1619P - Assessment of the pharmacokinetic interaction of enzalutamide with oxycodone in men with prostate cancer: The ENZYME study

Background

Up to 90% of patients with castration-resistant prostate cancer (CRPC) will develop symptomatic metastases requiring pain medication. Oxycodone is an opioid metabolized primarily by cytochrome P450 (CYP) 3A4 to the inactive metabolite noroxycodone and by CYP2D6 to the active metabolite oxymorphone. Both are further metabolized to noroxymorphone by CYP3A4 and 2D6. Enzalutamide (ENZ) is a widely used androgen receptor antagonist for the treatment of CRPC and a strong inducer of CYP3A4. Due to this CYP3A4 induction, it is expected that ENZ will reduce the analgesic effects of oxycodone. This is the first study investigating the effect of ENZ on the pharmacokinetics of oxycodone.

Methods

We performed a prospective, two-arm parallel study in men with prostate cancer. Patients in arm 1 were treated with ENZ 160 mg once daily for at least 40 days; patients in control arm 2 were not treated with ENZ. All patients received a single oral dose of 15 mg normal-release oxycodone, followed by blood sampling up to 8 hours after dosing. Plasma concentrations of oxycodone, noroxycodone, oxymorphone and noroxymorphone were quantified using a validated LC-MS/MS method. The difference in geometric mean of the maximum plasma concentration (C_max) and area under the curve (AUC_0-8h) between the arms was determined.

Results

In total 27 patients were included, of who one subject was excluded since he was a CYP2D6 poor metabolizer. In the ENZ arm (n=13), mean AUC_0-8h and C_max of oxycodone were resp. 44.7% (p<.001) and 35.5% (p=.004) lower compared to the control arm (n=13). ENZ decreased AUC_0-8h and C_max of the active metabolite oxymorphone with resp. 74.2% (p<.001) and 56.0% (p=.001). In contrast, ENZ increased AUC_0-8h and C_max of the CYP3A4-dependent inactive metabolite noroxycodone with resp. 61.2% (p=.001) and 78.2% (p=.001) and of the inactive metabolite noroxymorphone with resp. 45.0% (p=.032) and 59.8% (p=.027).

Conclusions

ENZ decreases exposure to oxycodone and its active metabolite oxymorphone. This interaction is clinically relevant because pain may not be adequately controlled and there is a risk of overdose upon ENZ discontinuation. A switch to an opioid that is not metabolised by CYP3A4, e.g. morphine, may be necessary to achieve adequate and safe pain management during treatment with ENZ.

Clinical trial identification

NL75669.075.20.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.