A Novel Empirical Autoinduction Model to Characterize the Population Pharmacokinetics and Recommend Dose for Repotrectinib in Adult and Adolescents With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements

Repotrectinib has received regulatory approval in the United States for the treatment of patients diagnosed with ROS1-positive non-small cell lung cancer (NSCLC), as well as for individuals with solid tumors that exhibit an NTRK gene fusion. To support its clinical use and regulatory approval, a comprehensive Population Pharmacokinetic (PopPK) model was developed for this drug. The model was constructed based on pharmacokinetic data collected from a total of 644 individuals. This dataset included 620 adults, comprised of 118 healthy volunteers and 502 patients who participated across seven separate clinical studies, in addition to 24 pediatric patients from a single pediatric study.

The pharmacokinetic modeling approach employed a two-compartment model characterized by first-order absorption and the inclusion of an absorption lag time. A key feature of the model was the incorporation of a time-varying clearance mechanism, designed to reflect the phenomenon of autoinduction—where the drug accelerates its own metabolism over time. Specifically, clearance was described using a model dependent on both time and drug concentration at trough levels (Ctrough), allowing for a gradual and continuous increase in drug clearance as exposure progresses. This Ctrough-based modeling approach, while empirical, proved effective in capturing the dynamic changes in clearance over time, offering a more physiologically plausible and numerically efficient alternative to dose-driven or semi-mechanistic enzyme turnover models. Unlike models requiring complex differential equations to simulate enzyme induction, the chosen method reduced computational demands and avoided sudden shifts in concentration levels.

The PopPK model estimated that the maximum level of drug-induced clearance (CLMAX) could reach approximately 4.9 times the baseline clearance value. Furthermore, the influence of patient-specific factors was incorporated into the model. Body weight was found to affect both the drug’s clearance and its volume of distribution. These effects were captured using allometric scaling, with scaling exponents of 0.477 for clearance and 0.962 for volume of distribution. Age also played a significant role, particularly influencing the CLMAX parameter. Younger patients tended to show higher levels of maximum clearance compared to older individuals.

To evaluate the clinical implications of these findings, simulations were conducted to assess various dosing strategies. The results demonstrated that a flat dosing regimen—such as administering 160 mg once daily for the first 14 days, followed by 160 mg twice daily thereafter—achieved similar levels of drug exposure in both adult and adolescent patient populations. These findings provided critical support for the dosing recommendations submitted to health authorities and contributed to the eventual regulatory approval of repotrectinib in both adult and adolescent patients with NTRK fusion-positive solid tumors.