Ioannis Loisios Konstantinidis1, Matthias Hoch1, AnaPaula Cardoso2, Heidi Einolf3
1Novartis Biomedical Research, PK Sciences, 2Novartis Development, Clinical Development, 3Novartis Biomedical Research, PK Sciences
Introduction: Asciminib (ASC) is a first-in-class BCR-ABL1 inhibitor that specifically targets the ABL Myristoyl Pocket (STAMP). It is approved for adults with Ph+ CML-CP at doses of 40 mg twice daily (BID) and 80 mg once daily (QD). ASC is primarily metabolized by CYP3A4 and UGT enzymes, while biliary secretion via BCRP also plays a substantial role in its elimination [1]. ASC is administered as a tablet in the fasted state only, as low and high-fat meals have been shown to reduce ASC exposure by 30% and ~65%, respectively [2]. In a relative bioavailability (rBA) study comparing the adult and pediatric formulations (PF) in healthy adults under fasted, low-fat (LFF), and high-fat (HFF) fed states, a more pronounced negative food effect was observed for the PF versus the adult formulation (AF). Both formulations demonstrated similar performance in the fasted state [3]. An adult PBPK model for ASC was extrapolated to the pediatric population, accounting for the food effect to determine the starting dose for the pediatric study ASC4KIDS using the pediatric formulation (PF) in low-fat fed (LFF) state. The phase Ib/II ASC4KIDS study evaluates the pharmacokinetics (PK) and safety profile of ASC in pediatric patients (pts) aged 1-<18 years (yrs) treated at least with one prior tyrosine kinase inhibitor (TKI). Objectives: 1.To extrapolate a previously established adult PBPK model of ASC to predict the dose and steady-state exposures in pediatric patients (pts) aged 1 to <18 yrs under LFF conditions that match the adult exposure after 40 mg BID and 80 mg QD using the adult formulation (AF) in fasted state. 2.To compare the PBPK-predicted pediatric exposures with the observed from the exploratory group (pts 14-18 yrs treated with the AF 40 mg BID in fasted state) and Part 1 (pts 2-16 yrs treated with the PF 1.3 mg/kg in the LFF state). Methods: PBPK modeling: The PBPK model for ASC has been validated to describe the PK of ASC in healthy adults and cancer pts after single and multiple dosing, as well as the effect of food in healthy adults [2,3]. The PBPK model was updated to predict the food effect on the PF prior to pediatric dosing extrapolation. The updated PBPK model was then applied within the pediatric module of Simcyp to predict the exposure of ASC in pediatric pts with body weight (BW) normalized dosing (mg/kg). Moreover, allometric dose scaling was applied and compared to PBPK predictions.[4] Pediatric study (ASC4KIDS): In a multi-center, open-label, single arm study including pts aged 1–<18 yrs with Ph+ CML-CP, without T315I mutation, treated with =1 prior TKIs, the PK of ASC was characterized with the PF (fed). In an exploratory group, pts 14-<18 yrs old were treated with the ASC AF (40 mg BID fasted). In Part 1, pts received the PF at an initial dose of 1.3 mg/kg BID (LFF) to assess ASC exposure (AUClast and Cmax) over the first 28 days of treatment. Safety was continuously evaluated. In Part 2, additional pts will be treated with the PF dose confirmed in Part 1. In Part 3, 10 more pts will be enrolled to receive ASC PF 2.6 mg/kg once daily (fed). Results: For pediatric pts = 1 year of age, a 1.3 mg/kg BID or 2.6 mg/kg QD dose was suggested. The results indicated that a 40 mg BID or 80 mg QD dose given under fasted conditions to adolescents aged =14 to <18 yrs (BW =40 kg) would achieve similar exposures to those observed in adults given the same dose. Allometry predicted the exposure to be ~5-60% lower than the PBPK predicted exposures, especially in the age groups 5-8 and 8-12 yrs. In the ASC4KIDS study, 4 pts (15-16 yrs) and 9 pts (2-16 yrs) were enrolled into the exploratory AF group and PF group, respectively. The average ASC exposure in the AF group was comparable to that observed in adults. The average ASC exposure in the PF group was also comparable to that observed in adults (median AUClast: 5051 vs 5130 hr*ng/mL; median Cmax: 711 vs 939 ng/mL, respectively). Based on these data, the PF dose of 1.3 mg/kg BID (LFF) predicted by the PBPK model was confirmed as the pediatric dose. Conclusion: The PBPK proposed pediatric doses of ASC 1.3 mg/kg BID (LFF) in pediatric pts aged =1 to <18 yrs using the PF and 40 mg BID (fasted) dose using the AF in adolescent pts (=14 to <18 yrs) were confirmed in study ASC4KIDS. This highlights the value of PBPK modeling and simulations in predicting doses in pediatric studies, expediting pediatric drug development of ASC.
[1] Hoch et al (2024) Clin Pharmacokinet. 63(11):1513-1528 [2] Hoch et al (2022) Clin Pharmacol Drug Dev. 11(2):207-219. [3] Hoch et al (2023) Clin Pharmacol Drug Dev. 12(5):484-492 [4] Mahmood et al (2014) Clin Pharmacokinet 53:327-46
Reference: PAGE 33 (2025) Abstr 11548 [www.page-meeting.org/?abstract=11548]
Poster: Drug/Disease Modelling - Paediatrics