biostudies-literatureAshraf MWVarsinais-Suomen SairaanhoitopiiriTurun Yliopisto687-697https://www.ebi.ac.uk/biostudies/studies/S-EPMC6202471biostudies-literatureUnknown7(10)Low-dose oral S-ketamine is increasingly used in chronic pain therapy, but extensive cytochrome P450 (CYP) mediated metabolism makes it prone to pharmacokinetic drug-drug interactions (DDIs). In our study, concentration-time data from five studies were used to develop a semimechanistic model that describes the ticlopidine-mediated inhibition of S-ketamine biotransformation. A mechanistic model was implemented to account for reversible and time-dependent hepatic CYP2B6 inactivation by ticlopidine, which causes elevated S-ketamine exposure in vivo. A pharmacokinetic model was developed with gut wall and hepatic clearances for S-ketamine, its primary metabolite norketamine, and ticlopidine. Nonlinear mixed effects modeling approach was used (NONMEM version 7.3.0), and the final model was evaluated with visual predictive checks and the sampling-importance-resampling procedure. Our final model produces biologically plausible output and demonstrates that ticlopidine is a strong inhibitor of CYP2B6 mediated S-ketamine metabolism. Simulations from our model may be used to evaluate chronic pain therapy with S-ketamine.CPT: pharmacometrics & systems pharmacologySemimechanistic Population Pharmacokinetic Model to Predict the Drug-Drug Interaction Between S-ketamine and Ticlopidine in Healthy Human Volunteers.PMC620247113821Peltoniemi MASaari TIAshraf MWOlkkola KTNeuvonen PJfalseSemimechanistic Population Pharmacokinetic Model to Predict the Drug-Drug Interaction Between S-ketamine and Ticlopidine in Healthy Human Volunteers.Low-dose oral S-ketamine is increasingly used in chronic pain therapy, but extensive cytochrome P450 (CYP) mediated metabolism makes it prone to pharmacokinetic drug-drug interactions (DDIs). In our study, concentration-time data from five studies were used to develop a semimechanistic model that describes the ticlopidine-mediated inhibition of S-ketamine biotransformation. A mechanistic model was implemented to account for reversible and time-dependent hepatic CYP2B6 inactivation by ticlopidine, which causes elevated S-ketamine exposure in vivo. A pharmacokinetic model was developed with gut wall and hepatic clearances for S-ketamine, its primary metabolite norketamine, and ticlopidine. Nonlinear mixed effects modeling approach was used (NONMEM version 7.3.0), and the final model was evaluated with visual predictive checks and the sampling-importance-resampling procedure. Our final model produces biologically plausible output and demonstrates that ticlopidine is a strong inhibitor of CYP2B6 mediated S-ketamine metabolism. Simulations from our model may be used to evaluate chronic pain therapy with S-ketamine.2018-01-01T00:00:00Z2018 Oct2026-06-18T05:09:12.204Z2019-03-27T00:05:26ZS-EPMC62024713009185810.1002/psp4.12346