Category: Clinical Pharmacology
Purpose: Physiologically based pharmacokinetic (PBPK) analysis is a modeling approach which integrates anatomical and physiological parameters of the gastrointestinal (GI) tract as well as the physicochemical properties of drug product to predict drug in vivo performance. This modeling approach has been increasingly used as a biopharmaceutics tool to evaluate the impact of drug product quality attributes on in vivo performance. This study focuses on the evaluation of the biopredictive capability of the dissolution methods listed in USP monographs and the impact of drug release on pharmacokinetics (PK) performance using PBPK modeling and simulation
Methods: The software GastroPlus Version 9.6 (Simulation Plus) was used to develop the PBPK model for diltiazem drug products. The physicochemical parameters of the drug substance (e.g., solubility, permeability and protein binding) were obtained from published studies. The plasma concentration-time profiles of diltiazem in healthy humans from the administrations of intravenous (IV), oral solution and ER formulations were used to develop and verify the model. The in vitro dissolution testing results of market Diltiazem HCl Extended Release Capsules (including both RLD and generic products) were obtained from a previous study which is described in the study entitled: Dissolution Testing of Diltiazem HCl Extended-Release Capsule Products (submitted to AAPS abstract 2019). Using the verified model, the in vivo dissolution profile was deconvoluted from the plasma concentration-time profile of ER drug products. The in vitro dissolution profiles from the study of market drugs different dissolution methods/media were compared to the deconvoluted in vivo dissolution profiles. The selection of in vitro dissolution test method was discussed taking into consideration formulation characteristics. Using the in vitro dissolution profiles from the most relevant method, the PK profiles in healthy humans under the fasted condition were simulated. The impact of the in vitro dissolution difference on the in vivo performance of drug products was assessed.
Results: The mechanistic absorption model (ACAT) was combined with a 2-compartment model and a fixed first-pass effect (60%) was developed based on the PK data from IV data (20 mg) and oral solution (90 mg). The model was further verified with published PK data from various ER formulations with different doses. The predicted PK parameters (Cmax and AUC) for the two Reference Listed Drug products of Diltiazem ER capsules (Tiazac and Cardizem CD) were in a good agreement with the observed data (prediction error < 20%) for both products. Deconvolution was performed on the plasma concentration-time profiles of Tiazac Capsules (240 mg) capsules and Cardizem CD capsules (360 mg) and the in vivo dissolution profiles were similar with their respective in vitro dissolution profiles. As the drug release takes more than 24 hours, a significant fraction of drug ( >40%) was absorbed in colon. The dissolution method using a medium at pH 6.8 or above could be more biorelevant than pH 1.2 considering most of drug was absorbed in distal gastrointestinal tract. However, the pH of the medium might not be critical if the release mechanism of functional polymer is pH-independent. For tested generic ER capsule products, the in vitro dissolution showed two different dissolution behaviors: single Weibull and double Weibull function. For generic products which have in vitro dissolution following a single Weibull function, the predicted Cmax and AUC based on the PBPK model indicate the tested generic products are bioequivalent to the corresponding RLDs. The dissolution profile following a double Weibull function was attributed to two different ER beads with different coating weight gains in the same capsules which are designed to release at two different rates (fast and slow). The double Weibull dissolution behavior may explain observed PK profiles which showed two peaks in most subjects.
Conclusion: A PBPK model was successfully developed and used to assess the in vitro dissolution methods for diltiazem ER products. The modeling approach can be very helpful to establish an in vitro in vivo relationship via a biopredictive in vitro dissolution test. A verified PBPK model can be effectively used to support formulation and process development, design space establishment and clinically relevant product specifications.
Zongming Gao– Research Scientist, US Food and Drug Administration, St. Louis, Missouri
Fuxing Tang– Silver Spring, Maryland
Stephanie Choi– Chemist, US Food and Drug Administration, Silver Spring, Maryland
Roxana Toth– St. Louis, Missouri
Jason Rodriguez– FDA, Saint Louis, Missouri