Pharmacy Blog – Dr Vibore

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).

Rifabutin bioavailability is increased by amprenavir,atazanavir,fosamprenavir/ritonavir, indinavir, lopinavir/ritonavir, nelfinavir, tipranavir/ritonavir, and especially ritonavir, with an increased risk of toxicity. Rifabutin modestly decreases bioavailability of indinavir, nelfinavir, and particularly saquinavir(with an increased risk of therapeutic failure), but has no effect onamprenavir, atazanavir, and ritonavir-boosted fosamprenavir.The combination of rifabutin with protease inhibitors may beused,but dosage adjustments of rifabutin or both drugs are often necessary.Rifampicin (rifampin) bioavailability is increased by indinavir,but amprenavir has no effect. Rifampicin markedly reduces thebioavailability of amprenavir,atazanavir/ritonavir, indinavir,indinavir with ritonavir, lopinavir/ritonavir, nelfinavir and saquinavir, but only modestly reduces that of ritonavir. The effects of rifampicin on lopinavir/ritonavir and saquinavir/ritonavir can be overcome by increasing protease inhibitor dose, butthis appears to increase adverse effects (hepatotoxicity).

Rifabutin. When amprenavir 1.2 g twice daily was given with rifabutin 300mg daily to 11 healthy subjects for 10 days there was an almost threefold increase in AUC of rifabutin, but pharmacokinetics of amprenavir were not significantly altered. The combination was poorly tolerated,with 5 of 11 subjects stopping treatment between days 1 and 9 due to adverse events (See reference number 1). When reduced doses of rifabutin (150 mg every other day) were given with fosamprenavir/ritonavir 700/100 mg twice daily rifabutin AUC was unchanged and maximum level was decreased by 14%, when compared with rifabutin 300mg once daily given alone. However, 25-O-desacetylrifabutin AUC and maximum level were increased 11-fold and sixfold, respectively, which could potentially lead to an increase of rifabutin-related adverse events such as uveitis. Based on historical comparison,rifabutin did not appear to reduce amprenavir exposure from fosamprenavir/ritonavir (See reference number 2,3).

1.2 g twice daily with rifampicin 600mg daily to for 4 days pharmacokinetics of rifampicin were not affected, but AUC of amprenavir was reduced by 82%. The maximum plasma level of amprenavir was also reduced by 70%,from 9.2 to 2.78 micrograms/mL (See reference number 1). It is expected that concurrent use of fosamprenavir or fosamprenavir/ritonavir with rifampicin will also result in large decreases in plasma concentrations of amprenavir (See reference number 2,3).

Rifabutin. The manufacturer notes that atazanavir 400mg daily given with rifabutin 150mg once daily for 14 days did not have any important effect on AUC of atazanavir. However, AUC of rifabutin 150mg was 2.3-fold higher than historical data for a standard 300mg dose (See reference number 4).

Rifampicin (Rifampin). When rifampicin 600mg daily was given with atazanavir/ritonavir 300/100 mg once daily, AUC and minimum levels of atazanavir were markedly reduced, by 72 % and 98%, respectively (See reference number 5).

Although there are no data, manufacturer predicts that rifabutin will decrease ritonavir-boosted darunavir levels, and that darunavir/ritonavir will increase rifabutin levels. They also predict that rifampicin will markedly reduce ritonavir-boosted darunavir levels (See reference number 6,7).

1. Rifabutin. When 10 healthy subjects were given rifabutin 300mg once daily with indinavir 800mg every 8 hrs to for 10 days, indinavir maximum serum levels and AUC were reduced by about one-third, whereas rifabutin maximum serum levels and AUC were increased two- to threefold (See reference number 8). When same dose of indinavir (800 mg every 8 hours) was given with half dose of rifabutin (150 mg once daily), AUC of indinavir was similarly reduced (by 32%), but increase in AUC of rifabutin was less (54% increase) (See reference number 8). In a further study, pharmacokinetics of indinavir 1 g every 8 hrs (increased dose) and rifabutin 150mg daily (reduced dose) were investigated in healthy and HIV-positive subjects. The indinavir AUC was same with this increased dose as with indinavir 800mg every 8 hrs alone. However, despite halving rifabutin dose, AUC was still up to 70 % higher than with 300mg dose alone (See reference number 9). When combination was used in practice, there were no treatment failures in 25 patients being treated with rifabutin while receiving HAART (containing indinavir and/or nelfinavir). The rifabutin was given as 300mg twice weekly and indinavir dose was increased from 800mg to 1.2 g every 8 hrs to achieve satisfactory levels (See reference number 10).

2. Rifampicin (Rifampin). A study in 11 AIDS patients given indinavir 800mg every 8 hrs and rifampicin 600mg daily for 14 days found that AUC of rifampicin was increased by 73 % (See reference number 11). In a similar study looking at effects of rifampicin on indinavir, indinavir AUC and maximum serum levels were decreased by 92 % and 86%, respectively (See reference number 12). In another study, giving rifampicin 300mg daily for 4 days to 6 HIV-positive patients already receiving ritonavir-boosted indinavir (indinavir/ritonavir 800/100 mg twice daily) decreased median indinavir plasma levels (measured 12 hrs after last dose) by 87 % and median ritonavir levels by 94 % (See reference number 13).

When healthy subjects were given lopinavir/ritonavir 400/100 mg twice daily with rifabutin 150 or 300mg daily for 10 days AUC of rifabutin was increased threefold and AUC of lopinavir was increased by 17 % (See reference number 14)

Rifampicin (Rifampin). Rifampicin 600mg daily for 10 days decreased AUC of lopinavir (given as lopinavir/ritonavir 400/100 mg twice daily) by 75 % in a study in healthy subjects (See reference number 14). A dose titration of lopinavir/ritonavir was carried out in healthy subjects to try and overcome interaction with rifampicin (See reference number 15). In 10 evaluable subjects, use of rifampicin 600mg daily with lopinavir/ritonavir 800/200 mg twice daily decreased minimum lopinavir level by 57 % without affecting maximum level, when compared with lopinavir/ritonavir 400/100 mg twice daily without rifampicin. In another 9 evaluable subjects, rifampicin 600mg daily with lopinavir/ritonavir 400/400 mg twice daily did not alter maximum or minimum level of lopinavir, but markedly increased ritonavir levels, when compared with lopinavir/ritonavir 400/100 mg twice daily without rifampicin. Of 29 subjects who received adjusted doses of lopinavir/ritonavir with rifampicin, 9 subjects had grade 2 to 3 elevations in liver enzymes, and this was more common in lopinavir/ritonavir 400/400 mg group than lopinavir/ritonavir 800/200 mg group (See reference number 15).

Rifabutin. When rifabutin 300mg daily for 8 days was given with nelfinavir 750mg every 8 hrs for 7 to 8 days, nelfinavir AUC was reduced by 32 % and rifabutin AUC was increased by 207 % (See reference number 16). When nelfinavir 750mg every 8 hrs was given with half dose of rifabutin (150 mg daily), nelfinavir AUC was reduced by a similar amount (23%), whereas rifabutin AUC was increased by a lower amount (83%) (See reference number 17,18).

Rifampicin (Rifampin). Rifampicin 600mg daily for 7 days decreased AUC of nelfinavir 750mg every 8 hrs for 6 days by 82 % (See reference number 16). A 7-monthold infant with HIV and tuberculosis was given a rifampicin-based antimycobacterial regimen with nelfinavir-based HAART. Nelfinavir plasma levels were found to be very low,so ritonavir was added. This improved nelfinavir levels, and also greatly increased those of principal active metabolite of nelfinavir. The regimen was well tolerated and had a good clinical response (See reference number 19).

1. Rifabutin. In a study in 5 healthy subjects when ritonavir 500mg twice daily was given with rifabutin 150mg daily for 8 days, maximum serum level of rifabutin was increased threefold and AUC was increased fourfold (and AUC of its active metabolite, 25-O-desacetylrifabutin, 35-fold). Seven subjects had to be withdrawn due to adverse events,primarily leucopenia (See reference number 20). Retrospective analysis of regimens containing ritonavir found that concurrent use of rifabutin was associated with a higher incidence of rifabutin-related adverse effects including arthralgia, joint stiffness, uveitis and leucopenia (See reference number 21).

