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

The urgent need for safe, efficacious, and accessible drug treatments to treat coronavirus disease 2019 (COVID-19) prompted a global effort to evaluate drug repurposing opportunities. Pyronaridine and amodiaquine are both components of approved antimalarials with in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In vitro activity does not always translate to clinical efficacy across a therapeutic dose range. This study applied available, verified, physiologically based pharmacokinetic (PBPK) models for pyronaridine, amodiaquine, and its active metabolite N-desethylamodiaquine (DEAQ) to predict drug concentrations in lung tissue relative to plasma or blood in the default healthy virtual population. Lung exposures were compared to published data across the reported range of in vitro EC50 values against SARS-CoV-2. In the multicompartment permeability-limited PBPK model, the predicted total Cmax in lung mass for pyronaridine was 34.2 µM on Day 3, 30.5-fold greater than in blood (1.12 µM) and for amodiaquine was 0.530 µM, 8.83-fold greater than in plasma (0.060 µM). In the perfusion-limited PBPK model, the DEAQ predicted total Cmax on Day 3 in lung mass (30.2 µM) was 21.4-fold greater than for plasma (1.41 µM). Based on the available in vitro data, predicted drug concentrations in lung tissue for pyronaridine and DEAQ, but not amodiaquine, appeared sufficient to inhibit SARS-CoV-2 replication. Simulations indicated standard dosing regimens of pyronaridine-artesunate and artesunate-amodiaquine have potential to treat COVID-19. These findings informed repurposing strategies to select the most relevant compounds for clinical investigation in COVID-19. Clinical data for model verification may become available from ongoing clinical studies.

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

Drug resistance to sulfadoxine-pyrimethamine and amodiaquine threatens the efficacy of malaria chemoprevention interventions in children and pregnant women. Combining pyronaridine (PYR) and piperaquine (PQP), both components of approved antimalarial therapies, has the potential to protect vulnerable populations from severe malaria. This randomized, double-blind, placebo-controlled (double-dummy), parallel-group, single site phase I study in healthy adult males or females of Black sub-Saharan African ancestry investigated the safety, tolerability, and pharmacokinetics of PYR + PQP (n = 15), PYR + placebo (n = 8), PQP + placebo (n = 8), and double placebo (n = 6) administered orally once daily for 3 days at the registered dose for the treatment of uncomplicated malaria. All participants completed the study. Forty-five adverse events were reported in 26 participants, most (41/45) were mild/moderate in severity, with no serious adverse events, deaths, or study withdrawals. Adverse events were reported in 66.7% (10/15) of participants administered PYR + PQP, 87.5% (7/8) with PYR + placebo, 50.0% (4/8) with PQP + placebo, and 83.3% (5/6) with placebo. For PYR containing regimens, five of 23 participants had asymptomatic transient increases in alanine and/or aspartate aminotransferase. With PQP containing regimens, four of 23 participants had mild Fridericia-corrected QT interval prolongation. Liver enzyme elevations and prolonged QTc interval were consistent with observations for PYR-artesunate and dihydroartemisinin-PQP, respectively, administered to healthy adults and malaria patients. Increases in PYR and PQP exposures were observed following co-administration versus placebo, with substantial interparticipant variability. The findings suggest that PYR + PQP may have potential in chemoprevention strategies. Further studies are needed in the target populations to assess chemoprotective efficacy and define the benefit-risk profile, with special considerations regarding hepatic and cardiac safety.