Ashraf , M W , Peltoniemi , M A , Olkkola , K T , Neuvonen , P J & Saari , T I 2018 , ' Semimechanistic Population Pharmacokinetic Model to Predict the Drug-Drug Interaction Between S-ketamine and Ticlopidine in Healthy Human Volunteers ' , CPT : Pharmacometrics & Systems Pharmacology , vol. 7 , no. 10 , pp. 687-697 . https://doi.org/10.1002/psp4.12346
Title: | Semimechanistic Population Pharmacokinetic Model to Predict the Drug-Drug Interaction Between S-ketamine and Ticlopidine in Healthy Human Volunteers |
Author: | Ashraf, Muhammad W.; Peltoniemi, Marko A.; Olkkola, Klaus T.; Neuvonen, Pertti J.; Saari, Teijo I. |
Contributor organization: | Department of Diagnostics and Therapeutics Department of Clinical Pharmacology HUS Perioperative, Intensive Care and Pain Medicine |
Date: | 2018-10 |
Language: | eng |
Number of pages: | 11 |
Belongs to series: | CPT : Pharmacometrics & Systems Pharmacology |
ISSN: | 2163-8306 |
DOI: | https://doi.org/10.1002/psp4.12346 |
URI: | http://hdl.handle.net/10138/299660 |
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. |
Subject: |
CLINICAL PHARMACOKINETICS
PARAMETER UNCERTAINTY N-DEMETHYLATION IN-VITRO INHIBITION PHARMACODYNAMICS DISTRIBUTIONS INACTIVATION CYP2B6 VALUES 3121 General medicine, internal medicine and other clinical medicine |
Peer reviewed: | Yes |
Rights: | cc_by |
Usage restriction: | openAccess |
Self-archived version: | publishedVersion |
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