CYP2D6 Phenotype-Specific Codeine Population Pharmacokinetics

ABSTRACT

Codeine's metabolic fate in the body is complex, and detailed quantitative knowledge of it, and that of its metabolites is lacking among prescribers. We aimed to develop a codeine pharmacokinetic pathway model for codeine and its metabolites that incorporates the effects of genetic polymorphisms. We studied the phenotype-specific time courses of plasma codeine, codeine-6-glucoronide, morphine, morphine-3-glucoronide, and morphine-6-glucoronide. A codeine pharmacokinetic pathway model accurately fit the time courses of plasma codeine and its metabolites. We used this model to build a population pharmacokinetic codeine pathway model. The population model indicated that about 10% of a codeine dose was converted to morphine in poor-metabolizer phenotype subjects. The model also showed that about 40% of a codeine dose was converted to morphine in EM subjects, and about 51% was converted to morphine in ultrarapid-metabolizers. The population model further indicated that only about 4% of MO formed from codeine was converted to morphine-6-glucoronide in poor-metabolizer phenotype subjects. The model also showed that about 39% of the MO formed from codeine was converted to morphine-6-glucoronide in extensive-metabolizer phenotypes, and about 58% was converted in ultrarapid-metabolizers. We conclude, a population pharmacokinetic codeine pathway model can be useful because beyond helping to achieve a quantitative understanding the codeine and MO pathways, the model can be used for simulation to answer questions about codeine's pharmacogenetic-based disposition in the body. Our study suggests that pharmacogenetics for personalized dosing might be most effectively advanced by studying the interplay between pharmacogenetics, population pharmacokinetics, and clinical pharmacokinetics.

KEYWORDS :

• codeine
• CYP2D6
• CYP3A4
• CYP2C8
• morphine
• pharmacogenetics
• pharmacogenomics
• clinical pharmacokinetics
• clinical pharmacology
• population pharmacokinetics

ACKNOWLEDGEMENT

Oscar A. Linares, M.D. is grateful to the University of Michigan Horace H. Rackham School of Graduate Studies and the Geriatrics Center. He conceived this work's modeling as a visiting scholar there while working with Dr. Loren A. Zech at NIH, NCI, Laboratory of Mathematical Biology. The authors thank three anonymous reviewers whose incisive reviews of a prior version of this manuscript substantially improved the work.

Declaration of interest: Dr. Fudin is an expert legal advisor and on the speakerś bureau for Millennium Health, LLC. He is a consultant to Zogenix, Inc. and to Practical Pain Management in the development of the online Opioid Calculator. Dr. Fudin's participation does not reflect the opinion of employers, employee affiliates, and/or pharmaceutical companies listed. Otherwise, authors report no conflicts of interest.