2. Rifampicin (Rifampin). When ritonavir 500mg every 12 hrs was given with rifampicin 300 or 600mg daily for 10 days, AUC of ritonavir was 35 % lower and maximum level 25 % lower than in subjects receiving ritonavir alone (See reference number 22).

Rifabutin. The AUC of saquinavir 600mg three times daily was reduced by about 40 % by rifabutin 300mg daily,in 12 HIV-positive subjects (See reference number 23). Similarly, AUC of saquinavir (soft capsules) 1.2 g three times daily was decreased by 47 % by rifabutin 300mg once daily in 14 HIV-positive patients. In addition, rifabutin AUC was increased by 44 % by saquinavir (See reference number 24). However,combined use of ritonavir and saquinavir (hard capsules), both 400mg twice daily, with intermittent rifabutin dosing (300 mg weekly or 150mg every 3 days) for 8 weeks was reported to be safe and manageable. Rifabutin did not significantly alter protease inhibitor levels, and rifabutin pharmacokinetics were similar to those usually seen with rifabutin 300mg daily alone (See reference number 25).

Rifampicin (Rifampin). Rifampicin 600mg once daily decreased AUC of saquinavir (soft capsules) 1.2 g three times daily by 70 % (See reference number 26). It was suggested that combination of ritonavir and saquinavir (both 400mg twice daily) could cancel out effects of rifampicin on saquinavir, so therapeutic levels of all three drugs could be achieved. This assumption has been confirmed in HIV-positive patients (See reference number 27,28). Five of 20 patients originally given combination developed hepatotoxicity, 2 of whom had comorbidities (See reference number 28). However, in a further study in healthy subjects, severe hepatotoxicity with transaminase elevations of about 20 times upper limit of normal occurred in 11 of 17 subjects after they took saquinavir/ritonavir 1000/100 mg twice daily with rifampicin 600mg once daily for 1 to 5 days (See reference number 29,30).

The manufacturer notes that tipranavir/ritonavir 500/200 mg twice daily increased plasma rifabutin levels by up to threefold,and its active metabolite by up to 20-fold after a single 150mg dose of rifabutin (See reference number 31,32).

Although there are no data, manufacturer predicts that rifampicin will markedly reduce ritonavir-boosted tipranavir levels (See reference number 31,32).

Rifampicin is a potent inducer of cytochrome P450 isoenzyme CYP3A4, by which protease inhibitors are at least partially metabolised, and therefore it markedly reduces protease inhibitor levels. Rifabutin is a weak inducer of CYP3A4. The protease inhibitors are inhibitors of CYP3A4, with ritonavir being most potent, and can therefore increase levels of rifamycins.

Established interactions of clinical importance. The protease inhibitors increase levels of rifabutin, with a consequent increase in adverse effects unless rifabutin dose is reduced. Ritonavir is most potent pro-tease inhibitor in this regard, and combination has been considered contraindicated. However, CDC in US say that combination may be used if dose of rifabutin is markedly reduced (See reference number 33). In addition, rifabutin decreases levels of some protease inhibitors, particularly saquinavir, increasing risk of treatment failure. Rifabutin should not be used when saquinavir is sole protease inhibitor (no longer recommended). However,there is some evidence that rifabutin can be used with ritonavir-boosted saquinavir. table 1 below, summarises clinical recommendations for concurrent use of protease inhibitors and rifabutin. Therapy should be well monitored. Note that, in one analysis, use of rifabutin 150mg twice weekly with low-dose ritonavir and a second protease inhibitor was associated with low rifabutin levels (See reference number 34). Recommended doses of rifabutin in patients taking ritonavir-boosted protease inhibitors are 150mg every other day or three times per week (See reference number 33).

Rifampicin markedly reduces levels of many of protease inhibitors, and its use with unboosted protease inhibitors should be avoided, because of risk of reduced antiviral efficacy and emergence of resistant viral strains. There are limited data to suggest that ritonavir as sole pro-tease inhibitor, or ritonavir used as a pharmacokinetic enhancer with other protease inhibitors such as saquinavir, can be used with rifampicin (See reference number 33). However, further study has shown a high incidence of hepatotoxicity with saquinavir/ritonavir 1000/100 mg twice daily and rifampicin, and manufacturers of ritonavir and saquinavir advise that these drugs should not be given together with rifampicin (See reference number 22,29,30,35). Current UK guidelines state that,until more data are available, ritonavir-boosted protease inhibi

5 Summary of manufacturers’ dosage recommendations (unless stated other

Rifabutin dose at least halved (150 mg daily or every other day,or 300mg three times per week). Amprenavir dose unchanged.

Not recommended (indinavir levels markedly reduced,rifampicin levels raised).

3,6-8

3,9, 10

May be used at usual doses,although limited data (ritonavir levels reduced). May lead to loss of virologic response.

3,11

3,12, 13

14,15

3,16

Not recommended (lopinavir levels markedly reduced). However, adjusted doses of lopinavir/ritonavir (800/200 mg or 400/400 mg twice daily) may overcome pharmacokinetic interaction, but have a high incidence of elevated liver enzymes, and so if used, close monitoring is needed.

3,17-19

Rifampicin dose unchanged. Saquinavir/ritonavir 400/400 mg twice daily. Note that a regimen of 1000/100 mg twice daily with rifampicin was associated with severe hepatotoxicity, and combination is contraindicated.

3,20, 21

22,23

Agenerase (Amprenavir). GlaxoSmithKline UK. UK Summary of product characteristics,February 2007.

Agenerase (Amprenavir). GlaxoSmithKline. US Prescribing information,May 2005.

Centers for Disease Control and Prevention. Updated guidelines for use of rifamycins for treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. January 20,2004. Available at http://www.cdc.gov/tb/TB_HIV_Drugs/default.htm (accessed 22/08/07).

Telzir (Fosamprenavir). GlaxoSmithKline UK. UK Summary of product characteristics,February 2007.

Lexiva (Fosamprenavir). GlaxoSmithKline. US Prescribing information,February 2007.

Jaruratanasirikul S,Sriwiriyajan S. Pharmacokinetics of rifampicin administered alone and with indinavir. J Antimicrob Chemother (1999) 44 (Suppl A),58.

Crixivan (Indinavir sulfate). Merck Sharp & Dohme Ltd. UK Summary of product characteristics,May 2007.

Crixivan (Indinavir sulfate). Merck & Co.,Inc. US Prescribing information,November 2006.

Viracept (Nelfinavir mesilate). Roche Products Ltd. UK Summary of product characteristics,January 2007.

Viracept (Nelfinavir mesilate). Agouron Pharmaceuticals,Inc. US Prescribing information,January 2007.

Norvir Soft Capsules (Ritonavir). Abbott Laboratories. US Prescribing information,January 2006.

Reyataz (Atazanavir sulfate). Bristol-Myers Squibb Pharmaceuticals Ltd. UK Summary of product characteristics,April 2007.

5 Summary of manufacturers’ dosage recommendations (unless stated otherwise) for combined use of protease inhibitors and rifamycins (continued)

Reyataz (Atazanavir sulfate). Bristol-Myers Squibb Company. US Prescribing information,March 2007.

Prezista (Darunavir). Janssen-Cilag Ltd. UK Summary of product characteristics,February 2007.

Prezista (Darunavir). Tibotec,Inc. US prescribing information,June 2006.

Justesen US,Andersen ÅB, Klitgaard NA, Brøsen K, Gerstoft J, Pedersen C. Pharmacokinetic interaction between rifampin and combination of indinavir and low-dose ritonavir in HIV-infected patients. Clin Infect Dis (2004) 38,426-9.

Kaletra (Lopinavir/ritonavir). Abbott Laboratories Ltd. UK Summary of product characteristics,March 2007.

Kaletra Tablets (Lopinavir/ritonavir). Abbott Laboratories. US Prescribing information,January 2007.

la Porte CJL,Colbers EPH, Bertz R, Voncken DS, Wikstrom K, Boeree MJ, Koopmans PP, Hekster YA, Burger DM. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrob Agents Chemother (2004) 48,1553–60.

