Tramadol-Related Deaths: Genetic Analysis in Relation to Metabolic Ratios

Tramadol (TR) metabolism is mainly dependent on the enzymatic activity of CYP2D6, which is controlled by genetic polymorphisms. Individuals are classified as poor (PMs), intermediate (IMs), extensive (EMs) or ultrarapid metabolizers (UMs) according to their genotype or phenotype. The determination of the metabolic phenotype for CYP2D6 can be of utmost importance in forensic and clinical contexts that involve TR intake. The present study aimed to describe CYP2D6 genetic variants in cases of TR-related deaths and to assess which metabolic ratio(s) (MRs) would allow to determine CYP2D6 phenotype without having to perform genetic analyses. Forty-eight postmortem blood samples were selected from TR-related death cases previously analyzed in a forensic context in North of France between 2013 and 2019. Initial available data included blood concentrations of TR and its two main metabolites (M1 & M2) determined using a LC-MS/MS method. TR metabolism was expressed as various MRs comprising TR/M1, TR/M2 and M2/M1. After DNA extraction, sequencing was used for genetic variant detections that affect CYP2D6 activity/expression. In the present study, the allelic variants with the higher frequency were CYP2D6*1 (68%), followed by *4 (21%). The most frequent phenotype is EMs (59.6%), followed by IMs (23.4%), PMs (12.8%) and UMs (6.4%). There was no significant correlation between each calculated MR and the genotypically predicted phenotypes, except for M2/M1 which appears related to the PM phenotype. The observed distribution of CYP2D6 genetic variants in this TR-related death population was similar to that found in the general Caucasian population. The present study displayed that the blood M2/M1 ratio could be the best-correlated TR MR to the PM phenotype, and could thus be used in forensic contexts where genetic analyses are not possible or poorly informative. For the other phenotypes, especially the UM phenotype, genetic analysis appears to be the only reliable method to predict the CYP2D6 phenotype.

CYP2D6 phenotype explains reported yohimbine concentrations in four severe acute intoxications

The indole alkaloid yohimbine is an alpha-2 receptor antagonist used for its sympathomimetic effects. Several cases of yohimbine intoxication have been reported and the most recent one involved four individuals taking a yohimbine-containing drug powder. All individuals developed severe intoxication symptoms and were admitted to the hospital. Even though all individuals were assumed to have taken the same dose of the drug powder, toxicology analyses revealed yohimbine blood concentrations of 249–5631 ng/mL, amounting to a 22-fold difference. The reason for this high variability remained to be elucidated. We used recently reported knowledge on the metabolism of yohimbine together with state-of-the art nonlinear mixed-effects modelling and simulation and show that a patient’s cytochrome P450 2D6 (CYP2D6) phenotype can explain the large differences observed in the measured concentration after intake of the same yohimbine dose. Our findings can be used both for the identification of safe doses in therapeutic use of yohimbine and for an explanation of individual cases of overdosing.

Using the drug repositioning approach to develop a novel therapy, tipepidine hibenzate sustained-release tablet (TS-141), for children and adolescents with attention-deficit/hyperactivity disorder

