Population Pharmacokinetics of Tafenoquine, a Novel Antimalarial

Abstract

Tafenoquine is a novel 8-aminoquinoline antimalarial drug recently approved by the U.S. Food and Drug Administration (FDA) for the radical cure of acute Plasmodium vivax malaria, which is the first new treatment in almost 60 years. A population pharmacokinetic (POP PK) analysis was conducted with tafenoquine exposure data obtained following oral administration from 6 clinical studies in phase 1 through phase 3 with a nonlinear mixed effects modeling approach. The impacts 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 pharmacokinetics of tafenoquine were 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 and Q/F, respectively), apparent volume of distribution for central and peripheral compartments (V₂/F and V₃/F, respectively), formulation on systemic bioavailability (F1) and absorption rate constant (K_a ), and health status on apparent volume of distribution. The key tafenoquine population parameter estimates were 2.96 liters/h for CL/F and 915 liters for V₂/F in P. vivax-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 pediatric populations.

Keywords: 8-aminoquinoline; antimalarial; population pharmacokinetics; tafenoquine.

FIG 1

Goodness-of-fit plots for the final model. The circles represent the observed data (DV), individual predictions (IPRED), population predictions (PRED), and conditional weighted residuals (CWRES). The solid line represents the line of unity, and the dashed red line represents the trend line for the corresponding data.

FIG 2

Visual predictive checks for the final model across different studies and formulations at the 300-mg dose (A) and for the TAF116564 (GATHER) study for external model validation (B). The blue bands and lines represent the 95% prediction intervals and median predictions, respectively. The red dots and red lines represent the observed data and observed medians, respectively.

FIG 3

Comparisons of post hoc exposure estimates (AUC_0–60 and C_max) across studies at the 300-mg dose. The lower and upper hinges of the box plot correspond to the first and third quartiles, respectively (25th and 75th percentiles, respectively), and the line represents the median. The upper and the lower whiskers represent the 95% confidence intervals. AUC_0–t summarized the AUC up to day 60.