Invirase (Saquinavir mesilate). Roche Products Ltd. UK Summary of product characteristics,May 2007.

Invirase (Saquinavir mesilate). Roche Pharmaceuticals. US Prescribing information,September 2005.

Aptivus (Tipranavir). Boehringer Ingelheim Ltd. UK Summary of product characteristics,March 2007.

Aptivus (Tipranavir). Boehringer Ingelheim. US Prescribing information,February 2007.

tors should not be used with rifampicin. They say that rifampicin should be switched to rifabutin for use with protease inhibitors, or protease inhibitor should be changed to an alternative antiretroviral if this is possible (See reference number 36). Similarly,US guidelines say that rifampicin may only be used with full-dose ritonavir, and cannot be used safely with ritonavir-boosted regimens. They recommend use of rifabutin (See reference number 37).

Polk RE,Brophy DF, Israel DS, Patron R, Sadler BM, Chittick GE, Symonds WT, Lou Y,Kristoff D, Stein DS. Pharmacokinetic interaction between amprenavir and rifabutin or rifampin in healthy males. Antimicrob Agents Chemother (2001) 45, 502–508.

Telzir (Fosamprenavir calcium). GlaxoSmithKline UK. UK Summary of product characteristics,February 2007.

Lexiva (Fosamprenavir calcium). GlaxoSmithKline. US Prescribing information,June 2007.

Reyataz (Atazanavir sulfate). Bristol-Myers Squibb Pharmaceuticals Ltd. UK Summary ofproduct characteristics,April 2007.

Reyataz (Atazanavir sulfate). Bristol-Myers Squibb Company. US Prescribing information,March 2007.

Prezista (Darunavir ethanolate). Janssen-Cilag Ltd. UK Summary of product characteristics,July 2007.

Prezista (Darunavir). Tibotec,Inc. US Prescribing information, June 2006.

Kraft WK,McCrea JB, Winchell GA, Carides A, Lowry R, Woolf EJ, Kusma SE, DeutschPJ, Greenberg HE, Waldman SA. Indinavir and rifabutin drug interactions in healthy volunteers. J Clin Pharmacol (2004) 44, 305–13.

Hamzeh FM,Benson C, Gerber J, Currier J, McCrea J, Deutsch P, Ruan P, Wu H, Lee J, Flexner C, for the AIDS Clinical Trials Group 365 Study Team. Steady-state pharmacokinetic interaction of modified-dose indinavir and rifabutin. Clin Pharmacol Ther (2003) 73, 159–

69.

Narita M,Stambaugh JJ, Hollender ES, Jones D, Pitchenik AE, Ashkin D. Use of rifabutinwith protease inhibitors for human immunodeficiency virus-infected patients with tuberculosis. Clin Infect Dis (2000) 30, 779–83. Correction. ibid. 992.

Jaruratanasirikul S,Sriwiriyajan S. Pharmacokinetics of rifampicin administered alone andwith indinavir. J Antimicrob Chemother (1999) 44 (Suppl A), 58.

McCrea J,Wyss D, Stone J, Carides A, Kusma S, Kleinbloesem C, Al-Hamdan Y, Yeh K,Deutsch P. Pharmacokinetic interaction between indinavir and rifampin. Clin Pharmacol Ther (1997) 61, 152.

Justesen US,Åndersen AB, Klitgaard NA, Brøsen K, Gerstoft J, Pedersen C. Pharmacokinetic interaction between rifampin and the combination of indinavir and low-dose ritonavir inHIV-infected patients. Clin Infect Dis (2004) 38, 426–9.

Bertz R,Hsu A, Lam W, Williams L, Renz C, Karol M, Dutta S, Carr R, Zhang Y, Wang Q,Schweitzer S, Foit C, Andre A, Bernstein B, Granneman GR, Sun E. Pharmacokinetic interactions between lopinavir/ritonavir (ABT-378r) and other non-HIV drugs (abstract P291).AIDS (2000) 14 (Suppl 4), S100.

la Porte CJL,Colbers EPH, Bertz R, Voncken DS, Wikstrom K, Boeree MJ, Koopmans PP,Hekster YA, Burger DM. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combinedwith rifampin in healthy volunteers. Antimicrob Agents Chemother (2004) 48, 1553–60.

Kerr B,Yuep G, Daniels R, Quart B, Kravcik S, Sahai J, Anderson R. Strategic approach tonelfinavir mesylate (NFV) drug interactions involving CYP3A metabolism. 6(See reference number th) EuropeanConference on Clinical Aspects and Treatment of HIV-infection, Hamburg, 1997. 256.

Viracept (Nelfinavir mesilate). Roche Products Ltd. UK Summary of product characteristics,January 2007.

Viracept (Nelfinavir mesylate). Agouron Pharmaceuticals,Inc. US Prescribing information,January 2007.

Bergshoeff AS,Wolfs TFW, Geelen SPM, Burger DM. Ritonavir-enhanced pharmacokinetics of nelfinavir/M8 during rifampin use. Ann Pharmacother (2003) 37, 521–5.

Cato A,Cavanaugh J, Shi H, Hsu A, Leonard J, Granneman R. The effect of multiple dosesof ritonavir on the pharmacokinetics of rifabutin. Clin Pharmacol Ther (1998) 63, 414–21.

Sun E,Heath-Chiozzi M, Cameron DW, Hsu A, Granneman RG, Maurath CJ, Leonard JM. Concurrent ritonavir and rifabutin increases risk of rifabutin-associated adverse events. 11(See reference number th)International Conference on AIDS, Vancouver, 1996. Mo.B.171.

Norvir (Ritonavir). Abbott Laboratories. US Prescribing information,January 2006.

Sahai J,Stewart F, Swick L, Gallicano K, Garber G, Seguin I, Tucker A, Bristow N, Cameron

W. Rifabutin (RBT) reduces saquinavir (SAQ) plasma levels in HIV-infected patients. Intersci Conf Antimicrob Agents Chemother (1996) 36,6.

24. Moyle GJ,Buss NE, Goggin T, Snell P, Higgs C, Hawkins DA. Interaction between saquinavir soft-gel and rifabutin in patients infected with HIV. Br J Clin Pharmacol (2002) 54, 178–

82.

25. Gallicano K,Khaliq Y, Carignan G, Tseng A, Walmsley S, Cameron DW. A pharmacokineticstudy of intermittent rifabutin dosing with a combination of ritonavir and saquinavir in patients infected with human immunodeficiency virus. Clin Pharmacol Ther (2001) 70, 149–

58.

Rolla VC,da Silva Vieira MA, Pereira Pinto D, Lourenço MC, de Jesus C da S, Gonçalves Morgado M, Ferreira Filho M, Werneck-Barroso E. Safety, efficacy and pharmacokinetics ofritonavir 400mg/saquinavir 400mg twice daily plus rifampicin combined therapy in HIV patients with tuberculosis. Clin Drug Invest (2006) 26, 469–79.

Invirase Hard Capsules (Saquinavir mesilate). Roche Products Ltd. UK Summary of productcharacteristics,May 2007.

Invirase (Saquinavir mesylate). Roche Pharmaceuticals. US Prescribing information,July2007.

Aptivus (Tipranavir). Boehringer Ingelheim Ltd. UK Summary of product characteristics,March 2007.

Aptivus (Tipranavir). Boehringer Ingelheim. US Prescribing information,February 2007.

Centers for Disease Control and Prevention. Updated guidelines for the use of rifamycins forthe treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors,January 20th 2004. Available at:http://www.cdc.gov/tb/TB_HIV_Drugs/default.htm (accessed 21/08/07).

Spradling P,Drociuk D, McLaughlin S, Lee LM, Peloquin CA, Gallicano K, Pozsik C, Onorato I, Castro KG, Ridzon R. Drug-drug interactions in inmates treated for human immunodeficiency virus and Mycobacterium tuberculosis infection or disease: an institutional tuberculosis outbreak. Clin Infect Dis (2002) 35, 1106–12.

Norvir Soft Capsules (Ritonavir). Abbott Laboratories Ltd. UK Summary of product characteristics,May 2007.

