite compartment enabled an adequate description of whole blood pharmacokinetics. Simulations showed that free pyronaridine concentrations in the parasite compartment were over 10-fold higher than that in whole blood. Higher parasitemia was associated with increased area under the curve (AUC)0-24h and Cmax, mainly on day 1, as parasitemia decreased rapidly. However, the subsequent decrease in Hb had the opposite effect, lowering AUC0-24h and Cmax on the following days.
Conclusions: This study demonstrates the value of PBPK modeling in elucidating key pharmacokinetic mechanisms, revealing the critical roles of lysosomal sequestration, Hb level, and parasitemia in pyronaridine disposition.
期刊介绍：
Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics.
Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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