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Importance of Characterizing Determinants of Variability in Exposure: Application to Dasatinib in Subjects With Chronic Myeloid Leukemia

From Bristol-Myers Squibb, Research and Development, Princeton, New Jersey. Dr Blackwood-Chirchir is a former employee of Bristol-Myers Squibb.

Characterizing the key determinants of variability in the exposure of orally administered drugs may be important in understanding the implications of exposure variability on clinical responses. In particular, partitioning overall variability into interoccasion variability (IOV) and interindividual variability (IIV) allows a better assessment of the clinical importance of exposure variability. The IOV characterizes the dose-to-dose variability in exposure within a subject and is likely to be less clinically relevant than IIV for chronically administered drugs as the effect of IOV averages out over repeated dosing. The main aims of this model-based analysis were (1) to characterize the IOV and IIV of dasatinib, a novel, orally administered, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases that is indicated for the treatment of chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia and (2) to demonstrate using simulated data that it is possible to estimate IIV and IOV in relative bioavailability (F_R) of an orally administered drug, given an adequate sampling scheme. Variability in dasatinib exposure was estimated to be mainly due to IOV in F_R (44% coefficient of variation [CV]) and, to a lesser extent, due to IIV in F_R and IIV in clearance (32% and 25% CV, respectively). The IIV is expected to be more clinically relevant than IOV for chronically administered oral drugs such as dasatinib, as the overall variability in cumulative exposure will be mainly due to IIV. The analysis of simulated data demonstrated that models ignoring either IIV or IOV in F_R resulted in upwardly biased estimates of interindividual or residual variability. Thus, it may be important to account for both IIV and IOV in F_R, particularly for orally administered agents that exhibit absorption-related variability in exposure.

Key Words: Dasatinib • modeling and simulation • model-based analysis • absorption modeling • chronic myeloid leukemia • SRC • BCR-ABL

Address for reprints: Amit Roy, PhD, Strategic Modeling & Simulation Group, Discovery Medicine & Clinical Pharmacology, Route 206 & Province Line Rd, Bristol-Myers Squibb R&D, Princeton, NJ 08543; e-mail: amit.roy{at}bms.com.

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