Pozniak AL,Miller RF, Lipman MCI, Freedman AR, Ormerod LP, Johnson MA, Collins S,Lucas SB, on behalf of the BHIVA guidelines writing committee. BHIVA treatment guidelines for TB/HIV infection, February 2005. Available at:http://www.bhiva.org/files/file1001577.pdf (accessed 21/08/07).

US Department of Health and Human Services; Panel on Antiretroviral Guidelines for Adultsand Adolescents. Guidelines for the use of antiretroviral agents in HIV-infected adults andadolescents. October 10,2006; 1–113. Available at: http://www.aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf (accessed 21/08/07)

Table 1 Summary of the manufacturers’ dosage recommendations (unless stated other		wise) for combined use of protease inhibitors and rifamycins
Protease inhibitor	Rifabutin	Rifampicin	Refs
Protease inhibitors
Amprenavir	Rifabutin dose at least halved (150 mg daily or every other day, or 300mg three times per week). Amprenavir dose unchanged.	Not recommended (amprenavir levels markedly reduced).	1-3
Fosamprenavir	Rifabutin dose at least halved (150 mg daily or 300mg three times per week). Fosamprenavir dose unchanged.	Not recommended (amprenavir levels expected to be markedly reduced).	3-5
Indinavir	Rifabutin dose halved (150 mg daily or 300mg three times per week). Indinavir dose increased (1 to 1.2 g every 8 hours).	Not recommended (indinavir levels markedly reduced, rifampicin levels raised).	3, 6-8
Nelfinavir	Rifabutin dose at least halved (150 mg once daily or 300mg three times per week). Nelfinavir dose unchanged (1.25 g twice daily preferred) or increase to 1 g every 8 hours.	Not recommended (nelfinavir levels markedly reduced).	3, 9, 10
Ritonavir alone	Rifabutin dose reduced by at least 75 % (150 mg every other day or three times per week). Further dose reductions may be necessary.* Ritonavir dose unchanged.	May be used at usual doses, although limited data (ritonavir levels reduced). May lead to loss of virologic response.	3, 11
Saquinavir alone	Not recommended (saquinavir levels reduced).	Not recommended (saquinavir levels markedly reduced).	3
Ritonavir boosted protease inhibitors
Atazanavir/ritonavir	Rifabutin dose reduced by up to 75 % (150 mg every other day or three times per week). Atazanavir/ritonavir dose unchanged.	Not recommended (atazanavir levels markedly reduced).	3, 12, 13
Darunavir/ritonavir	Rifabutin dose reduced to 150mg every other day.	Not recommended (darunavir levels predicted to be markedly reduced).	14, 15
Fosamprenavir/ritonavir	Rifabutin dose reduced by at least 75 % (150 mg every other day or three times per week). Fosamprenavir/ritonavir dose unchanged.	Not recommended (amprenavir levels predicted to be markedly reduced).	3-5
Indinavir/ritonavir	Rifabutin dose reduced by at least 75 % (150 mg every other day or three times per week). Indinavir/ritonavir dose unchanged.	Not recommended (indinavir levels markedly reduced).	3, 16
Lopinavir/ritonavir	Rifabutin dose reduced by at least 75 % (150 mg every other day or three times per week). Lopinavir/ritonavir dose unchanged.	Not recommended (lopinavir levels markedly reduced). However, adjusted doses of lopinavir/ritonavir (800/200 mg or 400/400 mg twice daily) may overcome the pharmacokinetic interaction, but have a high incidence of elevated liver enzymes, and so if used, close monitoring is needed.	3, 17-19
Saquinavir/ritonavir	Rifabutin dose reduced by at least 75 % (150 mg every other day or three times per week). Appropriate saquinavir/ritonavir dose not established. Consider usual dose (1000/100 mg twice daily).	Rifampicin dose unchanged. Saquinavir/ritonavir 400/400 mg twice daily. Note that a regimen of 1000/100 mg twice daily with rifampicin was associated with severe hepatotoxicity, and the combination is contraindicated.	3, 20, 21
Tipranavir/ritonavir	Rifabutin dose reduced by at least 75 % (150 mg every other day or three times per week). Further dose reductions may be necessary. Tipranavir/ritonavir dose unchanged.	Not recommended (tipranavir levels predicted to be markedly reduced).	22, 23

Food increases bioavailability of atazanavir, darunavir, lopinavir/ritonavir soft capsules and solution, nelfinavir, saquinavir(all formulations) and tipranavir, but decreases that of indinavir.Food only minimally affects bioavailability of amprenavir,fosamprenavir, lopinavir/ritonavir tablets and ritonavir. Mixingritonavir with enteral feeds does not affect pharmacokineticsof ritonavir.

Clinical evidence,mechanism, importance and management

A single 600mg dose of indinavir was given to 7 HIV-positive subjects immediately after various types of meal. The protein, carbohydrate, fat and high-viscosity meals reduced AUC of indinavir by 68%, 45%, 34 % and 30%, respectively. The fat meal was associated with largest inter-subject variation in bioavailability. The effect of protein meal was attributed to fact that it raised gastric pH and therefore impaired absorption of indinavir (a weak base). The impairment of indinavir absorption caused by other meals, which did not alter gastric pH, may have been due to delayed gastric emptying (See reference number 1). A similar study comparing a full breakfast with light breakfasts (toast or cereal) on indinavir absorption found that full breakfast reduced absorption of indinavir by 78 % and reduced its maximum serum levels by 86%, while light breakfasts had no significant effect (See reference number 2). The manufacturers advise that indinavir is given 1 hour before or 2 hrs after meals,or with low-fat light meals only (See reference number 3,4). The US information gives examples of a light meal,such as dry toast with jam, juice, and coffee with skimmed milk and sugar; or corn flakes, skimmed milk and sugar (See reference number 4).

The manufacturers of atazanavir note that administration with a light or high-fat meal decreased wide variation in plasma levels

Darunavir with Ritonavir. The manufacturers of darunavir notes that relative bioavailability of darunavir (with low-dose ritonavir) is 30 % lower when it is given without food, compared with intake with food. Therefore,darunavir tablets should be taken with ritonavir and with food. They say that type of food does not affect exposure to darunavir (See reference number 7,8).

Lopinavir/Ritonavir. A moderate-fat meal increased AUC and maximum level of lopinavir capsules by 48 % and 23%, respectively, and a high-fat meal by 96 % and 43%, respectively. The corresponding increases for lopinavir solution were 80 % and 54 % for moderate-fat meal, and 130 % and 56 % for high-fat meal (See reference number 9). The manufacturers of lopina

vir/ritonavir soft capsules and oral solution say that it should be taken with food (See reference number 9,10). No clinically significant difference was seen in bioavailability of lopinavir/ritonavir tablets between fasting and fed subjects, therefore manufacturers say that it can be taken with or without food (See reference number 10,11).

Nelfinavir. When nelfinavir 400 or 800mg was given to 12 healthy subjects in fasted state, AUC was only 27 % to 50 % of that observed when nelfinavir was given with a meal (See reference number 12). Nelfinavir should be taken with

Saquinavir. The manufacturer of saquinavir hard capsules and tablets notes that, in a crossover study in 22 HIV-positive patients taking saquinavir/ritonavir 1000/100 mg twice daily and receiving three consecutive doses under fasting conditions or after a high-fat, high-calorie meal, AUC, maximum and minimum levels of saquinavir under fasting conditions were about 70 % lower than with a high-fat meal. There were no clinically significant differences in pharmacokinetic profile of ritonavir in fasting and fed conditions but ritonavir minimum level was about 30 % lower in fasting state, when compared with its administration with a meal (See reference number 15,16). Saquinavir/ritonavir should be given with,or up to 2 hrs after, a meal (See reference number 15-17).

Tipranavir. The US manufacturer states that bioavailability of tipranavir is increased if it is taken with a high-fat meal (See reference number 18). In a study,tipranavir capsules were given with a high-fat meal or a light snack of toast and skimmed milk. A high-fat meal enhanced AUC by 31%, but had minimal 16 % effect on peak tipranavir levels. The UK manufacturer states that food improves tolerability of tipranavir/ritonavir (See reference number 19). Both manufacturers recommend that tipranavir with ritonavir should be taken with

Amprenavir. Food resulted in a 25 % reduction in AUC of amprenavir, but no change in steady-state trough level. Consequently, manufacturers say it can be given with or without food,(See reference number 20,21) but US manufacturer says not with a high-fat meal (See reference number 21).

