When tenofovir disoproxil fumarate was administered with low dose ritonavir (as lopinavir/ritonavir), there was no significant effect on lopinavir/ritonavir PK parameters; tenofovir AUC and Cmin increased by 32% and 51%, but there was no change in Cmax. Coadministration as darunavir/ritonavir had no significant effect on darunavir/ritonavir PK parameters, but increased tenofovir AUC and Cmin by 22% and 37%. A higher risk of renal impairment has been reported in patients receiving tenofovir disoproxil fumarate in combination with a ritonavir or cobicistat boosted protease inhibitor. A close monitoring of renal function is required in these patients. In patients with renal risk factors, the co-administration of tenofovir disoproxil fumarate with a boosted protease inhibitor should be carefully evaluated.
Viread Summary of Product Characteristics, Gilead Sciences Ltd, September 2016.

Coadministration of low dose ritonavir (coformulated as lopinavir/ritonavir, 400/100 mg twice times daily for 14 days) and tenofovir-DF (300 mg once daily) was investigated in 24 healthy volunteers. There was no change in tenofovir Cmax; AUC and Cmin increased by 32% and 51% respectively. There was no change in Cmax, AUC or Cmin for lopinavir or ritonavir. When low dose ritonavir (100 mg twice daily for 14 days) was coadministered with saquinavir (1000 mg twice daily ) and tenofovir (300 mg once daily) in 35 healthy volunteers, there was no change in tenofovir AUC or Cmax, but Cmin increased by 23%. There was no change in ritonavir Cmax or AUC, but Cmin increased by 23%.
Viread Prescribing Information, Gilead Sciences Inc, February 2016.

The coadministration of tenofovir diproxil fumarate (300 mg once daily) was investigated in 18 HIV-1 infected individuals receiving saquinavir hard gel/ritonavir combination (1000/100 mg twice daily). On day 1, 12 h pharmacokinetic profiles for saquinavir and ritonavir were obtained, tenofovir was then added to the regimen and blood sampling repeated at days 3 and 14. Following the addition of tenofovir, saquinavir and ritonavir plasma concentrations were not significantly different compared with day 1. Geometric mean ratios (95% confidence intervals) for the AUC on days 3 and 14 were 1.16 (0.97, 1.59) and 0.99 (0.87, 1.30) for saquinavir and 1.05 (0.92, 1.28) and 1.08 (0.97, 1.30) for ritonavir.
Pharmacokinetics of saquinavir hard gel/ritonavir (1000/100 mg twice daily) when administered with tenofovir diproxil fumarate in HIV-1-infected subjects. Boffito M, Back D, Stainsby-Tron M, et al. Br J Clin Pharmacol, 2005, 59: 38-42.

The effect of tenofovir on the pharmacokinetics of lopinavir and ritonavir was investigated in 18 treatment experienced HIV+ patients. Lopinavir concentrations decreased in the presence of tenofovir (Cmin from 4.61 to 3.06 µg/ml; Cmax from 10.68 to 9.65 µg/ml). Decreases in ritonavir concentrations were also observed (Cmin from 0.63 to 0.35 µg/ml; Cmax from 1.02 to 0.72 µg/ml). Therapeutic drug monitoring of lopinavir when coadministered with tenofovir may be useful to indicate if individual dose modification of lopinavir and/or ritonavir is required.
Pharmacokinetic drug interaction of lopinavir/ritonavir in combination with tenofovir in experienced HIV+ patients. Breilh D, Rouzes A, Djabarouti S, et al. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, October/November 2004, abstract A-445.

Coadministration of hard gel saquinavir/ritonavir (1000/100 mg twice daily) alone and with tenofovir (300 mg once daily) was studied in 40 healthy subjects. The pharmacokinetics of tenofovir were not substantially effected by saquinavir/ritonavir (Cmin, Cmax and AUC increased by 23%, 15% and 14% respectively). Ritonavir exposure was slightly increased; Cmin, Cmax and AUC increased by 23%, 10% and 11% respectively. Saquinavir Cmin was moderately enhanced (47% increase); Cmax and AUC increased by 22% and 29% respectively. All subjects achieved a SQV Cmin above 100 ng/ml.
Pharmacokinetic assessment of tenofovir DF and ritonavir-boosted saquinavir in healthy subjects. Zong J, Chittick G, Blum MR, et al. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, October/November 2004, abstract A-444.

