Population Pharmacokinetics Modeling of Selpercatinib to Support Posology in Pediatric Patients With RET ‐Altered Metastatic Thyroid Cancer or Solid Tumors

ABSTRACT Selpercatinib is a first‐in‐class, highly selective, RET kinase inhibitor with CNS activity, approved for the treatment of RET‐altered lung, thyroid, and other cancers. We report pharmacokinetic analyses to identify factors affecting selpercatinib steady‐state exposure and support posology in pediatric patients. Population pharmacokinetic analyses using nonlinear mixed‐effects modeling were performed on data from two ongoing, open‐label, Phase 1/2 studies in adult and pediatric patients with advanced solid tumors. In LIBRETTO‐001 (NCT03157128) patients (≥ 12 years) received oral selpercatinib from 20 mg once daily through 240 mg twice daily (BID) during phase 1 and 160 mg BID in phase 2. In LIBRETTO‐121 (NCT03899792), patients (6 months–21 years) received doses based on body surface area (BSA), starting at a dose expected to match adult exposure of 160 mg BID. Overall, 8024 selpercatinib plasma concentration measurements from 830 patients were included in the pharmacokinetic analysis. The final model, a 2‐compartment disposition model with sequential zero‐ and first‐order absorption, was similar to a previously developed adult model, which identified weight, dose, and Asian race as covariates. Simulations performed using the final model suggested the following dose regimen as appropriate for patients aged 2–17 years: 40 mg three times a day for pediatric patients with a BSA of 0.33–0.65 m 2 ; BSA‐based dosing (92 mg/m 2 rounded for 40 and 80 mg capsules) for pediatric patients 2 to < 12 years, and BSA ≥ 0.66 m 2 ; and weight‐based dosing (120 mg BID < 50 kg and 160 mg BID ≥ 50 kg) for adolescent patients ≥ 12 years.