The manufacturer states that taking fosamprenavir tablet formulation with a high-fat meal did not alter plasma amprenavir pharmacokinetics (derived from fosamprenavir) when compared with taking this formulation in fasted state

Ritonavir. The US manufacturer notes that a meal increased absorption of ritonavir capsules by 13%, when compared with fasting state, whereas absorption of oral solution was decreased by 7 % (See reference number 24). See also Lopinavir and Saquinavir,above. Although these changes are modest manufacturers state that ritonavir capsules and solution are preferably taken with food (See reference number 24-26). There is also some evidence that mixing ritonavir with enteral feeds does not affect ritonavir pharmacokinetics. A 600mg dose of ritonavir oral solution was mixed with 240 mL of enteral feeds (either Advera or Ensure),chocolate milk or water within 1 hour of dosing. When given up to 15 minutes after a low-fat meal, pharmacokinetics of ritonavir in either of enteral feeds or milk were almost identical to those when ritonavir was given in water (See reference number 27).

Carver PL,Fleisher D, Zhou SY, Kaul D, Kazanjian P, Li C. Meal composition effects on theoral bioavailability of indinavir in HIV-infected patients. Pharm Res (1999) 16, 718–24.

Stone JA,Ju WD, Steritt A, Woolf EJ, Yeh KC, Deutsch P, Waldman S, Bjornsson TD. Effectof food on the pharmacokinetics of indinavir in man. Pharm Res (1996) 13 (Suppl 9), S414.

Crixivan (Indinavir sulfate). Merck Sharp & Dohme Ltd. UK Summary of product characteristics,May 2007.

Crixivan (Indinavir sulfate). Merck & Co.,Inc. US Prescribing information, November 2006.

Reyataz (Atazanavir sulfate). Bristol-Myers Squibb Pharmaceuticals Ltd. UK Summary ofproduct characteristics,April 2007.

Reyataz (Atazanavir sulfate). Bristol-Myers Squibb Company. US Prescribing information,March 2007.

Prezista (Darunavir ethanolate). Janssen-Cilag Ltd. UK Summary of product characteristics,July 2007.

Prezista (Darunavir). Tibotec,Inc. US Prescribing information, June 2006.

Kaletra Soft Capsules (Lopinavir/ritonavir). Abbott Laboratories Ltd. UK Summary of product characteristics,March 2007.

Kaletra (Lopinavir/ritonavir). Abbott Laboratories. US Prescribing information,January 2007.

Kaletra Tablets (Lopinavir/ritonavir). Abbott Laboratories Ltd. UK Summary of productcharacteristics,March 2007.

Quart BD,Chapman SK, Peterkin J, Webber S, Oliver S. Phase I safety, tolerance, pharmacokinetics and food effect studies of AG1343–a novel HIV protease inhibitor. The AmericanSociety for Microbiology in collaboration with NIH and CDC. 2(See reference number nd) National Conference Human Retroviruses and Related Infections, Washington DC, 1995. Abstract LB3.

Viracept (Nelfinavir mesilate). Roche Products Ltd. UK Summary of product characteristics,January 2007.

Viracept (Nelfinavir mesylate). Agouron Pharmaceuticals,Inc. US Prescribing information,January 2007.

Invirase Hard Capsules (Saquinavir mesilate). Roche Products Ltd. UK Summary of productcharacteristics,May 2007.

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.

Aptivus (Tipranavir). Boehringer Ingelheim Ltd. UK Summary of product characteristics,March 2007.

Agenerase (Amprenavir). GlaxoSmithKline UK. UK Summary of product characteristics,February 2007.

Agenerase (Amprenavir). GlaxoSmithKline. US Prescribing information,May 2005.

Telzir (Fosamprenavir calcium). GlaxoSmithKline UK. UK Summary of product characteristics,February 2007.

Lexiva (Fosamprenavir calcium). GlaxoSmithKline. US Prescribing information,June 2007.

Norvir (Ritonavir). Abbott Laboratories. US Prescribing information,January 2006.

Norvir Oral Solution (Ritonavir). Abbott Laboratories Ltd. UK Summary of product characteristics,May 2007.

Norvir Soft Capsules (Ritonavir). Abbott Laboratories Ltd. UK Summary of product characteristics,May 2007.

Bertz R,Shi H, Cavanaugh J, Hsu A. Effect of three vehicles, Advera:4.4pt; font-weight:normal; color:#000000″>(See reference number ®), Ensure:4.4pt; font-weight:normal; color:#000000″>(See reference number ®) and chocolate milk, on the bioavailability of an oral liquid formulation of Norvir (Ritonavir). Intersci Conf Antimicrob Agents Chemother (1996) 36, 5.

It is likely that phenobarbital and other barbiturates will increasethe metabolism of protease inhibitors, thereby reducing theirlevels and possibly resulting in failure of antiretrovirals. However,one case suggested that this may not have occurred withprimidone and ritonavir/saquinavir, although this should beviewed with caution.

Clinical evidence,mechanism, importance and management

The manufacturers of many of protease inhibitors predict that their levels may be reduced by phenobarbital, due to induction of cytochrome P450 isoenzyme CYP3A4 by which they are metabolised (see table 1 below,). There do not appear to be any controlled studies to demonstrate extent of pharmacokinetic interaction with different pro-tease inhibitors. Data from one case report of carbamazepine toxicity with ritonavir/saquinavir, , provide indirect evidence to suggest interaction with primidone is not clinically important. In this report,a patient taking an antiretroviral regimen including ritonavir and saquinavir had his antiepileptic medication changed from carbamazepine to primidone 500mg daily. The authors noted that during follow-up (duration not stated),viral load was still undetectable and seizures remained under control (See reference number 1). Primidone is metabolised to phenobarbital,and might have been expected to cause antiretroviral therapy failure. Alternatively, effect of ritonavir, which is a potent inhibitor of CYP3A4, may have been sufficient to offset increased clearance associated with phenobarbital.

Another patient(See reference number 2)taking phenobarbital,phenytoin and carbamazepine was found to have an unchanged phenobarbital level 2 days after switching from an antiretroviral regimen including indinavir to one containing ritonavir 300mg twice daily and saquinavir. His plasma levels of carbamazepine,, had doubled, and there was a 32.7 % drop in levels of phenytoin, .

The combination of protease inhibitors and barbiturates should be used with caution,with increased monitoring of antiviral efficacy.

Berbel Garcia A,Latorre Ibarra A, Porta Etessam J, Martinez Salio A, Perez Martinez DA, Saiz Diaz R, Toledo Heras M. Protease inhibitor-induced carbamazepine toxicity. Clin Neuropharmacol (2000) 23, 216–18.

Mateu-de Antonio J, Grau S, Gimeno-Bayón J-L, Carmona A. Ritonavir-induced carbamazepine toxicity. Ann Pharmacother (2001) 35, 125–6.

Table 1 Summary of the effect of the protease inhibitors and NNRTIs on cy		tochrome P450 isoenzymes
Antiviral	Substrate	Inhibits	Induces
Protease inhibitors
Amprenavir or Fosamprenavir	CYP3A4	CYP3A4
Atazanavir	CYP3A4	CYP3A4
Darunavir	CYP3A4	CYP3A4
Indinavir	CYP3A4	CYP3A4
Lopinavir	CYP3A4	CYP3A4
Nelfinavir	CYP3A4, CYP2C19, CYP2C9, CYP2D6	CYP3A4
Ritonavir	CYP3A4, CYP2D6	CYP3A4, CYP2D6	CYP3A4
Saquinavir	CYP3A4	CYP3A4
Tipranavir	CYP3A4	CYP3A4, CYP2D6	CYP3A4
NNRTIs (Non-nucleoside reverse transcriptase inhibitors)
Delavirdine	CYP3A4, CYP2D6	CYP3A4, CYP2C9, CYP2D6, CYP2C19
Efavirenz	CYP3A4, CYP2B6	CYP3A4, CYP2C9, CYP2C19	CYP3A4
Nevirapine	CYP3A4		CYP3A4

Probenecid inhibits renal secretion of active metabolite of oseltamivir and markedly raises its plasma levels, but this is notclinically relevant because of wide safety margin of oseltamivir. There was no pharmacokinetic interaction between amoxicillin and oseltamivir,and cimetidine did not alter oseltamivir pharmacokinetics.

