Liverpool HIV Interactions

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Potential Interaction

Dolutegravir (DTG)

Enzalutamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been assessed in pharmacokinetic studies. Enzalutamide is primarily metabolized by CYP2C8 and is a strong inducer of CYP3A4. Enzalutamide can induce UGT1A1. Dolutegravir is metabolized by UGT1A1 and to a lesser extent by CYP3A4. Dolutegravir has no inducing effects on CYPs. Coadministration is expected to decrease dolutegravir concentrations, thus dolutegravir should be administered at 50 mg twice daily in the absence of integrase class resistance. In the presence of integrase class resistance this combination should be avoided. Enzalutamide has a long half-life (5.8 days), therefore the dolutegravir dose should be kept at 50 mg twice daily for a minimum of 2 weeks (but preferably 4 weeks) following cessation of enzalutamide due to the persisting inducing effect upon discontinuation of a strong inducer.

Description:

The effect of enzalutamide on the pharmacokinetics of darunavir, ritonavir, etravirine and dolutegravir was determined in a 58-year-old white HIV+ male receiving darunavir/ritonavir (600/200 mg twice daily), dolutegravir (50 mg twice daily), etravirine (200 mg twice daily), and tenofovir disoproxil/emtricitabine daily. TDM of darunavir and etravirine were conducted at baseline and at weeks 2, 4, and 8 after enzalutamide initiation; dolutegravir TDM was obtained at baseline and at week 8. Results showed a 53% increase in darunavir concentrations at week 2 (associated with a more than five-fold increase in ritonavir concentrations), a 25% reduction at week 4 compared with week 2, and a further 8% decrease at week 8 compared with week 4, reflecting the long elimination half-life of enzalutamide. Etravirine concentrations decreased 6% by week 8 but remained above target. A significant impact of enzalutamide on dolutegravir concentrations was not observed. Doubling the ritonavir dose appeared to counteract the induction effect of enzalutamide on darunavir concentrations and may have helped ameliorate the impact on etravirine exposures. Using dolutegravir twice daily may have compensated for the potential induction effect of enzalutamide, etravirine, and ritonavir on dolutegravir exposures.

Successful use of the potent enzyme inducer enzalutamide in a treatment-experienced HIV-positive male with prostate cancer. Nhean S, Bravo J, Sheehan NL, et al. AIDS. 2018; 32(17):2640-2642.

Steady state pharmacokinetics of dolutegravir were estimated in an HIV+ patient receiving dolutegravir 50 mg once daily (with emtricitabine and tenofovir alafenamide) before starting enzalutamide, 15 and 30 days after starting enzalutamide at 120 mg daily, and 15 days after increasing the dose to 160 mg daily. No major differences were observed in dolutegravir pharmacokinetics after coadministration with enzalutamide compared to baseline assessments. However, high intra-individual variability in the pharmacokinetics of dolutegravir observed in this single patient means the data from this study cannot be considered conclusive and requires confirmation in a larger patient cohort. Coadministration should therefore be approached with caution.

Effects of the androgen receptor inhibitor enzalutamide on the pharmacokinetics of dolutegravir and tenofovir: a case report. Londero A, Fusi M, Cinausero M, et al. AIDS. 2022; 36(11):1603-1605.