Development of a Level A in Vitro-in Vivo Correlation for Veliparib (ABT-888) Extended Release Tablet Formulation

The aim of the current manuscript is to develop and validate a level A in vitro-in vivo correlation (IVIVC) for veliparib extended-release (ER) tablet formulations. The in vitro release profiles of veliparib formulations were determined using USP Dissolution Apparatus 2 with 900 mL of 0.1 N HCl at 75 rpm. In a clinical study, 24 subjects with solid tumors received one of the ER formulations (200 mg): fast (Formulation A), intermediate (Formulation B), and slow (Formulation C), and two 100 mg immediate release capsules (Formulation D). Blood samples were collected over a period of 48 h and analyzed using LCMS/MS. A linear correlation model was developed using fraction absorbed and fraction dissolved data from formulations A and B. Besides assessing internal predictability, external predictability was evaluated using formation C. Prediction errors were estimated for maximum observed plasma concentration (C-max) and area under the plasma-concentration time curve from zero to last measured time point (AUC(t)) to determine the predictive ability of the correlation. There was a significant linear relationship (r(2) = 0.944) between the fraction of drug absorbed and the fraction of drug dissolved. The prediction error using the internal validation for C-max and AUC(t) were below 15% for the individual formulations and below 10% for the average. The prediction error in AUC(t) and C-max for formulation C was 5% and 11%, respectively. A level A IVIVC for the veliparib ER tablet formulation was established. The IVIVC may allow the associated dissolution data to be used as a surrogate for bioavailability.