In a study in healthy subjects,oseltamivir 75mg twice daily for 4.5 days had no effect on pharmacokinetics of a single 500mg dose of amoxicillin given with last dose of oseltamivir. Similarly, amoxicillin had no effect on pharmacokinetics of active metabolite of oseltamivir (See reference number 1).

In a crossover study in 18 healthy subjects cimetidine 400mg every 6 hrs for 4 days had no effect on pharmacokinetics of a single 150mg dose of oseltamivir given on day 2 (See reference number 1)

In a crossover study in 18 healthy subjects probenecid 500mg every 6 hrs for 4 days approximately halved renal clearance of active metabolite of oseltamivir, and increased its AUC by about 2.5-fold when a single 150mg dose of oseltamivir was given on day 2 (See reference number 1).

Probenecid appears to completely inhibit renal tubular secretion of active metabolite of oseltamivir via anionic renal transporter process. Oseltamivir does not alter amoxicillin pharmacokinetics, suggesting minimal potential to inhibit renal anionic transport process (See reference number 1). Cimetidine, which inhibits renal tubular secretion of drugs via cationic secretion transport process, had no effect on oseltamivir.

Probenecid markedly increased AUC of active metabolite of oseltamivir, but because of large safety margin of oseltamivir, this increase is not considered to be clinically relevant (See reference number 1-3). Oseltamivir did not alter amoxicillin pharmacokinetics,and is therefore unlikely to interact with other renally secreted organic acids. Other drugs that are involved in active anionic tubular secretion mechanism are also unlikely to interact. Cimetidine does not interact with oseltamivir, and other drugs that are inhibitors of renal cationic secretion transport process are unlikely to interact (See reference number 1).

Although UK manufacturer does state that clinically important drug interactions involving competition for renal tubular secretion are unlikely, they recommend care should be taken when prescribing oseltamivir to patients taking other similarly excreted drugs with a narrow therapeutic margin, and they give chlorpropamide, methotrexate, and phenylbutazone as examples (See reference number 2).

1. Hill G,Cihlar T, Oo C, Ho ES, Prior K, Wiltshire H, Barrett J, Liu B, Ward P. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions viarenal secretion–correlation of in vivo and in vitro studies. Drug Metab Dispos (2002) 30, 13–

19.

Tamiflu (Oseltamivir phosphate). Roche Products Ltd. UK Summary of product characteristics,March 2007.

Tamiflu (Oseltamivir phosphate). Roche Pharmaceuticals. US Prescribing information,July2007.

The concurrent use of zidovudine and ganciclovir produces a verymarked increase in haematological toxicity,without any apparentincrease in efficacy. Didanosine serum levels are raised by ganciclovir, but there is some evidence suggesting that efficacy ofganciclovir prophylaxis is reduced. Ganciclovir does not appearto interact with stavudine,and there is no clinically importantpharmacokinetic interaction between ganciclovir and zalcitabine.Until further information is available, manufacturers of lamivudine advise avoidance of intravenous ganciclovir.

Buffered didanosine 200mg twice daily was given to 12 HIV-positive patients with oral ganciclovir 1 g three times daily. When didanosine was given 2 hrs before ganciclovir, maximum serum levels and AUC of didanosine were raised by about 47 % and 83%, respectively, and those of ganciclovir were decreased by about 26 % and 22%, respectively. When didanosine was given simultaneously with ganciclovir, maximum serum levels and AUC of didanosine were similarly raised, by about 53 % and 77%, respectively, but those of ganciclovir were unchanged. The renal clearance of didanosine was not significantly changed by ganciclovir (See reference number 1). Similar increases in didanosine levels with ganciclovir given intravenously(See reference number 2) and high-dose oral ganciclovir 2 g every 8 hrs have also been reported (See reference number 3). However, in contrast, an earlier study found that pharmacokinetics of didanosine (sachet preparation) were not altered by intravenous ganciclovir (See reference number 4).

Rates of dose-limiting intolerance to combination of didanosine and ganciclovir were reported to be similar to those seen with didanosine alone in one small study (15 of 32 patients tolerated usual doses of didanosine with ganciclovir) (See reference number 5). Analysis of results of a large randomised study unexpectedly suggested that there was an increased risk of cytomegalovirus infection in those patients taking ganciclovir and didanosine, when compared with those not taking didanosine (See reference number 6).

In a study of 11 HIV-positive patients, oral ganciclovir 1 g three times daily had no significant effect on pharmacokinetics of stavudine 40mg twice daily, nor were pharmacokinetics of ganciclovir affected by stavudine (See reference number 8). There were no serious or severe adverse events attributed to combination.

In a study in 10 HIV-positive patients, zalcitabine 750 micrograms every 8 hrs increased AUC of oral ganciclovir 1 g three times daily by 22%. There was no change in zalcitabine pharmacokinetics. There were no serious or severe adverse events attributed to combination (See reference number 8).

The efficacy of zidovudine 100 or 200mg every 4 hours, given alone or with intravenous ganciclovir 5 mg/kg twice daily for 14 days, then once daily for 5 days of each week, was assessed in 40 patients for treatment of cytomegalovirus (CMV). Severe haematological toxicity occurred in all of first 10 patients given zidovudine 1.2 g daily and ganciclovir. Consequently dose of zidovudine was reduced to 600mg daily. Overall 82 % of 40 patients enrolled experienced profound and rapid toxicity (anaemia, neutropenia, leucopenia, gastrointestinal disturbances). Zidovudine dosage reductions to 300mg daily were needed in many patients. No change in pharmacokinetics of zidovudine or ganciclovir was noted (See reference number 9).

Increased toxicity (myelotoxicity and pancytopenia) following use of both drugs has also been reported elsewhere (See reference number 11,12)

In contrast to first study,(See reference number 9) a specific study on pharmacokinetics of zidovudine and ganciclovir in HIV-positive subjects reported that oral ganciclovir increased maximum levels and AUC of zidovudine by 38 % and 15%, respectively, without altering renal clearance. Zidovudine did not alter ganciclovir pharmacokinetics (See reference number 1).

It is not known why ganciclovir increases levels of didanosine and zidovudine: it does not appear to be due to competition for active secretion by kidney tubules (See reference number 1)

The toxicity of zidovudine/ganciclovir combination may be simply additive,(See reference number 9) but in vitro studies with three human cell lines found synergistic cytotoxicity when both drugs were used (See reference number 13)

There is some in vitro evidence to suggest that ganciclovir antagonises anti-HIV activity of zidovudine and didanosine (See reference number 14)

The interactions between ganciclovir and didanosine or zidovudine would appear to be established, but clinical importance is uncertain. Zidovudine seems to be associated with greater toxicity than didanosine. However, there is also some evidence suggesting reduced ganciclovir efficacy in presence of didanosine, and this requires further study. Close and careful monitoring is required if either combination is used.

Ganciclovir does not appear to alter pharmacokinetics of stavudine or zalcitabine. Zalcitabine increased ganciclovir levels to a minor extent,although this is probably not clinically important.

1.

Cimoch PJ,Lavelle J, Pollard R, Griffy KG, Wong R, Tarnowski TL, Casserella S, Jung D.Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine,and probenecid in HIV-infected subjects. J Acquir Immune Defic Syndr Hum Retrovirol (1998) 17, 227–34.

2.

Frascino RJ,Anderson RD, Griffy KG, Jung D, Yu S. Two multiple dose crossover studiesof IV ganciclovir (GCV) and didanosine (ddI) in HIV infected persons. Intersci Conf Antimicrob Agents Chemother (1995) 35, 6.

3.

