Coadministration with darunavir/ritonavir decreased dolutegravir AUC, Cmax and C24 by 22%, 11% and 38%, respectively, due to induction of UGT1A1 and CYP3A enzymes. Coadministration with darunavir/ritonavir and etravirine decreased dolutegravir AUC, Cmax and Cmin by 25%, 12% and 36%, respectively; there was no effect on darunavir or ritonavir. No dose adjustment is necessary.

Based on drug interaction trial results, darunavir/ritonavir can be coadministered with dolutegravir without a dose adjustment. Coadministration of darunavir/ritonavir (600/100 mg twice daily) and dolutegravir (30 mg once daily) decreased dolutegravir Cmax, AUC and Cmin by 11%, 22% and 38%, respectively (n=15). Coadministration of darunavir/ritonavir (600/100 mg twice daily), etravirine (200 mg twice daily) and dolutegravir (30 mg once daily) decreased dolutegravir Cmax, AUC and Cmin by 12%, 25% and 37%, respectively (n=9).

Coadministration of dolutegravir and darunavir/ritonavir decreased dolutegravir AUC, C24h and Cmax by 22%, 38% and 11% respectively. There was no effect on darunavir pharmacokinetics using cross-study comparisons to historical pharmacokinetic data. Boosted darunavir and dolutegravir can be used without dose adjustment.

No dosage adjustments are recommended when darunavir/ritonavir is co-administered with dolutegravir. Coadministration of dolutegravir (30 mg once daily) and darunavir/ritonavir (600/100 mg once twice daily) was studied in 15 subjects. Dolutegravir Cmax, AUC and Cmin decreased by 11%, 22% and 38%, respectively. Coadministration of dolutegravir (50 mg once daily) and darunavir/ritonavir (600/100 mg twice daily) and etravirine (200 mg twice daily) was studied in 9 subjects. Dolutegravir Cmax, AUC and Cmin decreased by 12%, 25% and 37%, respectively.

Darunavir/ritonavir has been shown to reduce dolutegravir exposure due to induction of glucuronidation. This decrease could potentially be relevant during acute HIV infection when a rapid reduction of very high plasma viremia is warranted. This study evaluated the pharmacokinetics of dolutegravir in the presence of darunavir/ritonavir in individuals enrolled in the Netherlands Cohort Study on Acute HIV infection (NOVA). Study participants were started on darunavir/ritonavir (800/100 mg once daily), dolutegravir (50 mg twice daily) and two NRTIs for four weeks (phase I) and then switched to dolutegravir 50 mg once daily with two NRTIs (phase II). Dolutegravir concentrations were measured during phase I and phase II at arbitrary timepoints after dosing. A population pharmacokinetic model was used to predict total dolutegravir pharmacokinetic parameters during phase I and II. Overall, 46 participants were included. Predicted steady-state dolutegravir trough concentrations (CV%) during phase I and II were 2.7 (36.8%) and 1.28 (52.4%), respectively, representing a geometric mean ratio (CI) of 2.09 (1.75-2.5). Compared to dolutegravir once daily without darunavir/ritonavir, total exposure during dolutegravir twice daily increased but did not double (geometric mean ratio: 1.59 (1.42-1.78)). The metabolic ratio of dolutegravir-glucuronide/total dolutegravir increased by 30% during coadministration of darunavir/ritonavir. Unbound dolutegravir fractions and the apparent oral clearance were similar during phase I and II (GMR (CI) 0.98 (0.90-1.97) and 1.08 (0.96-1.2), respectively. Nearly all participants (n= 45) had trough dolutegravir levels above the in vivo EC90 value of 0.32 mg/L during both phases. Available viral loads were <80 copies/mL at week 8. Two participants had a viral load of 940 and 280 copies/mL but both had dolutegravir >EC90, of note their viral load was very high at baseline. The authors conclude that the decrease in dolutegravir exposure when given once daily in presence of darunavir/ritonavir is not clinically relevant when initiating this treatment in individuals with acute HIV infection. Almost all participants in both dolutegravir dosing regimens had trough concentrations >EC90. This study suggests that dolutegravir can be given at 50 mg once daily in presence of darunavir/ritonavir in individuals with acute HIV infection.