Liverpool HIV Interactions

Potential Interaction

Etravirine (ETR)

Dolutegravir (DTG)

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.

No Interaction Expected

Dolutegravir (DTG)

Darunavir + ritonavir (DRV/r)

Quality of Evidence: Moderate

Summary:

Darunavir/ritonavir had no clinically significant effect on the pharmacokinetics of dolutegravir. Coadministration of darunavir/ritonavir (600/100 mg twice daily) and dolutegravir (30 mg once daily) decreased dolutegravir Cmax, AUC and Ctrough by 11%, 22% and 38%, respectively. Coadministration with darunavir/ritonavir and etravirine 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. No dose adjustment is necessary.

Description:

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.

Tivicay Summary of Product Characteristics, ViiV Healthcare, March 2019.

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).

Tivicay US Prescribing Information, ViiV Healthcare, July 2019.

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.

Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, September 2022

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.

Prezista Prescribing Information, Janssen Pharmaceuticals Inc, March 2023.

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.

Pharmacokinetics of twice daily dolutegravir combined with once-daily ritonavir boosted darunavir in treatment-naïve individuals enrolled in the Netherlands Cohort Study on acute HIV infection (NOVA). Zino L, Prins H, Svenssen E, et al. International Workshop on Clinical Pharmacology of HIV, Hepatitis, and other antiviral drugs, September 2021, abstract 5.

No Interaction Expected

Etravirine (ETR)

Darunavir + ritonavir (DRV/r)

Quality of Evidence: Low

Summary:

Etravirine and darunavir/ritonavir can be coadministered without any dose adjustments. Etravirine exposures from Phase 3 trials with darunavir/ritonavir as part of the background regimen were determined to be safe and effective. Coadministration decreased etravirine Cmax, AUC and Cmin by 32%, 37% and 49%, respectively; darunavir Cmax, AUC and Cmin increased by 11%, 15% and 2%, respectively. When etravirine was added to raltegravir/darunavir/ritonavir, raltegravir AUC, Cmax and Cmin increased by 29%, 21% and 54%, respectively and darunavir AUC, Cmax and Cmin increased by 14%, 6%, and 29%, respectively.

Description:

Coadministration of a lower than recommended etravirine dose (100 mg twice daily) and darunavir/ritonavir decreased etravirine AUC, Cmax and Cmin by 37%, 32% and 49%, respectively. Darunavir AUC increased by 15% and there was no significant effect on Cmax or Cmin. Darunavir coadministered with low dose ritonavir and etravirine 200 mg twice daily can be used without dose adjustments.

Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, September 2022.

No dosage adjustments are recommended when darunavir/ritonavir is co-administered with etravirine. Coadministration of etravirine (200 mg twice daily) and darunavir/ritonavir (600/100 mg twice daily) was studied in 15 subjects. Darunavir AUC, Cmax and Cmin increased by 15%, 11% and 2%, respectively. Etravirine AUC, Cmax and Cmin decreased by 37%, 32% and 49%, respectively.

Prezista Prescribing Information, Janssen Pharmaceuticals Inc, March 2023.

Etravirine and darunavir/ritonavir can be used without dose adjustments. Coadministration with darunavir/ritonavir (600/100 mg twice daily) increased darunavir AUC (15%) and Cmax (11%), but had no effect on Cmin. Etravirine AUC decreased by 37%, Cmax decreased by 32% and Cmin decreased by 49%.

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

The mean systemic exposure (AUC) of etravirine was reduced when etravirine was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, etravirine and darunavir/ritonavir can be co-administered without dose adjustments. Coadministration of darunavir/ritonavir (600/100 mg twice daily) and etravirine was studied in 15 subjects. Data from 14 subjects showed that etravirine Cmax, AUC and Cmin decreased by 32%, 37% and 49%, respectively. Darunavir Cmax, AUC and Cmin increased by 11%, 15% and 2%, respectively.

Intelence US Prescribing Information, Janssen Therapeutics, July 2019.

