Combining physiologically based pharmacokinetic modeling and simulations and allometry to inform the starting dose of asciminib in pediatric patients
Ioannis Loisios-Konstantinidis (1), Matthias Hoch (1), Heidi Einolf (2)
(1) Novartis Institute for Biomedical Research, PK Sciences, Basel, Switzerland, (2) Novartis Institute for Biomedical Research, PK Sciences, East Hanover, NJ, USA
Introduction: Asciminib (Scemblix®), is a first-in-class BCR-ABL1 inhibitor that has been approved by the FDA for the treatment of adult patients with Ph+ CML-CP previously treated with ≥2 tyrosine kinase inhibitors (TKIs) at 40 mg BID and 80 mg QD as well as for those patients harboring the T315I mutation at 200 mg BID. Asciminib exhibits over proportional PK with dose and it is mainly metabolized by CYP3A4 and UGTs, while biliary secretion via BCRP plays an equally important role in its elimination. The fractional contributions of CYP3A4, UGTs and BCRP in the overall clearance of asciminib are 36%, 29% and 31%, respectively [1]. Asciminib is administered as a tablet in the fasted state only since low and high fat meals have been shown to reduce the exposure of asciminib by 30% and ~65%, respectively [2]. In a relative bioavailability (rBA) study between the adult and the pediatric formulation in healthy adults in fasted, low fat (LFF) and high fat (HFF) fed states, a more pronounced negative food effect was observed for the pediatric (mini-tablet) formulation comparing to the adult formulation, while the two formulations demonstrated similar performance in the fasted state.
Objectives: 1) To extrapolate a previously established adult PBPK model of asciminib to predict the dose and steady-state exposure in pediatric patients between ages of 1 and <18 years under LFF conditions that matches the adult exposure after 40 mg BID and 80 mg QD; 2) Predict the steady state exposure of adolescents after administration of flat adult doses of 40 mg BID or 80 mg QD in fasted state; 3) Compare the PBPK-predicted pediatric exposure/dose with allometric scaling
Methods: The established PBPK model for asciminib has been validated to describe the PK of asciminib in healthy adults and cancer patients after single and multiple dosing as well as the effect of food in healthy adults who received the adult tablet formulation [3]. The absorption component of the PBPK model was updated accordingly to predict the effect of food on the mini-tablet formulation prior to pediatric dosing extrapolation. The updated PBPK model was then applied within the pediatric module of Simcyp to predict the exposure of asciminib in pediatric patients with a dose normalized for the body weight (mg/kg). Two ontogenies were used for CYP3A4, one inherent to the Simcyp model and one recently published (2). \For allometry, the pediatric clearance (CLped) over bioavailability (F), i.e. CLped/F, was calculated from the adult clearance (CLadult) over F (CLadult/F) observed in the LFF arm of the rBA study using the pediatric formulation and scaled for BW using different exponents depending on the age of pediatric patients [4].
Results: For pediatric patients ≥ 1 year of age, a 1.3 mg/kg BID or 2.6 mg/kg QD dose was suggested. The results also indicated that with a 40 mg BID or 80 mg QD dose given under fasted conditions to adolescents aged ≥14 to <18 years of age (BW ≥40 kg) would achieve similar exposures as those observed in adults given the same dose. In comparison to the PBPK model, allometry predicted the exposure to be ~5-60% lower than the PBPK predicted exposures, using the Upreti ontogeny and ~30-60% lower using the built-in Simcyp ontogeny for CYP3A4. The maximum absolute differences between allometry and PBPK predicted daily exposures were found in the age groups 5-8 and 8-12 years (53-63%), using either ontogeny for CYP3A4. This was likely attributed to differences between the PBPK model ontogenies of the several asciminib clearance pathways (e.g., slow ontogenies for UGT2B7, UGT2B17) versus the use of a constant exponent of 0.75 used in the allometric scaling above 5 years of age.
Conclusions: This modeling and simulation study suggested that weight-based dosing of asciminib (~1.3 mg/kg BID or 2.6 mg/kg QD) results in a consistent exposure in pediatric patients from ≥1 to <18 years of age under low fat fed conditions. In adolescent patients using the adult formulation, there is the possibility to administer the adult 40 mg BID or 80 mg QD dose under fasted conditions for those who are ≥14 to <19 years of age (population median BW ≥51 kg). The model-based pediatric dosing recommendation have been used to inform the starting dose of the ongoing pediatric PK study.
References:
[1] Tran et al. Xenobiotica (2020) 50(2):150-169
[2] Hoch et al. Clin Pharmacol Drug Dev (2022) 11(2):207-219
[3] Loisios-Konstantinidis et al. (2023) (manuscript in preparation)
[4] Mahmood et al. Clin Pharmacokinet (2014) 53:327-46