Predictions of drug-drug interactions for gabapentin using physiologically-based pharmacokinetics

• Grant number: 20/00756-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: April 01, 2020
• End date: December 31, 2020
• Field of knowledge: Biological Sciences - Pharmacology - Clinical Pharmacology
• Principal Investigator: Natália Valadares de Moraes
• Grantee: Thayna Pizzocaro Gomez
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Modeling and simulation (M&S) in physiologically-based pharmacokinetics (PBPK) studies have recently been recognized by American and European regulatory agencies for decision-making in drug development. This approach has been used to explore and quantitatively predict drug-drug interactions in virtual populations. In this study, modeling and simulation in PBPK will be used to predict the effect of drug-drug interactions on gabapentin pharmacokinetics. Clinically, gabapentin is used to treat neuropathic pain and as an adjunct in the treatment of epilepsy. Models will be evaluated using the PKSim® software (version 8) to predict the data generated by the research group in a cross-over clinical trial in patients with neuropathic pain treated with a single dose of gabapentin. Gabapentin has variable bioavailability in the gastrointestinal tract, which is probably related to its saturable absorption mediated by the L-type amino acid transporter (LAT). The drug does not bind to plasma proteins, is not metabolized in humans and is mainly eliminated unchanged in urine. Studies suggested that active tubular secretion in the kidneys contributes to the excretion of gabapentin. Data in our research group showed that gabapentin is a substrate for kidney transporters MATE1, OCTN1 and OCT2. Data generated here can contribute for the comprehension of the physiological mechanisms regulating gabapentin pharmacokinetics and to a better design of clinical studies involving gabapentin. (AU)