Selecting in vitro dissolution tests using population pharmacokinetic modelling to help bioequivalence studies
Kairui Feng1, Robert H. Leary1, Michael Dunlavey1, Amin Rostami-Hodjegan1,2
1. Certara, USA, 2. University of Manchester, UK
Objectives: Before conducting bioequivalence (BE) studies or any related pilot studies for in vivo clinical trials, selecting an appropriate in vitro dissolution test is a key analytical test for detecting physical changes in an active pharmaceutical ingredient (API) for any solid oral dosage forms. The main objective of this work is to build population pharmacokinetic (Pop-PK) models with direct in vitro-in vivo correlation (IVIVC) for selecting effective test technology matching the in vivo human absorption of API from the innovator and hence to indicate the performance of the test formulation (T) – either success or likely failure mechanisms related to the in vivo human studies.
Methods: Nifedipine was taken as an example to demonstrate the benefit of Pop-PK modelling with direct IVIVC. A total of 34 in vitro dissolution experiments were performed using USP1, USP2, USP3, and USP4 methodologies with various combinations of pH, volumes (mL), media type (FaSSGF with or without grapefruit juice), rotation speed (rmp), dipping rate(dpm), flow rate (mL/min), and ethanol content (%v/v) . The in vitro dissolution profiles were then fitted by using the best selected sigmoidal models such as a Hill equation or cumulative Weibull distribution. The fitted in vitro dissolution models were then differentiated to provide the input rate added to the IVIVC models which were directly incorporated in PK models . Nonlinear mixed effect modeling (NLME) was used to estimate PK models with direct IVIVC by fitting 30 subjects blood samples created from [4, 5,6] for both Caucasian population and south Asian population. The best fitted models with related in vitro dissolution experiments were selected for test formulation dissolution experiments. Both test and reference formulation (T&R) in vitro dissolution were used for simulation using parallel design and 2 by 2 crossover design. Simulated PK parameters such as Cmax and AUC were used to determine the bioequivalence between T&R using ANOVA analysis.
Results: Both Caucasian and south Asian data show consistent results for the in vitro dissolution test methods that USP2 is the preferred method and in vitro dissolution tests without grapefruit juice match better with the in vivo concentration. Lower bound and upper bound dissolution profiles for T are created to test the BE with R. The BE test results showed that the T is bioequivalent with the R if the variation of in vitro dissolution of the T is within the test bounds. The results indicated that the T is more likely to be successful if the in vitro dissolution is within the test bounds and only if the in vitro dissolution experiments were done using the selected test technology.
Conclusions: The direct IVIVC method using population PK analysis is a novel approach for bioequivalence studies. The method helps to identify in vitro dissolution tests and test bounds, to propose ranges of dissolution profiles and hence to increase the successful rate of test formulation and hence reduce the number of BE studies performed during the initial approval process or certain scale-up and post approval changes .
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