Background Asverin® (tipepidine hibenzate) has been used as an antitussive for > 50 years in Japan. Studies revealed that tipepidine modulates monoamine levels, by inhibiting G-protein-activated inwardly rectifying potassium (GIRK) channels, expecting the potential therapeutic effects of tipepidine for attention-deficit/hyperactivity disorder (ADHD) in recent years. In this study, TS-141, a sustained-release tablet of tipepidine, was developed for the treatment of ADHD through a drug repositioning approach. Methods The sustained-release profile of TS-141 in healthy adults was investigated, and tipepidine exposure in the plasma after the TS-141 administration was compared to that of Asverin in the phase I study. Phase II study was conducted to examine the effects of TS-141 30 (once a day), 60 (once a day), 120 mg (60 mg twice a day), or placebo, that is within the exposure in the maximum dosage of Asverin, in children and adolescents with ADHD, and was designed as an 8-week treatment, randomized, parallel group, double-blind, placebo-controlled trial recruiting 6–17-year-old children and adolescents diagnosed with ADHD. A total of 216 patients were randomized according to the CYP2D6 phenotype. The primary end-point was ADHD Rating Scale IV-J changes. Furthermore, effects of CYP2D6 phenotype on the efficacy in the subgroup analysis were investigated. Results TS-141 had the sustained-release profile, and the CYP2D6 phenotype had effects on the plasma exposure of tipepidine. ADHD RS-IV-J scores in all TS-141 dosages decreased from their baseline scores; however, no significant difference was observed in ADHD RS-IV-J score changes between the placebo and TS-141-administered groups. In patients with intermediate metabolizer CYP2D6, ADHD RS-IV-J score changes in the 120 mg group tended to be larger than that in the placebo group. Conclusions ADHD RS-IV-J changes on TS-141 may depend on the interaction between the TS-141 dose and CYP2D6 phenotype, suggesting that further clinical trials should be conducted with careful consideration of polymorphism. Drug repositioning approach of TS-141 was attempted at the same dose as that of antitussive; however, dose setting according to the indication was necessary. Trial registration Phase I study: JapicCTI-205235 (Registered 25 March 2020), Phase II study: JapicCTI-163244 (Registered 9 May 2016), https://www.clinicaltrials.jp/cti-user/trial/Show.jsp

Using the drug repositioning approach to develop a novel therapy, tipepidine hibenzate sustained-release tablet (TS-141), for children and adolescents with Attention-Deficit/Hyperactivity Disorder

Background Asverin® (tipepidine hibenzate) has been used as an antitussive for >50 years in Japan. Studies revealed that tipepidine modulates monoamine levels, by inhibiting G-protein-activated inwardly rectifying potassium (GIRK) channels, expecting the potential therapeutic effects of tipepidine for attention-deficit/hyperactivity disorder (ADHD) in recent years. In this study, TS-141, a sustained-release tablet of tipepidine, was developed for the treatment of ADHD through a drug repositioning approach. Methods The sustained-release profile of TS-141 in healthy adults was investigated, and tipepidine exposure in the plasma after the TS-141 administration was compared to that of Asverin in the phase I study. Phase II study was conducted to examine the effects of TS-141 30 (once a day), 60 (once a day), 120 mg (60 mg twice a day), or placebo, that is within the exposure in the maximum dosage of Asverin, in children and adolescents with ADHD, and was designed as an 8-week treatment, randomized, parallel group, double-blind, placebo-controlled trial recruiting 6–17-year-old children and adolescents diagnosed with ADHD. A total of 216 patients were randomized according to the CYP2D6 phenotype. The primary end-point was ADHD Rating Scale IV-J changes. Furthermore, effects of CYP2D6 phenotype on the efficacy in the subgroup analysis were investigated. Results TS-141 had the sustained-release profile, and the CYP2D6 phenotype had effects on the plasma exposure of tipepidine. ADHD RS-IV-J scores in all TS-141 dosages decreased from their baseline scores; however, no significant difference was observed in ADHD RS-IV-J score changes between the placebo and TS-141-administered groups. In patients with intermediate metabolizer CYP2D6, ADHD RS-IV-J score changes in the 120 mg group tended to be larger than that in the placebo group. Conclusions ADHD RS-IV-J changes on TS-141 may depend on the interaction between the TS-141 dose and CYP2D6 phenotype, suggesting that further clinical trials should be conducted with careful consideration of polymorphism. Drug repositioning approach of TS-141 was attempted at the same dose as that of antitussive; however, dose setting according to the indication was necessary. Trial Registration Phase I study: JapicCTI-205235 (Registered 25 March 2020), Phase II study: JapicCTI-163244 (Registered 9 May 2016), https://www.clinicaltrials.jp/cti-user/trial/Show.jsp

