{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Ashraf MW"],"funding":["Varsinais-Suomen Sairaanhoitopiiri","Turun Yliopisto"],"pagination":["687-697"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6202471"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["7(10)"],"pubmed_abstract":["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."],"journal":["CPT: pharmacometrics & systems pharmacology"],"pubmed_title":["Semimechanistic Population Pharmacokinetic Model to Predict the Drug-Drug Interaction Between S-ketamine and Ticlopidine in Healthy Human Volunteers."],"pmcid":["PMC6202471"],"funding_grant_id":["13821"],"pubmed_authors":["Peltoniemi MA","Saari TI","Ashraf MW","Olkkola KT","Neuvonen PJ"],"additional_accession":[]},"is_claimable":false,"name":"Semimechanistic Population Pharmacokinetic Model to Predict the Drug-Drug Interaction Between S-ketamine and Ticlopidine in Healthy Human Volunteers.","description":"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.","dates":{"release":"2018-01-01T00:00:00Z","publication":"2018 Oct","modification":"2026-06-18T05:09:12.204Z","creation":"2019-03-27T00:05:26Z"},"accession":"S-EPMC6202471","cross_references":{"pubmed":["30091858"],"doi":["10.1002/psp4.12346"]}}