Semi-mechanistic population pharmacokinetic model to predict the drug-drug interaction between S-ketamine and ticlopidine in healthy human volunteers.
CPT Pharmacometrics Syst Pharmacol. 2018 Aug 09;:
Authors: Ashraf MW, Peltoniemi MA, Olkkola KT, Neuvonen PJ, Saari TI
Low dose oral S-ketamine is increasingly used in chronic pain therapy, but extensive cytochrome P450 mediated metabolism makes it prone to pharmacokinetic drug-drug interactions. In our study, concentration-time data from five studies was used to develop a semi-mechanistic 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® 7.3.0), and the final model was evaluated with visual predictive checks and 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. This article is protected by copyright. All rights reserved.
PMID: 30091858 [PubMed – as supplied by publisher]