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 x 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 C(max) was correlated with SPT assessment (rho(S)= 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.

Figure 1

Pharmacodynamic assessments after oxycodone in CYP2D6 phenotypic groups (UM, EM and PM). The mean area under the time-effect curves over the 90 min after dosing with oxycodone (AUEC₉₀) and the time course over 6 h of the change from baseline values are shown on the left and right, respectively, in A–C. Note that all subjects received naloxone (NX; 0.8 mg i.v.) 90 min after oxycodone (arrow in time courses). In (A) data for each phenotypic group from the cold pressor test are shown and in (B) corresponding data from the subjective pain threshold after electrical stimulation and in (C) for the effects of oxycodone on pupil size are presented. In (D), the time courses for oxygen saturation (left) and for sedation (right) are presented. Phenotypic differences were demonstrated in the pharmacodynamic assessments. CYP2D6 PM had decreased pharmacodynamic effects whereas UM experienced increased effects, compared with EM for CYP2D6. Data shown are means (± s.e.mean). EM, extensive metabolizer; PM, poor metabolizer; UM, ultrarapid metabolizer.

Figure 2

Pharmacodynamic assessments in the different treatment arms and phenotypic groups for CYP2D6 (UM, EM and PM). The pharmacodynamic variables were measured after different treatments: oxycodone alone (O); oxycodone and quinidine (Q), oxycodone and ketoconazole (K), oxycodone with quinidine and ketoconazole (QK) and placebo (P) and in each phenotypic group (UM, EM and PM). The left hand graphs show the mean time course of effects over 6 h and each subject received naloxone (NX; 0.8 mg, i.v.) at 90 min after oxycodone or placebo (arrow in time course). In (A), the time course (left) and the AUEC₉₀ (right) of the subjective pain threshold (SPT) is shown. In (B), the time course (left) and the E_max for the sensitive pain threshold after electrical stimulation are shown. In (C) the time course (left) and the minimum pupil size are shown. In (D), the time course of the oxygen saturation of blood (left) and the time course of sedation (right) are presented. CYP2D6 blockade with quinidine reduced pharmacodynamic assessments such as the SPT by 30%. CYP3A4 blockade with ketoconazole had a major effect on all pharmacodynamic assessments and the SPT increased by 15%. Data shown are means (± s.e.mean). EM, extensive metabolizer; PM, poor metabolizer; UM, ultrarapid metabolizer.

Figure 3

Antagonistic effects of naloxone on the pharmacodynamic effects of oxycodone. The effects of naloxone on the objective nociceptive flexion reflex, subjective, sensitive and affective pain threshold after electrical stimulation, cold pressor test and pupil size assessments were measured in all subjects. Naloxone significantly reversed the pharmacodynamic effects of oxycodone, irrespective of CYP2D6 genotype. Data shown are means (± s.e.mean). **P < 0.005; *P < 0.05 significantly different from values before naloxone.