J. P. Bai,1 A. Babiskin,1 X. Zhang,1 R. A. Lionberger,1 G. Burckart,1 A. E. Mulberg,1 V. Sinha,1 T. Uno2; 1US Food and Drug Administration, Silver Spring, MD, 2Zikeikai-Aoimori Hospital, Aomori City, Japan

BACKGROUND: Bioequivalent studies are typically performed in healthy subjects. However, an approved generic is prescribed for the intended-to-treat patients with diverse disease background, in the presence or absence of co-morbidities, and including children and elderly if approved. One common question is whether bioavailability in healthy subjects reflects that in the indicated disease population of all age groups and disease background.
METHODS: To address this question, a comprehensive literature review of gastrointestinal (GI) physiological characteristics in elderly, children and GI diseases (irritable bowel symptom, ulcerative colitis, Crohn’s disease) was conducted. Physiologically-based absorption modeling was performed in these populations by referencing literature and considering the properties of the drug substance and formulation characteristics. The three drugs studied were amphetamine, omeprazole, and atorvastatin. PK data of omeprazole in extensive, intermediate and poor metabolizers were used for omeprazole considering CYP2C19 polymorphisms. Modeling and simulation was performed to determine whether a hypothetical generic product is bioequivalent to the innovator product in these populations.
RESULTS: For the three drugs studied, physiologically-based absorption-centric pharmacokinetic modeling of bioequivalence provides preliminary results to further our understanding of the effects of aging, developmental changes in children aged 6 and older, or specific GI diseases noted above on the bioavailability of drug.
CONCLUSION: Physiologically-based absorption and pharmacokinetic modeling and simulation could be a risk assessment tool in which evidence-based differences in GI diseases and physiological GI factors are considered.