Semimechanistic Population Pharmacokinetic Model to Predict the Drug-Drug Interaction Between S-ketamine and Ticlopidine in Healthy Human Volunteers

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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: University of Helsinki, Department of Diagnostics and Therapeutics
University of Helsinki, Department of Clinical Pharmacology
Date: 2018-10
Language: eng
Number of pages: 11
Belongs to series: CPT : Pharmacometrics & Systems Pharmacology
ISSN: 2163-8306
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
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