This research is intended to develop 3 computational pathways which will be used to investigate adverse events (AEs) reported for generic drugs, as well as to predict the relative risk of AEs for brand name drugs coming off patent in the next 5 years. The 3 computational pathways are: 1. A physiologically based PK model that integrates drug and formulation properties with biologic system properties to predict exposure to a drug product (PK). Sensitivity analysis is used to identify factors which are most likely to cause differences in PK between a generic and brand name product. 2. An empirical PK/PD model which simulates the clinical response of two drug products with different PK profiles as a function of time after administration. The PD profiles are compared to determine how sensitive they are to changes in PK. 3. A system pharmacology model that maps the targets and pathways of a drug to determine the likelihood of that drug causing the purported AEs. The model includes other drugs which are positive controls for the AE of interest to determine similarity of target and pathway with the generic drug.
The FDA Office of Generic Drugs (OGD) frequently receives reports of bioinequivalence between generic and brand name products from professionals and/or patients. It is challenging to determine if these reports are real or causal, or artifacts of drug substitution such as patient preference for a given dosage form, or perceived adverse events or loss of efficacy. In order to rigorously investigate such reports, and to determine their causality, this research proposal will develop a quantitative ad model-based approach integrating 3 different computational platforms or pathways. The product of this research is intended to be used by FDA to supplement their investigation of any purported bioinequivalence of genetic products. This research is intended to develop 3 computational pathways which will be used to investigate adverse events (AEs) reported for generic drugs, as well as to predict the relative risk of AEs for brand name drugs coming off patent in the next 5 years. The 3 computational pathways are: 1. A physiologically based PK model that integrates drug and formulation properties with biologic system properties to predict exposure to a drug product (PK). Sensitivity analysis is used to identify factors which are most likely to cause differences in PK between a generic and brand name product. 2. An empirical PK/PD model which simulates the clinical response of two drug products with different PK profiles as a function of time after administration. The PD profiles are compared to determine how sensitive they are to changes in PK. 3. A system pharmacology model that maps the targets and pathways of a drug to determine the likelihood of that drug causing the purported AEs. The model includes other drugs which are positive controls for the AE of interest to determine similarity of target and pathway with the generic drug.