Jung D,Griffy K, Dorr A, Raschke R, Tarnowski TL, Hulse J, Kates RE. Effect of high-doseoral ganciclovir on didanosine disposition in human immunodeficiency virus (HIV)-positivepatients. J Clin Pharmacol (1998) 38, 1057–62.

4.

Hartman NR,Yarchoan R, Pluda JM, Thomas RV, Wyvill KM, Flora KP, Broder S, JohnsDG. Pharmacokinetics of 2:6.6pt; font-weight:normal; color:#000000″>′,3:6.6pt; font-weight:normal; color:#000000″>′-dideoxyinosine in patients with severe human immunodeficiency infection. II. The effects of different oral formulations and the presence of other medications. Clin Pharmacol Ther (1991) 50, 278–85.

5.

Jacobson MA,Owen W, Campbell J, Brosgart C, Abrams DI. Tolerability of combined ganciclovir and didanosine for the treatment of cytomegalovirus disease associated with AIDS.Clin Infect Dis (1993) 16 (Suppl 1), S69–S73.

6.

Brosgart CL,Louis TA, Hillman DW, Craig CP, Alston B, Fisher E, Abrams DI, Luskin-Hawk RL, Sampson JH, Ward DJ, Thompson MA, Torres RA. A randomized, placebo-controlled trial of the safety and efficacy of oral ganciclovir for prophylaxis of cytomegalovirusdisease in HIV-infected individuals. AIDS (1998) 12, 269–77.

7.

Epivir (Lamivudine). GlaxoSmithKline UK. UK Summary of product characteristics,March2007.

8.

Jung D,AbdelHameed MH, Teitelbaum P, Dorr A, Griffy K. The pharmacokinetics and safety profile of oral ganciclovir combined with zalcitabine or stavudine in asymptomatic HIV-and CMV-seropositive patients. J Clin Pharmacol (1999) 39, 505–12.

9.

Hochster H,Dieterich D, Bozzette S, Reichman RC, Connor JD, Liebes L, Sonke RL, SpectorSA, Valentine F, Pettinelli C, Richman DD. Toxicity of combined ganciclovir and zidovudinefor cytomegalovirus disease associated with AIDS. An AIDS clinical trials group study. Ann Intern Med (1990) 113, 111–17.

Millar AB,Miller RF, Patou G, Mindel A, Marsh R, Semple SJG. Treatment of cytomegalovirus retinitis with zidovudine and ganciclovir in patients with AIDS: outcome and toxicity.Genitourin Med (1990) 66, 156–8.

Jacobson MA,de Miranda P, Gordon SM, Blum MR, Volberding P, Mills J. Prolonged pancytopenia due to combined ganciclovir and zidovudine therapy. J Infect Dis (1988) 158, 489–

90.

Pinching AJ,Helbert M, Peddle B, Robinson D, Janes K, Gor D, Jeffries DJ, Stoneham C,Mitchell D, Kocsis AE, Mann J, Forster SM, Harris JRW. Clinical experience with zidovudine for patients with acquired immune deficiency syndrome and acquired immune deficiency syndrome-related complex. J Infect (1989) 18 (Suppl 1), 33–40.

Prichard MN,Prichard LE, Baguley WA, Nassiri MR, Shipman C. Three-dimensional analysis of the synergistic cytotoxicity of ganciclovir and zidovudine. Antimicrob Agents Chemother (1991) 35, 1060–5.

Medina DJ,Hsiung GD, Mellors JW. Ganciclovir antagonizes the anti-human immunodeficiency virus type 1 activity of zidovudine and didanosine in vitro. Antimicrob Agents Chemother (1992) 36, 1127–30.

Probenecid reduces loss of zalcitabine and zidovudine, increasing their serum levels. The combination of zalcitabine andprobenecid is well tolerated, but incidence of adverse effectsappears to be greatly increased with combination of probenecid and zidovudine.

In a single-dose study,12 HIV-positive or AIDS patients were given zalcitabine 1.5mg alone or with probenecid 500 mg,given 8 and 2 hrs before then 4 hrs after. The renal clearance of zalcitabine was decreased 42 % by probenecid, its half-life was increased by 47 % and its AUC was increased by 54 % (See reference number 1).

In 12 patients with AIDS or AIDS-related complex concurrent use of zidovudine and probenecid 500mg every 8 hrs for 3 days increased AUC of zidovudine by an average of 80 % (range 14 to 192%) (See reference number 2)

Other studies in patients(See reference number 3-5) and healthy subjects(See reference number 6) found that probenecid roughly doubled AUC of zidovudine when given in a variety of dosing schedules (See reference number 3,4). However, effects on zidovudine pharmacokinetics were minimal if two drugs were given 6 hrs apart (See reference number 5). Another report describes a very high incidence of rashes in 6 out of 8 HIV-positive men given zidovudine with probenecid 500mg every 6 hours. The rash and other symptoms (such as malaise, fever and myalgia) were sufficiently severe for probenecid to be withdrawn in 4 of them (See reference number 7). A later study found that when using only 250mg of probenecid every 8 hrs AUC of zidovudine was increased by 70 % but adverse effects still occurred, although incidence was possibly somewhat lower (See reference number 8). Conversely, others reported successful use of probenecid 500mg three times daily with a reduced dose of zidovudine (600 mg daily) in 7 patients without any occurrence of rash (See reference number 9).

Experimental clinical evidence indicates that probenecid reduces metabolism (glucuronidation) of zidovudine by liver enzymes, and inhibits renal secretion of zidovudine glucuronide metabolite (See reference number 2-4,6,10,11). The interaction with zalcitabine is presumably due to inhibition of zalcitabine secretion in renal tubules (See reference number 1).

The concurrent use of zidovudine and probenecid should be well monitored to ensure that zidovudine levels do not rise excessively. Reduce zidovudine dosage as necessary. However, apparent increase in adverse effects during concurrent use seen by one group of researchers(See reference number 7,8)should be borne in mind.

The concurrent use of zalcitabine and probenecid was well tolerated, and because zalcitabine half-life is short compared to its dosing schedule significant accumulation would not be expected.

Massarella JW,Nazareno LA, Passe S, Min B. The effect of probenecid on the pharmacokinetics of zalcitabine in HIV-positive patients. Pharm Res (1996) 13, 449–52.

Kornhauser DM,Petty BG, Hendrix CW, Woods AS, Nerhood LJ, Bartlett JG, Lietman PS.Probenecid and zidovudine metabolism. Lancet (1989) 2, 473–5.

Hedaya MA,Elmquist WF, Sawchuk RJ. Probenecid inhibits the metabolic and renal clearances of zidovudine (AZT) in human volunteers. Pharm Res (1990) 7, 411–17.

de Miranda P,Good SS, Yarchoan R, Thomas RV, Blum MR, Myers CE, Broder S. Alteration of zidovudine pharmacokinetics by probenecid in patients with AIDS or AIDS-relatedcomplex. Clin Pharmacol Ther (1989) 46, 494–500.

McDermott J,Kennedy J, Ellis-Pegler RB, Thomas MG. Pharmacokinetics of zidovudineplus probenecid. J Infect Dis (1992) 166, 687–8.

Campion JJ,Bawdon RE, Baskin LB, Barton CI. Effect of probenecid on the pharmacokinetics of zidovudine and zidovudine glucuronide. Pharmacotherapy (1990) 10, 235.

Petty BG,Kornhauser DM, Lietman PS. Zidovudine with probenecid: a warning. Lancet (1990) 1, 1044–5.

Petty BG,Barditch-Crovo PA, Nerhood L, Kornhauser DM, Kuwahara S, Lietman PS. Unexpected clinical toxicity of probenecid (P) with zidovudine (Z) in patients with HIV infection. Intersci Conf Antimicrob Agents Chemother (1991) 31, 323.

Duckworth AS,Duckworth GW, Henderson G, Contreras G. Zidovudine with probenecid.Lancet (1990) 336, 441.

Sim SM,Back DJ, Breckenridge AM. The effect of various drugs on the glucuronidation ofzidovudine (azidothymidine; AZT) by human liver microsomes. Br J Clin Pharmacol (1991) 32, 17–21.

