Abstract 4635: Relative bioavailability of dovitinib (TKI258) formulations

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Dovitinib (TKI258) is a potent oral tyrosine kinase inhibitor of FGFR as well as VEGFR, PDGFR, cKIT, and FLT3. Early clinical trials used an oral solution or a clinical service form (CSF) capsule of a lactate anhydrous formulation, which was challenging to produce on a large scale. Thus, a lactate monohydrate salt was developed as the final market image (FMI) and has been tested in both capsule and tablet form. Methods: The objective was to characterize the relative bioavailability of the CSF capsule, the FMI capsule, and the FMI tablet to the oral solution. Relative bioavailability was quantified via the area under the concentration time curve from time zero until the last time point sampled (AUClast) and by the maximum concentration (Cmax) following a single dose. First, population pharmacokinetic (PK) modeling from 2 phase 1 studies was used to characterize the relative bioavailability of the CSF capsule to the oral solution. Then, results from 2 formal relative bioavailability studies (FMI capsule vs CSF capsule and FMI tablet vs CSF capsule) were used to bridge the FMI formulations to the oral solution. The ratio of an FMI formulation's AUClast or Cmax to that of the oral solution was found as the product of the ratio of the FMI formulation to the CSF capsule times the ratio of the CSF capsule to the oral solution. In the 2 phase 1 studies, the oral solution was used in 9 patients (dose range, 50-600 mg), and the CSF capsule was used in 67 patients (dose range, 200-600 mg). The sample sizes of the 2 relative bioavailability studies for the CSF capsule were 20 and 21 for the FMI capsule and tablet, respectively. Results: The population PK model showed that the ratios of PK parameters (90% CI) comparing the CSF capsule to the oral solution were 0.85 (range, 0.65-1.14) for AUClast and 0.85 (range, 0.64-1.12) for Cmax. Then using the bioavailability ratio of the FMI capsule to the CSF capsule (AUClast, 0.88 [range, 0.82-0.94]; Cmax, 0.97 [range, 0.89-1.06]), bridging found the AUClast ratio of the FMI capsule to the oral solution to be 0.75 (range, 0.56-1.02), and the Cmax ratio was 0.83 (range, 0.61-1.10). Similarly, the bioavailability ratio of the FMI tablet to the CSF capsule (AUClast, 0.97 [range, 0.88-1.07]; Cmax, 0.99 [range, 0.91-1.08]) was used to calculate the ratio of FMI tablet to the oral solution: 0.82 (range, 0.62-1.14) for AUClast and 0.85 (range, 0.62-1.13) for Cmax. Conclusions: The relative bioavailabilities of dovitinib CSF capsules (≈ 0.85), FMI capsules (0.75-0.83) and FMI tablets (0.82-0.85) to oral solution were found to be similar to each other with respect to both AUClast and Cmax. This is consistent with the fact that the FMI capsule and CSF capsule as well as the FMI tablet and CSF capsule were similarly bioavailable. Citation Format: Samira Garonzik, Jerry Nedelman, Jeffrey Scott, Jeffrey Cramer, Eugene Tan. Relative bioavailability of dovitinib (TKI258) formulations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4635. doi:10.1158/1538-7445.AM2014-4635