Using the drug repositioning approach to develop a novel therapy, tipepidine hibenzate sustained-release tablet (TS-141), for children and adolescents with Attention-Deficit/Hyperactivity Disorder

Background Asverin® (tipepidine hibenzate) has been used as an antitussive for >50 years in Japan. Studies revealed that tipepidine modulates monoamine levels, by inhibiting G-protein-activated inwardly rectifying potassium (GIRK) channels, expecting the potential therapeutic effects of tipepidine for attention-deficit/hyperactivity disorder (ADHD) in recent years. In this study, TS-141, a sustained-release tablet of tipepidine, was developed for the treatment of ADHD through a drug repositioning approach.Methods The sustained-release profile of TS-141 in healthy adults was investigated, and tipepidine exposure in the plasma after the TS-141 administration was compared to that of Asverin in the phase I study. Phase II study was conducted to examine the effects of TS-141 30 (once a day), 60 (once a day), 120 mg (60 mg twice a day), or placebo, that is within the exposure in the maximum dosage of Asverin, in children and adolescents with ADHD, and was designed as an 8-week treatment, randomized, parallel group, double-blind, placebo-controlled trial recruiting 6–17-year-old children and adolescents diagnosed with ADHD. A total of 216 patients were randomized according to the CYP2D6 phenotype. The primary end-point was ADHD Rating Scale IV-J changes. Furthermore, effects of CYP2D6 phenotype on the efficacy in the subgroup analysis were investigated. Results TS-141 had the sustained-release profile, and the CYP2D6 phenotype had effects on the plasma exposure of tipepidine. ADHD RS-IV-J scores in all TS-141 dosages decreased from their baseline scores; however, no significant difference was observed in ADHD RS-IV-J score changes between the placebo and TS-141-administered groups. In patients with intermediate metabolizer CYP2D6, ADHD RS-IV-J score changes in the 120 mg group tended to be larger than that in the placebo group.Conclusions ADHD RS-IV-J changes on TS-141 may depend on the interaction between the TS-141 dose and CYP2D6 phenotype, suggesting that further clinical trials should be conducted with careful consideration of polymorphism. Drug repositioning approach of TS-141 was attempted at the same dose as that of antitussive; however, dose setting according to the indication was necessary.Trial RegistrationPhase I study: JapicCTI-205235 (Registered 25 March 2020), Phase II study: JapicCTI-163244 (Registered 9 May 2016), https://www.clinicaltrials.jp/cti-user/trial/Show.jsp

Assessment of tramadol pharmacokinetics in correlation with CYP2D6 and clinical symptoms

ObjectivesDue to lack of adequate data on tramadol kinetic in relevance of CYP2D6 toxicity, this study was designed to investigate the effect of CYP2D6 phenotype in tramadol poisoning. The saliva, urine and blood samples were taken at the admission time. Consequently, concentration of tramadol and its major metabolites were measured.MethodsA pharmacokinetic and metabolic study was developed in cases of tramadol poisoned (n=96). Cases of tramadol poisoned evidenced seizure, hypertension, dizziness, nausea and vomiting symptoms participated.ResultsFemale cases showed higher N-desmethyltramadol (M2) tramadol concentrations than male cases: in urine (40.12 ± 124.53 vs. 7.3 ± 7.13), saliva (16.91 ± 26.03 vs. 5.89 ± 7.02), and blood (1.11 ± 1.56 vs. 0.3 ± 0.38) samples. Significant correlation between blood, saliva, and urine concentrations were found (r = 0.5). Based on the metabolic ratio of O-desmethyltramadol (M1) of male (0.53 ± 0.22) and female (0.43 ± 0.26), poisoning and severe symptoms like seizure in female occurs statistically fewer (13.04%) than in male (50.6%). Assessment of CYP2D6 phenotype showed all of the participants were extensive metabolizers (EM) and their phenotype was associated with clinical symptoms.ConclusionsAccording to our results, M1 as a high potent metabolite has an important role in toxicity and the likelihood of poisoning in people with EM phenotype. Finally, tramadol metabolic ratio may justify the cause of various symptoms in human tramadol poisoning.

