Population modelling of nilotinib exposure vs. longitudinal BCR::ABL1 response in patients with chronic phase chronic myeloid leukaemia using a semimechanistic disease model.

Aims: This study aims to evaluate the exposure-efficacy relationship of nilotinib and longitudinal BCR::ABL1 levels in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase (CML-CP) and those who are imatinib-resistant or intolerant using a semimechanistic disease model.

Methods: The analysis included 489 CML-CP patients from 3 nilotinib trials (NCT00109707; NCT00471497; NCT01043874) with duration of follow-up ranging from 2 to 9 years. The semimechanistic disease model of CML-CP consisted of quiescent leukaemic stem cells, proliferating drug-susceptible and -resistant bone marrow cells. Drug effect on the elimination of susceptible cells was characterized by a maximum response model based on the individual daily area under the concentration-time curve over the last 24 h 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 biphasic pattern of BCR::ABL1 transcript profiles. Line of therapy was a significant covariate of the drug kill effect, susceptible and resistant 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.

Conclusion: The ability to distinguish molecular response between lines of therapy is demonstrated using model-based analysis. These nilotinib information enable the extrapolation of novel tyrosine kinase inhibitors (e.g., asciminib) response to other lines of therapy in patients with CML-CP.