ArticleClinical pharmacokinetics2025
Importance of Lysosomal Trapping and Plasmodium Parasite Infection on the Pharmacokinetics of Pyronaridine: A Physiologically Based Pharmacokinetic Model-Based Study.
Article in Clinical pharmacokinetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Application of New Approach Methodologies to Improve Oral Biopharmaceutic Assessments.Pharmaceutics · 2026Review
- Pharmacokinetics of Lekethromycin in Swine Following Intramuscular Administration at Different Doses with a Single Intravenous Reference Dose for Absolute Bioavailability and Matrix Comparison.Veterinary sciences · 2026Article
- Lysosome as a Chemical Reactor.International journal of molecular sciences · 2025Review
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15 authors.
Funding
Abstract
BACKGROUND AND
objectivePyronaridine 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.
methodsData 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.
resultsData 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)
conclusionsThis 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.
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