Sy, Sherwin, Darstein, Christelle, Yang, Yiqun, Dasgupta, Kohinoor, Kapoor, Shruti, Hoch, Matthias and Grosch, Kai (2024) Population modeling of nilotinib exposure versus longitudinal BCR::ABL1 response in patients with chronic phase chronic myeloid leukemia using a semi-mechanistic disease model. British Journal of Clinical Pharmacology. ISSN 0306-52511365-2125

Abstract

Background: This study evaluated the exposure-efficacy relationship of nilotinib and longitudinal BCR::ABL1 levels in patients with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) and those who are imatinib-resistant or intolerant using a semi-mechanistic model.
Methods: The analysis included 489 CML-CP patients from three nilotinib trials (NCT00109707; NCT00471497; NCT01043874) with duration of follow-up ranging from 2 to 9 years. The semi-mechanistic disease model of CML-CP consisted of quiescent leukemic stem cells (q), proliferating drug-susceptible (p) and resistant (r) bone marrow cells. Drug effect on the elimination of p cells was characterized by an Emax model based on the individual daily AUC0-24h simulated using their empirical Bayes estimates from a population pharmacokinetic model. The influence of line of therapy was evaluated on model parameters and its impact was investigated through simulations of the major molecular response (MMR) rate, defined as the proportion of the simulated profiles that achieved BCR::ABL1 level of ≤0.1% at 48 and 96 weeks of treatment.
Results: The final disease model was based on a truncated 3-year data that characterized the bi-phasic pattern of BCR::ABL1 transcript profiles. Line of therapy was a significant covariate of the drug kill effect, p and r cells. Simulations of BCR::ABL1 time course predicted MMR rates at 48 weeks and 96 weeks for both nilotinib 300 and 400 mg twice-daily of 66-71% and 77-82% in first-line, and 34-39% and 46-54% in second-line, respectively. Results are consistent with observed MMR rates in the respective trials.
Conclusions: The current disease model was developed using time-course of BCR::ABL1 transcript profiles of nilotinib in first- and second-line CML-CP. The ability to distinguish molecular response between lines of therapy is demonstrated using model-based analysis. These nilotinib information enable the extrapolation of novel TKI’s (e.g., asciminib) response to other lines of therapy in patients with CML-CP.

Item Type:	Article
Keywords:	Nilotinib, BCR::ABL1, exposure-response, chronic myeloid leukemia
Date Deposited:	15 Jan 2025 00:45
Last Modified:	15 Jan 2025 00:45
URI:	https://oak.novartis.com/id/eprint/55009