Coadministration of ritonavir (100 mg once daily, given with atazanavir) and tenofovir (300 mg once daily) was investigated in 10 male HIV+ subjects. In the presence of tenofovir, there were decreases in ritonavir AUC (7011 to 5217 ng/ml.h), Cmax (886 to 642 ng/ml) and Cmin (43 to 39 ng/ml). Atazanavir concentrations were also decreased in the presence of tenofovir.
Pharmacokinetic parameters of atazanavir/ritonavir when combined to tenofovir in HIV-infected patients with multiple treatment failures: a sub-study of PUZZLE2-ANRS 107 trial. Taburet AM, Piketty C, Gerard L, et al. 10th Conference on Retroviruses and Opportunistic Infections, Boston, February 2003. Abstract 537.

Coadministration of tenofovir (300 mg once daily) and darunavir/ritonavir (at a dose lower than recommended or with a different dosing regimen) increased tenofovir AUC, Cmax and Cmin by 22%, 24% and 37%, respectively. Darunavir AUC, Cmax and Cmin increased by 21%, 16% and 24%, respectively. The increase in tenofovir is from an effect on MDR1 transport in renal tubules. Monitoring of renal function may be indicated when darunavir coadministered with low dose ritonavir is given in combination with tenofovir, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

The interaction between darunavir/ritonavir and tenofovir was evaluated in clinical studies and no dose adjustment is needed for either drug. Coadministration of tenofovir (300 mg once daily) and darunavir/ritonavir (300/100 mg twice daily) was studied in 12 subjects. Darunavir and tenofovir exposure was increased. Darunavir Cmax, AUC and Cmin increased by 16%, 21% and 24%, respectively. Tenofovir Cmax, AUC and Cmin increased by 24%, 22% and 37%, respectively. Darunavir/ritonavir and tenofovir disoproxil fumarate can be coadministered without any dose adjustments.
Prezista Prescribing Information, Tibotec Inc, June 2012.

When tenofovir disoproxil fumarate (300 mg once daily) was administered with darunavir/ritonavir (300/100 mg twice daily), there was no sigificant effect on darunavir/ritonavir PK parameters. Tenofovir AUC increased by 22% and Cmin increased by 37%. No dose adjustment is recommended. The increased exposure of tenofovir could potentiate tenofovir associated adverse events, including renal disorders. Renal function should be closely monitored.
Viread Summary of Product Characteristics, Gilead Sciences Ltd, September 2016.

Darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations. Coadministration of darunavir/ritonavir (300/100 mg twice daily) and tenofovir-DF (300 mg once daily) was studied in 12 subjects. Tenofovir Cmax, AUC and Cmin increased by 24%, 22% and 37%, respectively; darunavir Cmax, AUC and Cmin increased by 16%, 21% and 24%, respectively. Patients receiving tenofovir-DF concomitantly with ritonavir-boosted darunavir should be monitored for tenofovir-associated adverse reactions. Tenofovir-DF should be discontinued in patients who develop tenofovir-associated adverse reactions.
Viread Prescribing Information, Gilead Sciences International Inc, February 2016.

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.

Proton pump inhibitors and H2-receptor antagonists (e.g. omeprazole or ranitidine) may reduce concentrations for co-administered protease inhibitors. For specific information regarding the impact of co-administration of acid reducing agents, refer to the SmPC of the co-administered protease inhibitor. Based on interaction studies with the ritonavir boosted protease inhibitors (lopinavir/ritonavir, atazanavir), concurrent administration of omeprazole or ranitidine does not significantly modify ritonavir efficacy as a pharmacokinetic enhancer despite a slight change of exposure (about 6 - 18%).
Norvir Summary of Product Characteristics, AbbVie Ltd, September 2016.

