Tafenoquine is a novel 8-aminoquinoline anti-malarial drug recently approved by US Food and Drug Administration (FDA) for the radical cure of acute P. vivax malaria - first new treatment in almost 60 years. Population pharmacokinetic (POP PK) analysis was conducted with tafenoquine exposure data following oral administration from 6 clinical studies in Phase 1 through Phase 3 with a nonlinear mixed effects modelling approach. The impact of patient demographics, baseline characteristics and extrinsic factors such as formulation were evaluated. Model performance was assessed using techniques such as bootstrapping, visual predictive checks and external data validation from a Phase 3 study not used in model fitting and parameter estimation. Based on the analysis, the systemic PK of tafenoquine was adequately described using a two-compartment model. The final POP PK model included body weight (allometric scaling) on apparent oral and intercompartmental clearance (CL/F, Q/F respectively), apparent volume of distribution for central and peripheral compartments (V2/F, V3/F respectively), formulation on systemic bioavailability (F1), absorption rate (KA) and health status on apparent volume of distribution. The key tafenoquine population parameters estimates were 2.96 L/hr for CL/F and 915 L for V2/F in P. vivax malaria infected subjects. Additionally, the analyses demonstrated no clinically relevant difference in relative bioavailability across the capsule and tablet formulations administered in these clinical studies. In conclusion, a POP PK model for tafenoquine was developed. Clinical trial simulations based on this model supported bridging the exposures across two different formulations. This POP PK model can be applied to aid and perform clinical trial simulations in other scenarios and populations such as pediatrics.
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