Precision dosing of imatinib: A model-based approach to optimize achievement of target exposure

Introduction: There is evidence of exposure-response relationship for imatinib in both chronic myeloid leukemia (CML) and gastrointestinal stromal tumour (GIST). However, standard dosages of imatinib are associated with trough plasma concentration (Cmin) lower than the target value in many patients. The aims of this study were to design a novel model-based dosing approach for imatinib and to compare the performance of this method with that of other dosing methods. Material and methods: Three target interval dosing (TID) methods based on stochastic control principles were developed to optimize the achievement of a tar- get Cmin interval or minimize underexposure to imatinib. A discretization of the popula- tion PK model published by Widmer et al. was performed to implement the method. We compared the performance of TID methods to that of traditional model-based target concentration dosing (TCD) as well as fixed-dose regimens in simulated patients (n = 800, with CML or GIST) and a real PK dataset from 85 patients with GIST. The proportion of patients with imatinib Cmin within the target interval was calculated in both datasets. Results: In simulated patients, both TID and TCD model-based approaches were effective with about 65% of Cmin achieving the target interval of 1000–2000 ng/mL but the TID approach was the best in minimizing underexposure at the same time (10.9%). The stan- dard 400 mg/24 h dosage of imatinib was associated with only 29% of target achieve- ment and a large proportion of underexposure (68%). Other fixed-dose regimens performed better but could not minimize over- or underexposure. The dosing regimens of imatinib calculated by the TID approach to achieve the target were quite variable in terms of interval (q8h, 12%; q12h, 21%, q24h, 67%) and dose (mean dose of 180, 266 and 639 mg, respectively). Results obtained using real PK parameters from 85 GIST patients were in agreement, with more than 75% of target achievement with TID and TCD approaches, compared with only 16.5% with the fixed regimen of 400 mg/24 h Discussion/Conclusion: Model-based, goal oriented dosing can improve initial dos- ing of imatinib. Combined with subsequent TDM, these approaches are rational basis for precision dosing of imatinib and other drugs with exposure-response relationships