Dolutegravir + Etravirine = Precautionary

Effect on Concentration

Dolutegravir
Decrease
Applies within class?
No
Etravirine
No change
Applies within class?
No

Pharmacologic Effects

Dolutegravir
Effect
N/A
Applies within class?
No
Etravirine
Effect
N/A
Applies within class?
No

Interaction History

N/A

Last Updated 13-Jul-2018

Summary

Effect of Etravirine on Dolutegravir is mitigated by additional boosted protease inhibitors. The use of etravirine with dolutegravir in the absence of boosted protease inhibitors is contraindicated

Sources

Effects of Etravirine Alone and with Ritonavir-Boosted Protease Inhibitors on the Pharmacokinetics of Dolutegravir. ^

Study Design

An open-label, 2-period, cross-over study in 16 healthy subjects, examined the effects of coadministration of etravirine (ETR) on dolutegravir (DTG) pharmacokinetics (PK). DTG was administered at 50mg orally every 24 hours for 5 days in period 1, followed by the same DTG dose coadminstered with ETR at 200mg every 12 hours for 14 days in period 2. All doses were given with a moderate fat meal, with no washout between periods. Part 2 was A randomized, open-label, cross-over study in 17 healthy subjects, examined the effects of coadministration of etravirine (ETR) and a boosted protease inhibitor (lopinavir/ritonavir (LPV/RTV) or darunavir/ritonavir (DRV/RTV)) on dolutegravir (DTG) pharmacokinetics (PK). DTG was administered at 50mg orally every 24 hours for 5 days in period 1, followed by the same DTG dose coadminstered with ETR/LPV/RTV at 200/400/100 mg q12hr or ETR/DRV/RTV 200/600/100 mg q12hr for 14 days in period 2. PK samples were collected on day 5 in period 1 and day 14 in period 2. All doses were given with a moderate fat meal and there was no washout between periods.

Study Results

The following geometric mean ratios (GMR) with 90% confidence intervals (CI) were obatined for DTG Cmax, AUC(0-t), and Ct, 0.48 (0.43-0.54), 0.29 (0.26-0.34), and 0.12 (0.09-0.16), respectively. The manufacturer states that using cross-study comparisons to historical PK data for etravirine, DTG did not appear to affect the PK of etravirine. for part 2, The resulting geometric mean ratios (GMR) and 90% confidence intervals (CI) for DTG when coadministered with ETR/LPV/RTV for Cmax, AUC0-t, and Ct were 1.07 (1.02-1.13), 1.11 (1.02-1.20), and 1.28 (1.13-1.45), respectively. The GMR (90% CI) for DTG when coadministered with ETR/DRV/RTV for Cmax, AUC(0-t), and Ct were 0.88 (0.78-1.00), 0.75 (0.69-0.81), and 0.63 (0.52-0.76), respectively.

Study Conclusions

This combination without specific ritonavir-boosted protease inhibitors is contraindicated. ***The manufacturer states that 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.

References

Song I, Borland J, Min S. Effects of etravirine alone and with ritonavir-boosted protease inhibitors on the pharmacokinetics of dolutegravir. Antimicrobial Agents And Chemotherapy . 2011; 7: 3517-3521.