Development and application of a PBPK modeling strategy to support antimalarial drug development

Abstract

As part of a collaboration between Medicines for Malaria Venture (MMV), Certara UK and Monash University, physiologically‐based pharmacokinetic (PBPK) models were developed for 20 antimalarials, using data obtained from standardized in vitro assays and clinical studies within the literature. The models have been applied within antimalarial drug development at MMV for more than 5 years. During this time, a strategy for their impactful use has evolved. All models are described in the supplementary material and are available to researchers. Case studies are also presented, demonstrating real‐world development and clinical applications, including the assessment of the drug–drug interaction liability between combination partners or with co‐administered drugs. This work emphasizes the benefit of PBPK modeling for antimalarial drug development and decision making, and presents a strategy to integrate it into the research and development process. It also provides a repository of shared information to benefit the global health research community.

PBPK‐led assessment of antimalarial drugs as candidates for Covid‐19: Simulating concentrations at the site of action to inform repurposing strategies

“…A full PBPK model including a permeability‐limited lung compartment was used to provide a prospective prediction of pyronaridine and amodiaquine total and unbound concentrations in the lung. 29 , 30 A perfusion‐limited model was similarly used for the metabolite DEAQ. 31 Artesunate concentrations were not evaluated as this drug does not show in vitro antiviral activity against SARS‐CoV‐2.…”

“…Compound files and validation data have been previously published in full. 29 Briefly, model input values for pyronaridine, amodiaquine, and DEAQ drug‐specific characteristics and PK parameters were obtained from the published literature, from in‐house data, or were predicted. All simulations were run using version 21 of the Simcyp Simulator.…”

“… 29 Concentration–time profiles for pyronaridine and amodiaquine/DEAQ were generated using the Simcyp ‘healthy volunteer’ virtual population. 29 …”

Randomized, placebo‐controlled, double‐blind phase I trial of co‐administered pyronaridine and piperaquine in healthy adults of sub‐Saharan origin

“…PBPK simulations were conducted using models developed and validated for PYR and PQP with Simcyp (version 19; Certara). 32 These predicted no clinically relevant change in PYR exposure when administered with PQP (i.e., <1.25‐fold increase in PYR exposure). Moreover, a clinical DDI study showed no significant increase in PYR exposure when PYR (associated with artesunate) was administered for 3 days together with the CYP3A4 inhibitor ritonavir over 17 days in healthy volunteers.…”

“…17 , 18 Furthermore, physiologically‐based pharmacokinetic (PBPK) modeling of potential PK drug–drug interactions (DDIs) using the known properties of the two compounds predicted no significant interaction at therapeutic drug exposures (N. Abla, personal communication). 32 This phase I study in healthy adults investigated the safety, tolerability, and PKs of PYR and PQP following co‐administration and when administered alone in comparison to placebo.…”