Rajendar K Mittapalli1, Silpa Nuthalapati2, Alyssa E Delke DeBord3, Hao Xiong2. 1. Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1N Waukegan Road, AP31-3, North Chicago, Illinois, 60064, USA. rajendar.mittapalli@abbvie.com. 2. Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1N Waukegan Road, AP31-3, North Chicago, Illinois, 60064, USA. 3. Process Engineering Sciences, Drug Product Development AbbVie Inc.,, North Chicago, Illinois, USA.
Abstract
PURPOSE: 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. METHODS: 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 (Cmax) and area under the plasma-concentration time curve from zero to last measured time point (AUCt) to determine the predictive ability of the correlation. RESULTS: There was a significant linear relationship (r2 = 0.944) between the fraction of drug absorbed and the fraction of drug dissolved. The prediction error using the internal validation for Cmax and AUCt were below 15% for the individual formulations and below 10% for the average. The prediction error in AUCt and Cmax for formulation C was 5% and 11%, respectively. CONCLUSIONS: 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.
PURPOSE: 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. METHODS: 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 (Cmax) and area under the plasma-concentration time curve from zero to last measured time point (AUCt) to determine the predictive ability of the correlation. RESULTS: There was a significant linear relationship (r2 = 0.944) between the fraction of drug absorbed and the fraction of drug dissolved. The prediction error using the internal validation for Cmax and AUCt were below 15% for the individual formulations and below 10% for the average. The prediction error in AUCt and Cmax for formulation C was 5% and 11%, respectively. CONCLUSIONS: 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.
Entities:
Keywords:
dissolution; extended-release formulation; in vitro/in vivo correlations (IVIVC); pharmacokinetics; veliparib
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