Liverpool HIV Interactions

Potential Interaction

Dolutegravir (DTG)

Etravirine (ETR)

Quality of Evidence: High

Summary:

Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. The etravirine product labels and the US Prescribing Information for dolutegravir do not recommend the use of dolutegravir and etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. However, the European SPC for dolutegravir suggests a dose of dolutegravir of 50 mg twice daily when coadministered with etravirine without boosted protease inhibitors to patients without INSTI resistance, but recommends dolutegravir and etravirine should be administered with atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir in INSTI-resistant patients. Coadministration of etravirine (200 mg twice daily) and dolutegravir (50 mg once daily) decreased dolutegravir Cmax, AUC and Ctrough by 52%, 71% and 88%, respectively. When the same doses were coadministered in the presence of ritonavir-boosted darunavir or lopinavir, dolutegravir Cmax, AUC and Ctrough decreased by 12%, 25% and 37%, respectively, with darunavir/lopinavir and increased by 7%, 11% and 28%, respectively, with lopinavir/ritonavir. When compared to historical data, dolutegravir did not appear to affect the pharmacokinetics of etravirine.

Description:

Coadministration of etravirine without boosted protease inhibitors decreased dolutegravir AUC, Cmax and Ctrough by 71%, 52% and 88%, respectively by induction of UGT1A1 and CYP3A enzymes. There was no effect on etravirine exposure. Coadministration with etravirine and lopinavir/ritonavir had no significant effect on dolutegravir exposure (AUC, Cmax and Ctrough increased by 10%, 7% and 28%, respectively). There was no effect on lopinavir or ritonavir exposure. Coadministration with etravirine and darunavir/ritonavir had no significant effect on dolutegravir exposure (AUC, Cmax and Ctrough decreased by 25%, 12% and 37%, respectively). There was no effect on darunavir or ritonavir exposure. The recommended adult dose of dolutegravir is 50 mg twice daily when co-administered with etravirine without boosted protease inhibitors. In paediatric patients the weight-based once daily dose should be administered twice daily. No dose adjustment is necessary when dolutegravir and etravirine are administered with darunavir/ritonavir or lopinavir/ritonavir. Dolutegravir should not be used with etravirine without co-administration of atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir in INI-resistant patients.
Tivicay Summary of Product Characteristics, ViiV Healthcare, March 2019.

Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. Coadministration of etravirine (200 mg twice daily) and dolutegravir (50 mg once daily) to 16 subjects decreased dolutegravir Cmax, AUC and Ctrough by 52%, 71% and 88%, respectively. When the same doses were coadministered in the presence of darunavir/ritonavir (600/100 mg twice daily, n=9), dolutegravir Cmax, AUC and Ctrough decreased by 12%, 25% and 37%, respectively. In contrast, coadministration of the same doses in the presence of lopinavir/ritonavir (400/100 mg twice daily, n=8) increased dolutegravir Cmax, AUC and Ctrough by 7%, 11% and 28%, respectively. Using cross-study comparisons to historical pharmacokinetic data, dolutegravir did not appear to affect the pharmacokinetics of etravirine. Use of dolutegravir with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended.

Tivicay US Prescribing Information, ViiV Healthcare, July 2019.

Etravirine significantly reduced plasma concentrations of dolutegravir. The effect of etravirine on dolutegravir plasma concentrations was mitigated by co-administration of darunavir/ritonavir or lopinavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. Etravirine should only be used with dolutegravir when co-administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. This combination can be used without dose adjustment. Coadministration of dolutegravir (50 mg once daily) and etravirine decreased dolutegravir AUC, Cmin and Cmax by 71%, 88% and 52%, respectively. Coadministration of dolutegravir (50 mg once daily) with darunavir/ritonavir (600/100 mg twice daily) and etravirine decreased dolutegravir AUC, Cmin and Cmax by 25%, 37% and 12%, respectively. Coadministration of dolutegravir (50 mg once daily) with lopinavir/ritonavir (400/100 mg twice daily) and etravirine increased dolutegravir AUC, Cmin and Cmax by 11%, 28% and 7%, respectively. There was no effect on etravirine AUC, Cmin or Cmax when compared to historical controls.

Intelence Summary of Product Characteristics, Janssen-Cilag Ltd, March 2019.

Etravirine significantly reduced plasma concentrations of dolutegravir. Using cross-study comparisons to historical pharmacokinetic data for etravirine, dolutegravir did not appear to affect the pharmacokinetics of etravirine. The effect of etravirine on dolutegravir plasma concentrations was mitigated by co-administration of darunavir/ritonavir or lopinavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. Dolutegravir should only be used with etravirine when co-administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Coadministration of dolutegravir (50 mg once daily) and etravirine decreased dolutegravir Cmax, AUC and Cmin by 52%, 71% and 88%, respectively (n=16). Coadministration of dolutegravir (50 mg once daily) with darunavir/ritonavir (600/100 mg twice daily) and etravirine decreased dolutegravir Cmax, AUC and Cmin by 12%, 25% and 37%, respectively (n=9). Coadministration of dolutegravir (50 mg once daily) with lopinavir/ritonavir (400/100 mg twice daily) and etravirine increased dolutegravir Cmax, AUC and Cmin by 7%, 11% and 28%, respectively (n=8).

Intelence US Prescribing Information, Janssen Therapeutics, July 2019.

Coadministration of dolutegravir (50 mg once daily) and etravirine (200 mg twice daily) was studied in 15 HIV-negative subjects. Etravirine significantly decreased dolutegravir AUC, Cmax and Ctrough by 70%, 52% and 88%, respectively. When the same doses were given in the presence of lopinavir/ritonavir (400/100 mg twice daily, n=8), dolutegravir pharmacokinetics were not significantly altered. However, when given with darunavir/ritonavir( 600/100 mg twice daily), dolutegravir AUC, Cmax and Ctrough decreased by 25%, 12% and 37%, respectively, but these changes were not considered as clinically significant. The combination of dolutegravir and etravirine alone should be avoided; however dolutegravir may be coadministered with etravirine without a dosage adjustment if lopinavir/ritonavir or darunavir/ritonavir is concurrently administered.

Effects of etravirine alone and with ritonavir-boosted protease inhibitors on the pharmacokinetics of dolutegravir. Song I, Borland J, Min S, et al. Antimicrob Agents Chemother, 2011, 55(7): 3517-21.

View all available interactions with Dolutegravir (DTG) by clicking here.