Healy, Paul;
Allegaert, Karel;
Della Pasqua, Oscar;
(2024)
Evaluation of the effect of CYP2D6 and OCT1 polymorphisms on the pharmacokinetics of tramadol: Implications for clinical safety and dose rationale in paediatric chronic pain.
British Journal of Clinical Pharmacology
10.1111/bcp.16201.
(In press).
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Abstract
AIMS: Our investigation aimed to assess the dose rationale of tramadol in paediatric patients considering the effect of CYP2D6/OCT1 polymorphisms on systemic exposure. Recommendations were made for the oral dose of tramadol to be used in a prospective study in children (3 months to < 18 years old) with chronic pain. METHODS: Intravenous pharmacokinetic and genotype data from neonatal patients (n = 46) were available for this analysis. The time course of tramadol and O-desmethyltramadol (M1) concentrations was characterized using a nonlinear mixed effects approach in conjunction with extrapolation principles. Clinical trial simulations were then implemented to explore the effects of polymorphism, maturation and developmental growth on the disposition of tramadol and M1. Reported efficacious exposure range in adult subjects were used as reference. RESULTS: The pharmacokinetics of tramadol and M1 was characterized by a two-compartment model. The total clearance of tramadol (CLPP) comprised CYP2D6-mediated metabolism (CLPM) and other pathways (CLPO). Age-related changes in CLPM, CLPO and M1 clearance (CLMO) were described by a sigmoid function, with CYP2D6 as a covariate on CLPP and CLPM, and OCT1 on CLMO. Simulation scenarios including different CYP2D6/OCT1 combinations revealed that steady-state concentrations are above the putative ranges for analgesia in >15% and >70% of subjects after doses of 3 and 8 mg/kg, respectively. CONCLUSIONS: In the absence of genotyping, reference exposure ranges can be used to define the dose rationale for tramadol in paediatric chronic pain. However, a starting dose of 0.5 mg/kg/day should be considered, followed by stepwise titration to the desired analgesic response.
| Type: | Article |
|---|---|
| Title: | Evaluation of the effect of CYP2D6 and OCT1 polymorphisms on the pharmacokinetics of tramadol: Implications for clinical safety and dose rationale in paediatric chronic pain |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/bcp.16201 |
| Publisher version: | http://dx.doi.org/10.1111/bcp.16201 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | CYP2D6, OCT1, chronic pain, dose rationale, extrapolation, paediatrics, tramadol |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10198637 |
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