PI-076

A. Babiskin, H. Kim, L. Fang, L. Lapteva, W. Jiang, R. Lionberger; Food and Drug Administration, Silver Spring, MD

BACKGROUND: The optimal pharmacokinetic (PK) metrics for evaluating bioequivalence (BE) of generic methylphenidate extended-release products are not known. The objective of the current study was to identify optimal BE metrics in the form of partial AUCs (pAUCs) that can detect clinically meaningful PK differences between formulations that differ in key formulation parameters.
METHODS: A physiologically-based absorption model based on the Advanced Compartment Absorption and Transit (ACAT) model was developed. The built model was validated on PK data from intravenous (IV), immediate-release (IR), and extended-release (ER) formulations. Sensitivity analyses on the release rate (i.e., Weibull function parameters) were conducted to generate the PK profiles of a wide range of potential generic products. The Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale (SKAMP) profiles, a measure intended to assess functional impairment related to attention deficit hyperactivity disorder, were simulated based on a published PK/PD model for methylphenidate products.
RESULTS: Three theoretical generic products were identified to have less SKAMP score reduction in the late afternoon compared to innovator product although they all pass the current BE criteria. The decline in predicted efficacy amongst these formulations in the late afternoon is correlated with pAUC difference during this time window, AUC8-12.
CONCLUSION: Alternative pAUC metrics such as AUC8-12 are needed to detect PK differences for generic methylphenidate extended-release products that differ in key formulation parameters.