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.