Population pharmacokinetics modeling of selpercatinib and simulation to support posology in paediatric and adolescent patients
Dan Liu (1) and Jan-Stefan van der Walt (2)
(1) Global PKPD and Pharmacometrics, Eli Lilly and Company, United Kingdom, (2) Occams Coöperatie U.A. The Netherlands.
Objectives:
Selpercatinib, a first-in-class highly selective and potent rearranged during transfection (RET) kinase inhibitor with central nervous system activity, is approved in multiple countries for the treatment of RET-altered lung or thyroid cancers.
Population PK analyses were performed with data from ongoing Phase 1/2 clinical trials to support the development of selpercatinib in RET fusion-positive non-small cell lung cancer (NSCLC), RET-mutant medullary thyroid cancer (MTC), and other tumors with increased RET activity [1].
The objectives of the analyses were to identify any intrinsic or extrinsic factors that affect selpercatinib steady-state exposure and to support posology in paediatric and adolescent patients.
Methods:
Data from two ongoing, open-label, multi-centre studies in adult patients (LIBRETTO-001) and children (LIBRETTO-121) with advanced solid tumors, including RET fusion-positive NSCLC, RET-mutant MTC, and other tumors were analyzed (data cut-off 13 January 2023 for both studies).
LIBRETTO-001 is a Phase 1 (dose escalation)/Phase 2 (dose expansion) study [2]. In this study, patients received oral selpercatinib from 20 mg once daily (QD) up to 240 mg twice daily (BID) during Phase 1, and 160 mg BID in Phase 2 [3].
LIBRETTO-121 is a Phase 1/2 study of oral selpercatinib in patients aged ≥ 6 months to ≤ 21 years [4]. In LIBRETTO-121, patients were dosed based on body surface area (BSA) with a starting dose of 92mg/m2 to match exposure in adults at 160 mg BID. Patients received actual doses from 40 mg to 160 mg BID. Plasma samples were collected 2 and 4 hours postdose on C1D1, and at pre-dose, 1, 2, 4 and 8 hours postdose on C1D8 and C3D1.
Population PK analyses were performed using nonlinear mixed-effects modeling (NONMEM®; version 7.5.0).
Results:
A total of 8024 concentration observation records from 830 patients (803 from LIBRETTO-001 and 27 from LIBRETTO-121, respectively) were included.
The PK of selpercatinib in pediatric, adolescent, and adults from studies LIBRETTO-001 and LIBRETTO-121 were jointly described using an updated population PK model. The final model is a 2-compartment disposition model with sequential zero- and first order absorption. The final model was similar to the previously developed adult model [3] identifying weight, dose, and Asian race as important covariates.
Simulations were performed for children sampled from NHANES with a minimum age of 6 months and indicated that BSA-based dosing (rounded for 40 mg and 80 mg capsules) would match the exposure in adults with cancer dosed with 160 mg BID.
Conclusions:
Adolescent patients aged 12 years or older (average BSA approximately 1.69 m²) with BSA-based dosing of 92 mg/m² BID are likely to have actual administered dose range from 120 to 160 mg BID, in line with adult weight-based dosing (120 mg BID in patients <50 kg and 160 mg BID in patients ≥50 kg). Hence, the following dose regimen is considered appropriate for patients from 2 to 17 years, i.e., BSA-based dosing (92 mg/m² rounded for 40 and 80 mg capsules) for pediatric patients 2 to <12 years), and weight-based dosing (120 mg BID <50 kg and 160 mg BID ≥50 kg) for adolescent patients ≥12 years or older.
References:
[1] Brandhuber BB, Haas J, Tuch BB, et al. ENA-0490 The development of LOXO-292, a potent, KDR/VEGFR2-sparing RET kinase inhibitor for treating patients with RET-dependent cancers. Poster presented at AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics 2016; Poster No. 441; November 29-December 2, 2016; Munich Germany
[2] ClinicalTrials.gov Identifier: NCT03157128
[3] Liu D, Wallin J, Akil A, et al. Population pharmacokinetics of selpercatinib in patients with an advanced solid tumor, including RET fusion-positive NSCLC, RET-mutant MTC, and other tumors with increased RET activity. PAGE 30 (2022) Abstr 9968. Poster presented at PAGE Conference 2022; Ljubljana, Slovenia
[4] ClinicalTrials.gov Identifier: NCT03899792