Using the drug repositioning approach to develop a novel therapy, tipepidine hibenzate sustained-release tablet (TS-141), for children and adolescents with Attention-Deficit/Hyperactivity Disorder

Background Asverin® (tipepidine hibenzate) has been used as an antitussive for > 50 years in Japan. Studies revealed that tipepidine modulates monoamine levels, by inhibiting G-protein-activated inwardly rectifying potassium (GIRK) channels, expecting the potential therapeutic effects of tipepidine for attention-deficit/hyperactivity disorder (ADHD) in recent years. In this study, TS-141, a sustained-release tablet of tipepidine, was developed for the treatment of ADHD through a drug repositioning approach. Methods The sustained-release profile of TS-141 in healthy adults was investigated, and tipepidine exposure in the plasma after the TS-141 administration was compared to that of Asverin in the phase I study. Phase II study was conducted to examine the effects of TS-141 30 (once a day), 60 (once a day), 120 mg (60 mg twice a day), or placebo, that is within the exposure in the maximum dosage of Asverin, in children and adolescents with ADHD, and was designed as an 8-week treatment, randomized, parallel group, double-blind, placebo-controlled trial recruiting 6–17-year-old children and adolescents diagnosed with ADHD. A total of 216 patients were randomized according to the CYP2D6 phenotype. The primary end-point was ADHD Rating Scale IV-J changes. Furthermore, effects of CYP2D6 phenotype on the efficacy in the subgroup analysis were investigated. Results TS-141 had the sustained-release profile, and the CYP2D6 phenotype had effects on the plasma exposure of tipepidine. ADHD RS-IV-J scores in all TS-141 dosages decreased from their baseline scores; however, no significant difference was observed in ADHD RS-IV-J score changes between the placebo and TS-141-administered groups. In patients with intermediate metabolizer CYP2D6, ADHD RS-IV-J score changes in the 120 mg group tended to be larger than that in the placebo group. Conclusions ADHD RS-IV-J changes on TS-141 may depend on the interaction between the TS-141 dose and CYP2D6 phenotype, suggesting that further clinical trials should be conducted with careful consideration of polymorphism. Drug repositioning approach of TS-141 was attempted at the same dose as that of antitussive; however, dose setting according to the indication was necessary. Trial Registration Phase I study: JapicCTI-205235 (Registered 25 March 2020), Phase II study: JapicCTI-163244 (Registered 9 May 2016), https://www.clinicaltrials.jp/cti-user/trial/Show.jsp

CYP2D6 PHENOTYPES AMONG JAVANESE AND SUNDANESE SUBJECTS IN INDONESIA

Objective: The objective of this study was to determine CYP2D6 phenotype in a Javanese and Sundanese healthy subject in Indonesia.Methods: Ninety unrelated healthy Indonesian subjects from Java and Sunda were studied. Metoprolol was used as phenotyping substrate. A 100 mgoral tablet of metoprolol was administered to all the subjects. Urinary metoprolol and α-hydroxymetoprolol were determined to calculate metoprololmetabolic ratio (MR). Determination of metoprolol and α-hydroxymetoprolol was carried out by high performance liquid chromatography method.Results: Metoprolol MR varied widely (from 0.08 to 72.75). One subject (1.11%) in the study was classified as poor metabolizer (PM), one subject(1.11%) as ultrarapid metabolizer, and the remaining 88 subjects (97.78%) were classified as extensive metabolizers.Conclusion: The frequencies of PM for the CYP2D6 phenotype (1.11%) in the Javanese and Sundanese population are in concordance with mostresults of oxidation metabolizers in other Asian populations.