Aya Ismail 1,2, Allan Kengo 3,4, Stephen Brand 5, Robin Eriksson 5, Wynand Smythe 6
1 DataClin CRO (Cairo, Egypt), 2 Egyptian Drug Authority (EDA) (Giza, Egypt), 3 Infectious Diseases Institute (, Uganda), 4 Gulu University (Gulu, Uganda), 5 Medicines for Malaria Venture (MMV) (Geneva, Switzerland ), 6 Certara (Cape town, South Africa)
Background: Pyronaridine is a long-acting antimalarial agent that binds to hematin, preventing hemozoin formation and leading to parasite death. It is currently used in the treatment of uncomplicated malaria in combination with artesunate [1]. However, its preclinical pharmacokinetic–pharmacodynamic (PK/PD) relationship remains insufficiently characterized. Developing a robust preclinical PK/PD model within Medicines for Malaria Venture’s (MMV) data-driven workflow may characterize pyronaridine’s exposure–response parameters and strengthen translational support for advancing future antimalarial medicine candidates [2].
Objectives: We aimed to develop a preclinical PK/PD model characterizing the relationship between pyronaridine exposure and parasitemia clearance in severe combined immunodeficiency (SCID) mice engrafted with P. falciparum-infected human red blood cells and to estimate an in vivo EC₅₀ for potential translation to humans.
Methods: Data from MMV were provided through the Applied Pharmacometrics Training fellowship by Pharmacometrics Africa. Pyronaridine in vitro killing profile data were analyzed to characterize parasite killing dynamics and to derive the 48-hour parasite reduction ratio (PRR₄₈), from which the maximal killing effect (Emax) was estimated. The in vivo dataset included pyronaridine pharmacokinetics and parasitemia data collected for up to 60 days in SCID mice (1–2% infected with P. falciparum) treated with 0.5–100 mg/kg pyronaridine for 1–3 days. The dataset was prepared using R software, and nonlinear mixed-effects modelling was performed in Phoenix®. Model fit was demonstrated by the good agreement between observed and predicted parasitemia–time profiles across the different treatment groups. Model parameter uncertainty was determined using a parametric bootstrap.
Results: Data were available from 22 SCID mice, including 3 untreated controls and 18 treated animals. Among the treated animals, 3 showed no parasite reduction, 11 showed parasite regrowth, and 8 showed no regrowth. Pyronaridine pharmacokinetics were best described by a two-compartment model with first-order absorption and elimination, with between-subject variability supported for all structural parameters. The parasitemia reduction was adequately described by an Emax model, with an additional first-order rate constant accounting for the clearance of dead parasites.
In untreated animals, parasitemia increased exponentially and was characterized by a fixed net parasite growth rate (GR) of 0.025 h⁻¹. In the treated animals, the maximum killing effect (Emax) was fixed at 0.12 h⁻¹, based on estimates derived from in vitro 48-h parasite reduction ratio (PRR₄₈) experiments. The baseline parasitemia was estimated to be 1.52% (95% CI: 1.38–1.64), and the EC₅₀ was 17.7 ng·mL⁻¹ (95% CI: 9.07–34.4) with an inter-individual variability of 33.7% CV, providing a quantitative measure of pyronaridine potency. The Hill coefficient (γ) was fixed at 7, and clearance of dead parasites (CLpara) was estimated to occur at a rate of 0.09 h⁻¹ (95% CI: 0.07–0.1). The final PK/PD model adequately captured the observed reductions in parasitemia, as well as the timing and extent of recrudescence where present.
Conclusions: A PK/PD model for pyronaridine in P. falciparum–infected SCID mice was developed, quantifying its exposure–response relationship and yielding an in vivo EC₅₀. This model provides a translational link between preclinical and clinical data and supports future development of a data-driven framework for antimalarial dose optimization and efficacy forecasting in humans.
References:
[1] Chu, W. Y., & Dorlo, T. P. (2023). Pyronaridine: a review of its clinical pharmacology in the treatment of malaria. Journal of Antimicrobial Chemotherapy, 78(10), 2406-2418.
[2] Medicines for Malaria Venture (MMV). https://www.mmv.org/
[3] Bailly, C. (2021). Pyronaridine: An update of its pharmacological activities and mechanisms of action. Biopolymers, 112(4), e23398.
Reference: PAGE 34 (2026) Abstr 11881 [www.page-meeting.org/?abstract=11881]
Poster: Drug/Disease Modelling - Other Topics