Liverpool HIV Interactions

Do Not Coadminister

Ritonavir (RTV)

_ZZCobicistat (with ATV or DRV)

Quality of Evidence: Very Low

Summary:

Cobicistat should not be administered concurrently with ritonavir due to similar effects of cobicistat and ritonavir on CYP3A4. If switching from ritonavir to cobicistat, caution is required during the first two weeks of treatment with cobicistat, particularly if doses of any coadministered medicinal products have been titrated or adjusted during use of ritonavir. Unlike ritonavir, cobicistat is not an inducer of CYPs 1A2, 2B6, 2C8, 2C9, 2C19 or UGT1A1. Cobicistat is not interchangeable with ritonavir to increase systemic exposure of twice daily darunavir, fosamprenavir, saquinavir, or tipranavir due to lack of exposure data.

Description:

Cobicistat should not be used concurrently with ritonavir due to similar effects of cobicistat and ritonavir on CYP3A. Unlike ritonavir, cobicistat is not an inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or UGT1A1. If switching pharmacoenhancer from ritonavir to cobicistat, caution is required during the first two weeks of treatment with cobicistat, particularly if doses of any concomitantly administered medicinal products have been titrated or adjusted during use of ritonavir as a pharmacoenhancer.

Tybost Summary of Product Characteristics, Gilead Sciences Ltd, July 2014.

Coadministration with drugs or regimens containing ritonavir is not recommended due to similar effects of cobicistat and ritonavir on CYP3A. Cobicistat is not interchangeable with ritonavir to increase systemic exposure of darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir due to lack of exposure data.

Tybost Prescribing Information, Gilead Sciences, September 2014.

Do Not Coadminister

Etravirine (ETR)

_ZZCobicistat (with ATV or DRV)

Quality of Evidence: Very Low

Summary:

Coadministration is not recommended. Coadministration of etravirine and cobicistat is expected to decrease cobicistat plasma concentrations and consequently those of atazanavir or darunavir being boosted, leading to loss of therapeutic effect and possible development of resistance.

Description:

This interaction has not been studied. Co-administration of etravirine and cobicistat is expected to decrease cobicistat plasma concentrations. Atazanavir or darunavir plasma concentrations may decrease as a consequence of a reduction in cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Co-administration is not recommended.

Tybost Summary of Product Characteristics, Gilead Sciences Ltd, July 2014.

Darunavir or atazanavir in combination with etravirine is not recommended in combination with cobicistat because dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the antiretroviral agents, leading to loss of therapeutic effect and development of resistance.

Tybost Prescribing Information, Gilead Sciences, September 2014.

Potential Interaction

Etravirine (ETR)

Ritonavir (RTV)

Quality of Evidence: Moderate

Summary:

Etravirine can be administered with low dose ritonavir in some boosted PI regimens with caution.

Description:

Concomitant use of etravirine with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of etravirine. Co-administration of etravirine and ritonavir 600 mg twice daily is not recommended. Coadministration of ritonavir (600 mg twice daily) and etravirine was studied in 11 subjects and decreased etravirine Cmax and AUC by 32% and 46%, respectively.
Intelence US Prescribing Information, Janssen Therapeutics, July 2019.

The effect of ritonavir (600 mg twice daily) on the pharmacokinetics of etravirine (400 mg single dose, phase II formulation) was studied in 11 HIV- subjects. Coadministration decreased etravirine AUC by 46% and Cmax by 32%.
Drug interactions with TMC125, a potent next generation NNRTI. Baede P, Piscitelli S, Graham N, Van’t Klooster G. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, September 2002, abstract A-1827.

Potential Interaction

Ritonavir (RTV)

_ZZDarunavir

Quality of Evidence: Low

Summary:

Darunavir should only be used in combination with 100 mg of ritonavir as a pharmacokinetic enhancer. Increasing the dose of ritonavir did not significantly affect darunavir concentrations and is not recommended.

Description:

Darunavir has been approved for use with ritonavir as a pharmacokinetic enhancer at the noted doses:
Darunavir 600 mg twice daily with ritonavir 100 mg twice daily in antiretroviral treatment (ART) experienced patients.
Darunavir 800 mg once daily with ritonavir 100 mg once daily may be used in some ART experienced patients. (Refer to the darunavir SmPC for further information on once daily dosing in ART experienced patients.)
Darunavir 800mg once daily with ritonavir 100 mg once daily in ART-naïve patients.

Coadministration of darunavir (600 mg single dose) and ritonavir (100 mg twice daily) increased darunavir AUC by 14-fold. Ritonavir increases the serum levels of darunavir as a result of CYP3A inhibition. Darunavir must be given with ritonavir to ensure its therapeutic effect. Ritonavir doses higher than 100 mg twice daily have not been studied with darunavir. For further information, refer to the Summary of Product Characteristics for Prezista.

Norvir Summary of Product Characteristics, AbbVie Ltd, September 2016.

Coadministration is expected to increase darunavir concentrations. See the complete Prescribing Information for darunavir for details on co-administration with ritonavir.
Norvir Prescribing Information, AbbVie Inc, December 2016.

