Atazanavir/ritonavir, darunavir/ritonavir and lopinavir/ritonavir modestly increased levels of tenofovir, and there is at leastone case report of nephrotoxicity with combination of tenofovir, didanosine, and lopinavir/ritonavir. Saquinavir/ritonavir,tipranavir/ritonavir, and probably also fosamprenavir/ritonavir,have little effect on tenofovir levels. Tenofovir modestly decreasedatazanavir levels,and this was minimised when ritonavir was also given. Tenofovir had no important effect on ritonavir-boosteddarunavir,lopinavir, and tipranavir levels, and modestlyincreased those of ritonavir-boosted saquinavir in one of twostudies. Indinavir and nelfinavir do not interact pharmacokinetically with tenofovir.
The AUC of atazanavir was decreased by 25%, and trough level by 40 % when atazanavir 400mg daily was given with tenofovir disoproxil fumarate 300mg daily, and AUC of tenofovir was increased by 24 % (See reference number 1-3). Similar results were seen when administration was separated by 12 hrs (See reference number 3).
When atazanavir 300mg once daily was given with ritonavir 100mg once daily (as a pharmacokinetic booster), tenofovir disoproxil fumarate 300mg once daily reduced AUC of atazanavir by a similar amount (25%), but had less effect on trough level (23% reduction), when compared with atazanavir/ritonavir alone (See reference number 4). Similarly, pharmacokinetics of atazanavir/ritonavir did not differ significantly between patients taking tenofovir and those not (See reference number 5). Combined use increased tenofovir AUC by 37 % and minimum level by 29 % (See reference number 2,3).
The manufacturer notes that concurrent use of darunavir/ritonavir 300/100 mg twice daily with tenofovir disoproxil fumarate 300mg once daily modestly increased tenofovir AUC and minimum level by 22 % and 37%, respectively. Darunavir levels were not significantly changed (minimum level increased by 24%) (See reference number 6,7).
The US manufacturer notes that,in a phase III clinical study plasma amprenavir trough levels (derived from fosamprenavir) were similar in subjects receiving tenofovir with fosamprenavir and ritonavir to those in subjects not receiving tenofovir (See reference number 8). Similarly, in a pharmacokinetic study in healthy subjects, tenofovir disoproxil fumarate 300mg once daily had no significant effect on pharmacokinetics of amprenavir after fosamprenavir/ritonavir 1400/100 mg once daily or fosamprenavir/ritonavir 1400/200 mg once daily (See reference number 9).
The concurrent use of lopinavir/ritonavir 400/100 mg twice daily and tenofovir resulted in a 30 % increase in AUC and a 50 % increase in trough level of tenofovir, but no change in pharmacokinetics of lopinavir/ritonavir (See reference number 1,10). There is one case report of Fanconi syndrome with nephrogenic diabetes insipidus,which developed in a patient taking lopinavir/ritonavir 800/200 mg daily, tenofovir disoproxil fumarate 300mg daily, didanosine and lamivudine (for an interaction between tenofovir and didanosine, see NRTIs,). The tenofovir level was 3.7-fold higher than expected and didanosine level was eightfold higher than it had been before tenofovir was started. Lopinavir levels were unchanged (See reference number 11).
Tenofovir disoproxil fumarate 300mg once daily modestly increased saquinavir AUC and minimum level by 29 % and 47%, respectively, after administration of saquinavir/ritonavir 1000/100 mg twice daily in healthy subjects. The only change in tenofovir pharmacokinetics was a slight 23 % increase in minimum level (See reference number 10,12). In another study,(See reference number 13) mentioned by manufacturer of saquinavir,(See reference number 14,15) in 18 HIV-positive patients treated with saquinavir/ritonavir 1000/100 mg twice daily and tenofovir disoproxil fumarate 300mg once daily, saquinavir AUC and maximum values were just 1 % and 7 % lower, respectively, than those seen with saquinavir/ritonavir alone.
Tipranavir/ritonavir 500/100 mg twice daily had no effect on AUC and minimum level of a single 300mg dose of tenofovir disoproxil fumarate, but it decreased tenofovir maximum level by 23%. The tipranavir AUC and minimum level were decreased by 18 % and 21%,respectively. With an increased dose of tipranavir/ritonavir 750/200 mg twice daily, maximum level of tenofovir was reduced by 38 % with no change in AUC or minimum level, and decreases in tipranavir AUC and minimum levels were less (9% AUC and 12 % minimum level) (See reference number 16).
It has been suggested that ritonavir increases tenofovir levels via its effect on drug transporter proteins in renal tubuli (See reference number 6,11)
The modest increase in tenofovir levels with ritonavir-boosted atazanavir,darunavir and lopinavir is of uncertain clinical relevance. However,it has been suggested that higher tenofovir levels could potentiate tenofovir-associated adverse events, including renal disorders (See reference number 2,3,17). For this reason, UK manufacturer of darunavir says that monitoring of renal function may be indicated when ritonavir-boosted darunavir is given in combination with tenofovir, particularly in patients with underlying systemic or renal disease, or in patients taking nephrotoxic drugs (See reference number 6). The US manufacturer of lopinavir/ritonavir also recommends monitoring,(See reference number 18) and this seems a prudent precaution.