The addition of etravirine (200 mg twice daily) to raltegravir (400 mg twice daily) and darunavir/ritonavir (600/100 mg twice daily) lead to significant increases in the AUC, Cmax and Cmin of both raltegravir (29%, 21% and 54%, respectively) and darunavir (14%, 6%, and 29%, respectively). Ritonavir AUC, Cmax and Cmin decreased by 3%, 5% and 11%, respectively. The authors point to the marked variability of raltegravir pharmacokinetics (particularly higher trough concentrations after the evening dose), but do not offer an explanation for the increase.

Pharmacokinetics of etravirine, raltegravir and darunavir/ritonavir in treatment experienced patients. Barrail-Tran A, Yazdanpanah Y, Goldwirt L, et al. AIDS, 2010, 24(16): 2581-3.

The pharmacokinetic interaction between etravirine (100 or 200 mg twice daily) and darunavir/ritonavir (600/100 mg twice daily) was investigated in two groups of HIV- subjects. Coadministration of 100 mg etravirine with darunavir/ritonavir decreased the AUC, Cmax and Cmin of etravirine by 37%, 32% and 49% respectively. Coadministration had no significant effect on the pharmacokinetics of etravirine or ritonavir. Increasing the dose of etravirine to 200 mg (the dose chosen for Phase III trials) resulted in increases in etravirine AUC, Cmax and Cmin of 80%, 81% and 67% respectively when coadministered with darunavir/ritonavir and compared to etravirine 100 mg given alone. Darunavir AUC and Cmax were increased by 15% and 11% respectively, with no change in Cmin. Etravirine (200 mg twice daily) can be coadministered with darunavir/ritonavir without dose adjustments.

Pharmacokinetics of darunavir/ritonavir and TMC125 alone and coadministered in HIV-negative volunteers. Scholler-Gyure M, Kakuda TN, Sekar V, et al. Anitviral Ther, 2007, 12: 789-796.

The pharmacokinetics of etravirine and darunavir were determined in 10 HIV+ subjects receiving etravirine (200 mg twice daily, phase III formulation) and darunavir/ritonavir (600/100 mg twice daily). Darunavir exposure was similar to historical controls and etravirine concentrations were similar to those obtained when administered with a boosted PI.

Pharmacokinetics and antiretroviral response to darunavir/ritonavir and etravirine combination in patients with high-level resistance. Boffito et al. AIDS, 2007, 21: 1449-1455.

No Interaction Expected

Darunavir + ritonavir (DRV/r)

Piperacillin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Piperacillin is eliminated renally via glomerular filtration and active secretion by OAT1/3. Darunavir/ritonavir is unlikely to inhibit OATs at clinically relevant concentrations.

Description:

(See Summary)

No Interaction Expected

Etravirine (ETR)

Piperacillin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Piperacillin is eliminated renally via glomerular filtration and active secretion by OAT1/3.

Description:

(See Summary)

No Interaction Expected

Dolutegravir (DTG)

Piperacillin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Piperacillin is eliminated renally via glomerular filtration and active secretion by OAT1/3. Dolutegravir does not inhibit OATs.

Description:

(See Summary)

No Interaction Expected

Darunavir + ritonavir (DRV/r)

Tazobactam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tazobactam is only minimally metabolised and is eliminated renally via glomerular filtration and active secretion by OAT1/3. Darunavir/ritonavir is unlikely to inhibit OATs at clinically relevant concentrations.

Description:

(See Summary)

No Interaction Expected

Etravirine (ETR)

Tazobactam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tazobactam is only minimally metabolised and is eliminated renally via glomerular filtration and active secretion by OAT1/3.

Description:

(See Summary)

No Interaction Expected

Dolutegravir (DTG)

Tazobactam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tazobactam is only minimally metabolised and is eliminated renally via glomerular filtration and active secretion by OAT1/3. Dolutegravir does not inhibit OATs.

Description:

(See Summary)

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