Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety

Abstract

Background and purpose:The major drug-metabolizing enzymes for the oxidation of oxycodone are CYP2D6 and CYP3A. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug-drug interactions is well established. The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned and the importance of CYP3A-mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone has been poorly explored. Experimental approach: We conducted a randomized crossover (five arms) double-blind placebo-controlled study in 10 healthy volunteers genotyped for CYP2D6. Oral oxycodone (0.2 mg·kg -1 ) was given alone or after inhibition of CYP2D6 (with quinidine) and/or of CYP3A (with ketoconazole). Experimental pain (cold pressor test, electrical stimulation, thermode), pupil size, psychomotor effects and toxicity were assessed. Key results: CYP2D6 activity was correlated with oxycodone experimental pain assessment. CYP2D6 ultra-rapid metabolizers experienced increased pharmacodynamic effects, whereas cold pressor test and pupil size were unchanged in CYP2D6 poor metabolizers, relative to extensive metabolizers. CYP2D6 blockade reduced subjective pain threshold (SPT) for oxycodone by 30% and the response was similar to placebo. CYP3A4 blockade had a major effect on all pharmacodynamic assessments and SPT increased by 15%. Oxymorphone Cmax was correlated with SPT assessment (rS = 0.7) and the only independent positive predictor of SPT. Side-effects were observed after CYP3A4 blockade and/or in CYP2D6 ultra-rapid metabolizers. Conclusions and implications:The modulation of CYP2D6 and CYP3A activities had clear effects on oxycodone pharmacodynamics and these effects were dependent on CYP2D6 genetic polymorphism.

Human Experimental Pain Models for Assessing the Therapeutic Efficacy of Analgesic Drugs

“…Different opioids have been applied in studies using the cold pressor test and have been found to be effective. The model was even sensitive enough to separate the effects of different genotypes in the subjects (Eckhardt et al, 2000;Grach et al, 2004;Zwisler et al, 2009Zwisler et al, , 2010Samer et al, 2010). Fentanyl has been tested in the cold pressor test, and this model was sensitive to the analgesia induced.…”

“…Skin and teeth. Both morphine and oxycodone have been tested against cutaneous heat and cold pain, mechanical (pinching) pain, and electrical pain, and generally these models reflect analgesia from these opioids (Naef et al, 2003;Schulte et al, 2003;Joly et al, 2005;Staahl et al, 2006a;Olesen et al, 2010a;Samer et al, 2010). Three studies found sensitivity of electrical pain for morphine, whereas another did not (Schulte et al, 2003;Joly et al, 2005;Staahl et al, 2006a).…”

Evaluation of an Educational Program on Deciphering Heterogeneity for Medical Coverage Decisions

“…the virus, 2 dosing of aminoglycosides based on renal function, 3 or the likelihood of a serious drug-drug interaction based on patient genotype. 4 Training and how to assess or evaluate the statistical and clinical relevance of these differences has historically been limited. It is imperative that medical and pharmacy managers possess relevant knowledge to determine the extent that heterogeneity was evaluated in clinical trials.…”

Hysterectomy: Advances in Perioperative Care

“…In the past decade, research has given us a great amount of knowledge on the genetic disposition that explains these differences, and to what extent people react differently to pain. The opioid receptor and its determining gene (OPRM1) has been shown to have 17 variations (socalled polymorhism) that are unequally distributed between the sexes (Samer, 2010;Kolesnikov, 2011). Women are found to have μ receptor variations that predispose to longer clinical effects of an opioid, and twice as many side effects as men (Sarton, 2003;Niesters, 2010).…”