Abstract
Purpose
This population pharmacokinetic model was developed to characterize the pharmacokinetics of the oral irreversible ErbB family blocker afatinib in patients with solid tumors and to investigate the impact of selected intrinsic and extrinsic factors.
Methods
Data from 927 patients (4,460 plasma concentrations) with advanced solid tumors in 7 Phase II or III studies were analyzed. Afatinib was administered orally in continuous 3 or 4 week cycles (starting dose 20, 40 or 50 mg once-daily). Plasma concentration–time data for up to 7 months dosing were analyzed using nonlinear mixed-effects modeling.
Results
The pharmacokinetic profile of afatinib was best described by a two-compartment disposition model with first-order absorption and linear elimination. There was a slightly more than proportional increase in exposure with increasing dose, accounted for by a dose-dependent relative bioavailability. For the therapeutic dose of 40 mg, the estimated apparent total clearance and distribution volume at steady state were 734 mL/min and 2,370 L, respectively. While food intake, body weight, gender, Eastern Cooperative Oncology Group performance score, renal function, and the level of alkaline phosphatase, lactate dehydrogenase or total protein were statistically significant covariates influencing afatinib exposure, none resulted in a proportional change in exposure of more than 27.8 % in a typical patient at model extremes (2.5th and 97.5th percentiles of baseline values for continuous covariates). In simulations of the individual covariate effects, none caused a change in the typical profile exceeding the observed variability range (90 % prediction interval) of afatinib.
Conclusion
This population pharmacokinetic model adequately described the pharmacokinetics of afatinib in different cancer patient populations and therefore can be used for simulations exploring covariate effects and possible dose adaptations. The effect size for each of the individual covariates is not considered clinically relevant.
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Acknowledgments
These studies were sponsored by Boehringer Ingelheim Pharma GmbH & Co KG, Germany. Boehringer Ingelheim was responsible for the design and conduct of all of the studies, and the collection and management of the data. The authors were responsible for the analysis and interpretation of the data and the preparation of the manuscript. The authors thank the medical staff of Boehringer Ingelheim responsible for each study, the investigators of each study, along with Mehdi Shahidi (Boehringer Ingelheim), Victoria Zazulina (Boehringer Ingelheim), and Dietmar Gansser (Boehringer Ingelheim) and his staff, for conducting the bioanalytical portion of the studies.
Conflict of interest
All authors are employees of Boehringer Ingelheim Pharma GmbH & Co KG. The authors have no other conflict of interest directly related to the content of this study.
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Freiwald, M., Schmid, U., Fleury, A. et al. Population pharmacokinetics of afatinib, an irreversible ErbB family blocker, in patients with various solid tumors. Cancer Chemother Pharmacol 73, 759–770 (2014). https://doi.org/10.1007/s00280-014-2403-2
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DOI: https://doi.org/10.1007/s00280-014-2403-2