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Open Access 23-10-2024 | Codeine | Original Research Article

Population Pharmacokinetic Quantification of CYP2D6 Activity in Codeine Metabolism in Ambulatory Surgical Patients for Model-Informed Precision Dosing

Authors: Muhammad Waqar Ashraf, Satu Poikola, Mikko Neuvonen, Johanna I. Kiiski, Vesa K. Kontinen, Klaus T. Olkkola, Janne T. Backman, Mikko Niemi, Teijo I. Saari

Published in: Clinical Pharmacokinetics

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Abstract

Background and Objective

Codeine metabolism in humans is complex due to the involvement of multiple cytochrome P450 (CYP) enzymes, and has a strong genetic underpinning, which determines the levels of relevant CYP450 enzyme expression in vivo. Polymorphic CYP2D6 metabolises codeine to morphine via O-demethylation, while a strong correlation between CYP2D6 phenotype and opioidergic adverse effects of codeine is well documented. The aim of this study was to quantify the effect of CYP2D6 genotype on the biotransformation of codeine.

Methods

We conducted a prospective clinical trial with 1000 patients, during which ambulatory patients were administered 60 mg of codeine preoperatively and the association between CYP2D6 activity and morphine exposure across various CYP2D6 genotypes was quantified using a population pharmacokinetic model. Plasma concentration data for codeine and its primary metabolites were obtained from 997 patients and CYP2D6 genotype was screened for study subjects, and respective sums of activity scores assigned for each CYP2D6 allele were used as covariates in model development.

Results

Our final model predicts the disposition of codeine and the formation of morphine, codeine-6-glucuronide and morphine-3-glucuronide adequately while accounting for variability in morphine exposure on the basis of CYP2D6 genotype. In agreement with previous results, patients with decreased function alleles (CYP2D6*10 and *41) showed varying levels of decrease in CYP2D6 activity that were inconsistent with increasing activity scores. Model simulations demonstrate that morphine concentrations in ultrarapid CYP2D6 metabolisers reach systemic concentrations that can potentially cause respiratory depression (over 9.1 ng/mL), and have 218% higher exposure (19 versus 8.7 µg · h/L, p < 0.001) to morphine than normal metabolisers. Similarly, poor and intermediate metabolisers had significantly reduced morphine exposure (1.0 and 3.7 versus 8.7 µg · h/L, p < 0.001) as compared with normal metabolisers.

Conclusions

Our final model leads the way in implementing model-informed precision dosing in codeine therapy and identifies the use of genetic testing as an integral component in the effort to implement rational pharmacotherapy with codeine.
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Metadata
Title
Population Pharmacokinetic Quantification of CYP2D6 Activity in Codeine Metabolism in Ambulatory Surgical Patients for Model-Informed Precision Dosing
Authors
Muhammad Waqar Ashraf
Satu Poikola
Mikko Neuvonen
Johanna I. Kiiski
Vesa K. Kontinen
Klaus T. Olkkola
Janne T. Backman
Mikko Niemi
Teijo I. Saari
Publication date
23-10-2024
Publisher
Springer International Publishing
Keywords
Codeine
Morphine
Published in
Clinical Pharmacokinetics
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-024-01433-9