Modelagem farmacocinética baseada em fisiologia da Tafenoquina e suas interações medicamentosas

Abstract

Malaria is an infectious disease caused by protozoa of the Plasmodium genus, with six species relevant to humans. Among them, Plasmodium vivax stands out due to its ability to form hypnozoites, a latent hepatic stage responsible for infection recurrence. The current treatment for these hepatic forms involves the administration of primaquine for 7 to 14 days. Tafenoquine (TQ) is a newly approved antimalarial for the radical cure of P. vivax malaria; however, it presents potential drug interactions that require evaluation. Physiologically based pharmacokinetic (PBPK) modeling has emerged as a powerful tool for predicting drug interactions and understanding drug disposition in the body. This study aimed to develop and validate a PBPK model of TQ to assess potential drug interactions with other compounds. The model was developed using PK-Sim (v.11.3), incorporating literature data on TQ in adults. A whole-body model was built based on plasma concentration data of TQ after oral administration, integrating physiological parameters of healthy male individuals provided by the software and pharmacokinetic data from databases. Model evaluation was performed qualitatively by comparing observed and predicted data, demonstrating a good fit. Quantitative validation included calculating the MRD (1.6) and GMFE for the area under the curve (AUC) and Cmax (1 and 1.6, respectively), both within the acceptance range (0.5–2.0). The model was used to assess drug interactions with a substrate of the OCT2 and MATE transporters, showing no indication of an effect from TQ when administered as a single dose. In conclusion, the developed PBPK model demonstrated good descriptive and predictive performance on TQ pharmacokinetics, and there is no indication of clinical risk for the coadministration of a single dose of TQ with OCT2/MATE transporter substrates.