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There are no clinically significant interactions when emtricitabine is co-administered with indinavir, zidovudine, stavudine, famciclovir or tenofovir disoproxil fumarate.
Emtriva Summary of Product Characteristics, Gilead Sciences Ltd, April 2019.

No significant interactions were observed between emtricitabine and tenofovir. Coadministration of emtricitabine (200 mg once daily for 7 days) and tenofovir (300 mg once daily for 7 days) was studied in 17 HIV-negative subjects. There was no change in emtricitabine AUC and Cmax and a 20% increase in Cmin. Tenofovir AUC, Cmax and Cmin were unaltered.
Emtriva Prescribing Information, Gilead Sciences Inc, December 2018.

There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil fumarate was coadministered with emtricitabine.
Viread Summary of Product Characteristics, Gilead Sciences Ltd, September 2016.

Coadministration of tenofovir-DF (300 mg once daily) and emtricitabine (200 mg once daily for 7 days) was studied in 17 HIV-negative subjects. There was no change in tenofovir pharmacokinetic parameters. Emtricitabine AUC and Cmax were unaltered and there was a 20% increase in Cmin.
Viread Prescribing Information, Gilead Sciences International Inc, February 2016.

This interaction has not been studied. Based on the different elimination pathways of the other NRTIs zidovudine, emtricitabine, stavudine, lamivudine, that are primarily renally excreted, and abacavir for which metabolism is not mediated by CYP450, no interactions are expected for these medicinal compounds and darunavir coadministered with low dose ritonavir.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Based on the different elimination pathways of the NRTIs (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine and abacavir) that are primarily renally excreted, no drug interactions are expected for these drugs and darunavir/ritonavir.
Prezista Prescribing Information, Tibotec Inc, June 2012.

Coadministration of omeprazole (20 mg once daily) and darunavir/ritonavir (at a dose lower than recommended or with a different dosing regimen) had no effect on darunavir AUC, Cmax and Cmin. Darunavir coadministered with low dose ritonavir can be coadministered with proton pump inhibitors without dose adjustments.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

The interaction between darunavir/ritonavir and omeprazole was evaluated in clinical studies and no dose adjustment is needed for either drug. Coadministration of omeprazole (20 mg once daily) and darunavir/ritonavir (400/100 mg twice daily) was studied in 16 subjects. There was no significant change in darunavir exposure (Cmax, AUC and Cmin increased by 2%, 4% and 8% respectively).
Prezista Prescribing Information, Tibotec Inc, June 2012.

The effect of darunavir/ritonavir (600/100 mg twice daily) on the activity of CYP2C9, 2D6 and 2C19 was investigated in 12 HIV- subjects using single doses of a probe cocktail containing warfarin (10 mg with vitamin K, CYP2C9), dextromethorphan (30 mg, CYP2D6) and omeprazole (40 mg, CYP2C19). The AUC ratio of omeprazole to 5-OH omeprazole decreased by 31%, suggesting induction of CYP2C19.
Cocktail study to investigate the in-vivo drug interaction potential of darunavir co-administered with low-dose ritonavir on cytochrome P450 enzymes 2D6, 2C9 and 2C19. Sekar V, Spinosa-Guzman S, Meyvisch P, et al. 9th International Workshop on Clinical Pharmacology of HIV Therapy, New Orleans, April 2008.

The effect of ranitidine (150 mg twice daily) and omeprazole (20 mg once daily) on the plasma pharmacokinetics of a non-licensed dose of darunavir/ritonavir (400/100 mg twice daily) was investigated in 12 HIV-negative volunteers. Treatment was given for 4 days with an additional morning dose on day 5, and regimens were separated by a washout period of 7 days. Compared with darunavir/ritonavir alone, no significant changes in darunavir pharmacokinetic parameters were observed during coadministration with either ranitidine or omeprazole. No dose adjustments are required when darunavir/ritonavir is coadministered with omeprazole or ranitidine.
Pharmacokinetic interaction between darunavir boosted with ritonavir and omeprazole or ranitidine in human immunodeficiency virus-negative healthy volunteers. Sekar VJ, Lefebvre E, De Paepe E, et al. Antimicrob Agents Chemother, 2007, 51(3): 958-961.

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