Development, validation and application of physiologically based biopharmaceutics model to justify the change in dissolution specifications for DRL ABC extended release tablets.

ABSTRACT

OBJECTIVE: The generic drug product DRL ABC is an Extended Release (ER) Tablet manufactured by Dr. Reddy's Laboratories Limited and have multi point dissolution as part of release specification. A proposal is being made to revise the dissolution specification and the aim of present work was to evaluate if this would still provide bioequivalent product. METHODS: PBBM was developed for DRL ABC using literature reported pharmacokinetic (PK) data. The intravenous PK data and in vitro metabolic rate constants were utilized for developing PBPK model first, followed by that in conjugation with mechanistic ACATTM model, a PBBM is developed for per-oral immediate release formulations. The validated model was applied to predict clinical bioequivalence (BE) study data for the Reference (Innovator ER Tablet) and Test product. For Reference and Test product, in vivo dissolution profiles were mechanistically deconvoluted from plasma concentration (Cp)-time profiles. Further, mechanistic in vitro-in vivo relationship (IVIVR) applied to in vitro release profiles of two hypothetical Test product batches (one with single point low dissolution profile (SPLP) and other with overall low dissolution profile (LP)) in order to calculate their in vivo releases and population simulation was performed with 40 virtual subjects. RESULTS: Results from the cross-over virtual trials showed BE between the Reference and various Test product batches (SPLP and LP), with maximum Cp (Cmax) and area under the Cp-time curve (AUC0-inf) well within 80-125% range. CONCLUSION: PBBM in conjugation with IVIVR and virtual BE was successfully applied for justifying changes in dissolution specification of DRL ABC.