PII-163 - APPLICATION OF PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING TO SUPPORT BIOEQUIVALENCE EVALUATION OF MESALAMINE DELAYED RELEASE TABLETS

S. Thomas¹, F. Wu², L. Zhao³, L. Fang³; ¹U.S. Food and Drug Administration, U.S. Food and Drug Administration, Silver Spring, MD, United States, ²U.S. Food and Drug Administration, ³Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.

Background: The product specific guidance for mesalamine delayed release (DR) tablet recommends a fasting pharmacokinetic (PK) bioequivalence (BE) study, and a fed PK BE study and comparative three-stage dissolution studies with stage 3 at four different pH (6.5, 6.8, 7.2, and 7.5). For this case example, dissolution studies showed differences between test and reference listed drug (RLD) with f2 less than 50 at pH 6.5 and 6.8 buffer conditions for stage 3 of dissolution testing. The purpose of this study is to use physiologically based pharmacokinetic (PBPK) modeling to evaluate the risk of bioinequivalence for the test product at site of action.

Methods: PBPK model using GastroPlus 9.8.2 was developed in house for Mesalamine DR tablet. Intravenous PK data obtained from the literature were used to estimate disposition parameters. Three-stage dissolution data with stage 1 in 0.1N HCl for 2 hours, stage 2 in pH 6.4 phosphate buffer for 1 hour and stage 3 in pH 7.2 phosphate buffer for 8 hours was incorporated to inform the absorption parameters. pH-dependent solubility data were incorporated in the model. The intestinal transit time was optimized to mimic most drug absorption in the colon and no drug absorption in stomach and early small intestine (duodenum and jejunum) since the formulation shows delayed pH dependent drug release. The validated model was then used to evaluate whether the three-stage dissolution data with stage 3 at multiple pH is biopredictive. Population simulation was conducted to compare percentage of drug absorbed in the colon between test product and RLD to support BE assessment.

Results: Dissolution profile at for stage 3 at pH 6.8 was not biopredictive for the systemic exposure of test product with percent prediction error for Cmax and AUC ≥30%. The predicted amount of mesalamine in colon was found to be similar between RLD and test product at pH 6.9 and above as shown in Table 1. Further, model population simulations (n=25) showed that the percentage of drug absorbed in the colon is similar between RLD and test product with the 90% CI of the T/R ratio falling between 80-125%.

Conclusion: By incorporating the biopredictive dissolution data with stage 3 at pH 6.9 and above, the PBPK model predicted amount of mesalamine in colon was found to be similar between test product and RLD.