Is a Clinical Trial With a Non-Bioequivalent Batch Necessary? The Critical Role of Intrasubject Variability in...

Although physiologically based pharmacokinetic (PBPK) modeling is increasingly being used to support oral drug formulation bridging, the acceptance by regulatory agencies is low. One of the primary concerns is the absence of clinical pharmacokinetic (PK) data from a non-bioequivalent (non-BE) batch during model validation. Such data are strongly recommended by regulatory agencies to demonstrate that the models are sufficiently sensitive to detect formulation-driven changes in drug exposure. Herein, we investigated whether using clinical non-BE batch data is the most effective absorption model validation approach, using the bridging of adult and pediatric olaparib formulations as an example. Two olaparib PBPK models were developed: a "final" model and a "counterpart" model, each with comparable ability to predict the olaparib PK. Both models well predicted the clinical PK of a non-BE batch of 250 mg olaparib-manufactured intentionally with a slower release profile-and its lack of bioequivalence relative to ten 25 mg tablets, formulated for faster release, as a conservative scenario. The final model closely captured both observed intra- and intersubject variabilities in C_max and AUC, whereas the counterpart model was unable to reproduce the observed intrasubject variability. Our findings indicated that the clinical non-BE data may not be necessary in all cases. In certain scenarios, validation against intrasubject variability may meet the dual objectives of capturing PK variability and confirming sensitivity within the absorption model. Using the final model, we demonstrated BE between adult and pediatric formulations of olaparib in adults and showed minimal food effect on its exposure in pediatrics.