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

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 m2; BSA-based dosing (92 mg/m2 rounded for 40 and 80 mg capsules) for pediatric patients 2 to < 12 years, and BSA ≥ 0.66 m2; and weight-based dosing (120 mg BID < 50 kg and 160 mg BID ≥ 50 kg) for adolescent patients ≥ 12 years.