Population Pharmacokinetic Model for Tramadol and O-desmethyltramadol in Older Patients

Abstract

Background and ObjectivesTramadol is commonly prescribed to manage chronic pain in older patients. However, there is a gap in the literature describing the pharmacokinetic parameters for tramadol and its active metabolite (O-desmethyltramadol [ODT]) in this population. The objective of this study was to develop and evaluate a population pharmacokinetic model for tramadol and ODT in older patients. Methods Twenty-one patients who received an extended-release oral tramadol dose (25-100 mg) were recruited. Tramadol and ODT concentrations were determined using a validated liquid chromatography/tandem mass spectrometry method. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. The performance of the model was assessed by visual predictive check. Results A two-compartment, first-order absorption model with linear elimination best described the tramadol concentration data. The absorption rate constant was 2.96/h (between-subject variability [BSV] 37.8%), apparent volume of distribution for the central compartment (V 1 /F) was 0.373 l (73.8%), apparent volume of distribution for the peripheral compartment (V 2 /F) was 0.379 l (97.4%), inter-compartmental clearance (Q) was 0.0426 l/h (2.19%) and apparent clearance (CL/F) was 0.00604 l/h (6.61%). The apparent rate of metabolism of tramadol to ODT (k t ) was 0.0492 l/h (78.5%) and apparent clearance for ODT (CL m ) was 0.143 l/h (21.6%). Identification of Seniors at Risk score (ISAR) and creatinine clearance (CrCL) were the only covariates included in the final model, where a higher value for the ISAR increased the maximum concentration (C max ) of tramadol and reduced the BSV in Q from 4.71 to 2.19%. A higher value of CrCL reduced tramadol C max and halflife (T 1/2 ) and reduced the BSV in V 2 /F (from 148 to 97.4%) and in CL/F (from 78.9 to 6.61%). Conclusion Exposure to tramadol increased with increased frailty and reduced CrCL. Prescribers should consider patients frailty status and CrCL to minimise the risk of tramadol toxicity in such cohort of patients.

Influence of cytochrome P450 2D6*10/*10 genotype on the risk for tramadol associated adverse effects: a retrospective cohort study

“…Tramadol is available as a racemic mixture with different mechanistic effects of its (+)/(−) enantiomers, and its primary CYP2D6 derived metabolite, O -desmethyltramadol (ODT). The latter has a 200-fold greater affinity for µ-opioid receptors as compared with the parent tramadol ( Al-Qurain et al, 2022 ). The (+) enantiomer has a weak affinity for the μ-receptor and effectively inhibits serotonin reuptake, whereas the (−) enantiomer is a more effective inhibitor of noradrenaline reuptake.…”

“…CYP2D6 low metabolizers have been shown to have lower median plasma levels of the active metabolite) ODT) after a dose of tramadol as compared with higher metabolizers, and they are more often resistant to tramadol`s analgesic effect (R Core Team, 2021;Harrell, 2021;Ardakani et al, 2008;Wang et al, 2006;Stamer et al, 2003;Swen et al, 2011;Dong et al, 2015). On the other hand, rapid metabolizers display higher peak plasma concentrations of ODT after tramadol administration, accompanied by greater analgesia, and higher incidence of adverse events as compared with lower metabolizers (Wang et al, 2006;Wen et al, 2020).…”

“…To test the hypothesis that carriers of the CYP2D6*10/*10 are at increased risk of developing nervous system and gastrointestinal adverse effects, we fitted a binary logistic regression model with CYP2D6*10 allele carriage, age, daily tramadol dose, creatinine clearance, and concomitant use of CYP2D6 inhibitors as pre-specified explanatory variables ( Vazzana et al, 2015 ; DeLemos et al, 2017 ; Al-Qurain et al, 2022 ). Bootstrapping with 400 repetitions was used for internal validation and to derive bootstrapped 95% confidence intervals.…”