Darunavir must always be given orally with low dose ritonavir as a pharmacokinetic enhancer. Increasing the dose of ritonavir did not significantly affect darunavir concentrations and is not recommended. The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally in combination with ritonavir at 100 mg twice daily Therefore, darunavir must only be used in combination with low dose ritonavir as a pharmacokinetic enhancer.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir. When a single dose of 600 mg darunavir was given orally in combination with 100 mg ritonavir twice daily, there was an approximate 14-fold increase in the systemic exposure of darunavir. Therefore, darunavir should only be used in combination with 100 mg of ritonavir to achieve sufficient exposures of darunavir.
Prezista Prescribing Information, Tibotec Inc, June 2012.

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

Ritonavir (RTV)

Dolutegravir (DTG)

Quality of Evidence: Very Low

Summary:

Coadministration with ritonavir alone has not been studied. Based on studies with boosted PIs, ritonavir is not expected to significantly affect dolutegravir pharmacokinetics. Using cross-study comparisons to historical pharmacokinetic data, dolutegravir did not appear to affect the pharmacokinetics of ritonavir. No dosage adjustment is necessary.

Description:

(See Summary)

No Interaction Expected

_ZZDarunavir

_ZZCobicistat (with ATV or DRV)

Quality of Evidence: Moderate

Summary:

Cobicistat (150 mg once daily) must be coadministered with darunavir (800 mg once daily), taken orally with food. Safety and efficacy have not been established when used in any other dosing regimen or in combination with another antiretroviral that requires pharmacoenhancement by an inhibitor of CYP3A4 (i.e., another protease inhibitor or elvitegravir). If switching from ritonavir to cobicistat, caution is required during the first two weeks of treatment with cobicistat, particularly if doses of any other coadministered medicinal products have been titrated or adjusted during use of ritonavir.

Description:

Cobicistat (150 mg once daily) must be co-administered with darunavir (800 mg once daily), taken orally, once daily with food. Safety and efficacy have not been established for use of cobicistat with darunavir when used in any other dosing regimen. Cobicistat co-administered with darunavir should not be used in combination with another antiretroviral agent that requires pharmacoenhancement by means of co-administration with an inhibitor of CYP3A4 to reach the desired therapeutic plasma concentrations (i.e., another protease inhibitor or elvitegravir). Dosing recommendations for such combinations have not been established and co-administration may result in decreased plasma concentrations of darunavir and/or the other antiretroviral agents that require pharmacoenhancement leading to loss of antiviral activity and development of resistance.

Tybost Summary of Product Characteristics, Gilead Sciences Ltd, July 2014.

Cobicistat is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection. Cobicistat (150 mg once daily) must be coadministered with atazanavir (300 mg once daily) or darunavir (800 mg once daily). The use of cobicistat is not recommended with darunavir 600 mg twice daily.

Tybost Prescribing Information, Gilead Sciences, September 2014.

No Interaction Expected

Etravirine (ETR)

_ZZDarunavir

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 in creased 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, June 2012.

The interaction between darunavir/ritonavir and etravirine was evaluated in clinical studies and no dose adjustment is needed for either drug. 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, Tibotec Inc, June 2012.

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 2012.

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 Prescribing Information, Tibotec Pharmaceuticals Ltd, March 2012.

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

_ZZDarunavir

Dolutegravir (DTG)

Quality of Evidence: Low

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 32%, 11% and 38%, respectively by induction of UGT1A1 and CYP3A. 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.

Tivicay Summary of Product Characteristics, ViiV Healthcare, January 2017.

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) to 15 subjects decreased dolutegravir Cmax, AUC and Ctrough by 11%, 22% and 38%, respectively. Coadministration of darunavir/ritonavir (600/100 mg twice daily), etravirine (200 mg twice daily) and dolutegravir (50 mg once daily) to 9 subjects decreased dolutegravir Cmax, AUC and Ctrough by 12%, 25% and 37%, respectively. Using cross-study comparisons to historical pharmacokinetic data, dolutegravir did not appear to affect the pharmacokinetics of darunavir.

Tivicay US Prescribing Information, Viiv Healthcare, June 2016.

Coadministration of dolutegravir (30 mg once daily) and darunavir/ritonavir (600/100 mg twice daily) was studied in 15 HIV-negative subjects. Coadministration decreased dolutegravir AUC, Cmax and Ctrough by 22%, 11% and 38%, respectively. These changes were considered as non-clinically relevant and the authors recommended no dose adjustment. Note, this study was performed with a dose of dolutegravir lower than the licensed one

The effect of lopinavir/ritonavir and darunavir/ritonavir on the HIV integrase inhibitor S/GSK1349572 in healthy participants. Song I, Min SS, Borland J, et al. J Clin Pharmacol, 2011, 51: 237-242.

No Interaction Expected

_ZZCobicistat (with ATV or DRV)

Dolutegravir (DTG)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied. Cobicistat, an inhibitor of CYP3A4, could potentially increase dolutegravir concentrations although to a moderate extent as CYP3A4 does not play a major role in dolutegravir metabolism. No a priori dosage adjustment is recommended.

Description:

(See Summary)

Generate a personalised report in PDF format