The decrease in atazanavir levels with tenofovir is not of clinical importance if ritonavir is also used,and this combination has been used successfully as part of antiretroviral therapy in clinical studies (See reference number 1,2). Unboosted atazanavir should be used with caution(See reference number 19)or not given(See reference number 3) with tenofovir because of potential for reduced efficacy and development of resistance. Ritonavir-boosted darunavir and lopinavir levels were not significantly affected by tenofovir, amprenavir levels were also unaffected following boosted fosamprenavir administration, and increase in ritonavir-boosted saquinavir levels are not likely to be clinically relevant. The slight interaction between tenofovir and tipranavir/ritonavir is unlikely to be clinically relevant. There is no clinically relevant interaction between nelfinavir or indinavir and tenofovir.
Current UK guidelines give tenofovir as one of preferred drugs as part of a dual NRTI regimen, to be used with either fosamprenavir/ritonavir or lopinavir/ritonavir, for treatment of HIV infection in treatment naïve patients. They say that saquinavir/ritonavir is an alternative,and atazanavir/ritonavir may be used in specific groups (See reference number 20). US guidelines are similar (See reference number 21).
1.
Viread (Tenofovir disoproxil fumarate). Gilead Sciences International Ltd. UK Summary ofproduct characteristics,May 2007.
2.
Reyataz (Atazanavir sulfate). Bristol-Myers Squibb Pharmaceuticals Ltd. UK Summary ofproduct characteristics,April 2007.
3.
Reyataz (Atazanavir sulfate). Bristol-Myers Squibb Company. US Prescribing information,March 2007.
4.
Taburet A-M,Piketty C, Chazallon C, Vincent I, Gérard L, Calvez V, Clavel F, Aboulker JP, Girard P-M, and the ANRS Protocol 107 Puzzle 2 Investigators. Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infectedpatients. Antimicrob Agents Chemother (2004) 48, 2091–6.
5.
Hentig NV,Haberl A, Lutz T, Klauke S, Kurowski M, Harder S, Staszewski S. Concomitantintake of tenofovir disoproxil fumarate (TDF) does not impair plasma exposure of ritonavir(RTV) boosted atazanavir (ATV) in HIV-1 infected adults. Clin Pharmacol Ther (2005) 77, P18.
6.
Prezista (Darunavir ethanolate). Janssen-Cilag Ltd. UK Summary of product characteristics,July 2007.
7.
Prezista (Darunavir). Tibotec,Inc. US Prescribing information, June 2006.
8.
Lexiva (Fosamprenavir calcium). GlaxoSmithKline. US Prescribing information,June 2007.
9.
Kurowski M,Walli R, Breske A, Kruse G, Stocker H, Banik N, Richter H, Mazur D. Coadministration of tenofovir 300mg QD with fosamprenavir/ritonavir 1.400/100mg QD or1.400/200mg QD does not affect amprenavir pharmacokinetics. 6(See reference number th) International Workshopon Clinical Pharmacology of HIV Therapy, Québec, 28 – 30 April, 2005. Abstract 10.Available at: http://www.hivpresentation.com/assets/85C4305C-E0C4-D510-02B06CE974717ADB.PDF(accessed 21/08/07).
Viread (Tenofovir disoproxil fumarate). Gilead Sciences,Inc. US Prescribing information,May 2007.
Rollot F,Nazal E-M, Chauvelot-Moachon L, Kélaïdi C, Daniel N, Saba M, Abad S, Blanche
P. Tenofovir-related Fanconi syndrome with nephrogenic diabetes insipidus in a patient withacquired immunodeficiency syndrome: the role of lopinavir-ritonavir-didanosine. Clin Infect Dis (2003) 37,e174–e176.
Chittick GE,Zong J, Blum MR, Sorbel JJ, Begley JA, Adda N, Kearney BP. Pharmacokinetics of tenofovir disoproxil fumarate and ritonavir-boosted saquinavir mesylate administeredalone or in combination at steady state. Antimicrob Agents Chemother (2006) 50, 1304–10.
Boffito M,Back D, Stainsby-Tron M, Hill A, Di Perri G, Moyle G, Nelson M, Tomkins J,Gazzard B, Pozniak A. Pharmacokinetics of saquinavir hard gel/ritonavir (1000/100 mgtwice daily) when administered with tenofovir diproxil fumarate in HIV-1-infected subjects.Br J Clin Pharmacol (2005) 59, 38–42.
Invirase Tablets (Saquinavir mesilate). Roche Products Ltd. UK Summary of product characteristics,May 2007.
Invirase (Saquinavir mesylate). Roche Pharmaceuticals. US Prescribing information,July2007.
Aptivus (Tipranavir). Boehringer Ingelheim. US Prescribing information,February 2007.
Kaletra Tablets (Lopinavir/ritonavir). Abbott Laboratories Ltd. UK Summary of productcharacteristics,March 2007.
Kaletra (Lopinavir/ritonavir). Abbott Laboratories. US Prescribing information,January 2007.
Hodder S,Bristol-Myers Squibb Company, Klein R, Struble K, FDA. Letter to health careproviders. Re: Important new pharmacokinetic data for REYATAZ™ (atazanavir sulfate) incombination with Viread:6.6pt; font-weight:normal; color:#000000″>® (tenofovir disoproxil fumarate). August 8, 2003. Available at:http://www.fda.gov/oashi/aids/listserve/listserve2003.html (accessed 21/08/07).
Gazzard B on behalf of the writing committee,British HIV Association. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy(2006). HIV Med (2006) 7, 487–503. Available at:http://www.bhiva.org/files/file1001303.pdf (accessed 21/08/07).
US Department of Health and Human Services; Panel on Antiretroviral Guidelines for Adultand Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults andadolescents. October 10,2006; 1–113. Available at: http://www.aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf (accessed 21/08/07).