Kamali F,Rawlins MD. Influence of probenecid and paracetamol (acetaminophen) on zidovudine glucuronidation in human liver in vitro. Biopharm Drug Dispos (1992) 13, 403–9.

In patients with poor gastric acid production, orange juice andglutamic acid increase absorption of delavirdine.

Clinical evidence,mechanism, importance and management

When glutamic acid 1.36 g three times daily was given with delavirdine 400mg three times daily to 8 HIV-positive subjects with gastric hypoacidity, AUC of delavirdine was increased by 50 % (See reference number 1). Similarly,orange juice increased delavirdine absorption by 50 % to 70 % in subjects with gastric hypoacidity, but had less effect (0 to 30%) in those with normal gastric acidity. However, despite use of orange juice, AUC of delavirdine was still about 50 % lower in patients with gastric hypoacidity than those without (See reference number 2).

Delavirdine is a weak base that is poorly soluble at neutral pH (note that antacids reduce its absorption,see NNRTIs + Drugs that affect gastric pH interaction). Therefore, in subjects with gastric hypoacidity, absorption of delavirdine is reduced, and substances that lower gastric pH increase its absorption.

The clinical value of using glutamic acid or acidic beverages with delavirdine is unknown. Nevertheless, manufacturer recommends that, in patients with achlorhydria, delavirdine should be taken with an acidic beverage such as orange or cranberry juice (See reference number 3).

Morse GD,Adams JM, Shelton MJ, Hewitt RG, Cox SR, Chambers JH. Gastric acidification increases delavirdine mesylate (DLV) exposure in HIV+ subjects with gastric hypoacidity(GH). Clin Pharmacol Ther (1996) 59, 141.

Shelton MJ,Hewitt RG, Adams JM, Cox SR, Chambers JH, Morse GD. Delavirdine malabsorption in HIV-infected subjects with spontaneous gastric hypoacidity. J Clin Pharmacol (2003) 43, 171–9.

Rescriptor (Delavirdine mesylate). Pfizer Inc. US Prescribing information,June 2006.

Rifabutin and rifampicin (rifampin) cause a very marked fall indelavirdine plasma levels: rifabutin levels are raised when delavirdine dose is increased to compensate for this. Rifabutin doesnot affect efavirenz levels,whereas efavirenz decreases rifabutin levels. There is usually no important interaction between rifabutin and nevirapine,although some patients may have a higher riskof rifabutin adverse effects. Neither efavirenz nor nevirapine affect rifampicin levels, but rifampicin modestly reduces levels of these NNRTIs, and thereis some debate about whether it is necessary to increase their dose.

Clinical evidence,mechanism, importance and management

In a controlled study in 7 HIV-positive patients taking delavirdine mesilate 400mg three times daily for 30 days, addition of rifabutin 300mg daily from days 16 to 30 caused a fivefold increase in delavirdine clearance, and an 84 % fall in steady-state plasma levels (See reference number 1). This was presumably due to enzyme-inducing effects of rifabutin. A similar study using rifampicin in place of rifabutin found that rifampicin caused a 27-fold increase in clearance of delavirdine, and steady-state plasma levels became almost undetectable (See reference number 2).

In another study,(See reference number 3) where dose of delavirdine was titrated to achieve a trough level of at least 5 micromol/L, AUC of rifabutin was found to increase by 242%.

It has been recommended that combination of delavirdine and rifampicin should be considered as contraindicated because effects of interaction are so large (See reference number 2). The CDC in US and manufacturer recommend that neither rifabutin nor rifampicin should be used with delavirdine (See reference number 4,5)

Rifabutin. In a study in healthy subjects concurrent use of efavirenz 600mg once daily and rifabutin 300mg once daily for 2 weeks resulted in a modest 38 % decrease in AUC of rifabutin and a 45 % decrease in minimum levels, but no change in efavirenz levels (See reference number 6). The CDC in US state that combination is probably clinically useful, and they suggest increasing dose of rifabutin to 450mg or 600mg daily, or 600mg two to three times weekly (See reference number 4). In one study doubling rifabutin dose from 300mg twice weekly to 600mg twice weekly when starting efavirenz resulted in rifabutin AUCs that were 20 % higher than baseline values (See reference number 7). However,in one analysis, 8 of 35 patients (23%) taking efavirenz and given rifabutin 450mg once daily were found to have sub-therapeutic rifabutin levels, and they were switched to isoniazid (See reference number 8). Concurrent use should therefore be closely monitored.

In patients with HIV and tuberculosis concurrent use of HAART including efavirenz 600mg once daily with antitubercular therapy including rifampicin 480 to 720mg daily decreased AUC of efavirenz by 22 % and decreased trough concentration by 25 % (although large interpatient variability was observed). Overall pharmacokinetics of efavirenz 800mg daily with rifampicin were similar to those

of efavirenz 600mg daily without rifampicin. The pharmacokinetics of rifampicin were not substantially altered by efavirenz (See reference number 9). A similar 26 % reduction in efavirenz AUC was reported in a study in healthy subjects (See reference number 10). The CDC in US suggest that it may be advisable to increase efavirenz dose to 800mg daily when used with rifampicin,(See reference number 4) and UK manufacturer also recommends this (See reference number 11). However, in one analysis 7 of 9 patients receiving rifampicin and efavirenz 800mg daily developed significant clinical toxicity and were found to have efavirenz levels markedly higher than therapeutic range (See reference number 12). In another study in Thai patients taking rifampicin,median efavirenz plasma levels were comparable between those receiving 600mg daily and 800mg daily and similar virological outcomes were seen (See reference number 13,14). Therefore,a 600mg dose of efavirenz may be sufficient in some patients. Concurrent use should be well monitored.

Rifabutin. In one study, pharmacokinetics of nevirapine were only minimally affected by rifabutin in 19 patients, when compared with historical data (See reference number 15). The manufacturer notes that concurrent use of rifabutin with nevirapine caused a minor 9 % increase in nevirapine clearance and a 17 % increase in its AUC, and a 28 % increase in maximum steady-state rifabutin levels (See reference number 16,17). They say that because of high intersubject variability, some patients may experience large increases in rifabutin exposure and may be at higher risk of adverse effects. Concurrent use should be well monitored and undertaken cautiously. The CDC in US state that combination of nevirapine and rifabutin can be used (See reference number 4).

Rifampicin (Rifampin). The manufacturer states that AUC of nevirapine was reduced by 58 % by rifampicin in 14 subjects, when compared with historical data. There was no change in steady-state rifampicin pharmacokinetics (See reference number 16,17). Based on these pharmacokinetic data, manufacturer suggests that concurrent use of rifampicin with nevirapine is not recommended, and that rifabutin may be considered instead, with close monitoring of adverse effects (See reference number 16,17). A further study in HIV-positive patients with tuberculosis found that rifampicin caused a 31 % decrease in AUC of nevirapine and a non-significant 21 % decrease in its trough concentration (See reference number 18). The authors of this study suggested that there is probably no need to increase nevirapine dose, since trough levels were still sufficiently above level needed for antiviral activity (See reference number 18). Moreover, subsequent observational data supported continued efficacy of standard dose nevirapine when it was used with rifampicin (See reference number 19). Similarly, others have reported successful use of nevirapine with twice weekly rifampicin with little effect on trough nevirapine levels (See reference number 20). In yet another study, concurrent use of rifampicin and nevirapine reduced nevirapine levels by about 18 % with no reduction in virological response, although proportion of patients with trough levels below recommended level was much higher (29.7% versus 6.8%) at 8 weeks (See reference number 21). In contrast, in another study in 13 patients taking nevirapine 200mg twice daily, addition of rifampicin 450mg or 600mg daily caused a 46 % reduction in AUC of nevirapine, and a 53 % reduction in minimum levels, with 8 of patients having a nevirapine trough level below therapeutic range (3 micrograms/mL). In 7 of patients who had a reduction in minimum levels to less than therapeutic range, increasing dose of nevirapine to 300mg twice daily for 2 weeks increased levels to above therapeutic range in all patients without increasing adverse effects (See reference number 22). The CDC in US state that combination of nevirapine and rifampicin should only be used if clearly indicated and with careful monitoring, because of insufficient data on whether dose adjustments are necessary (See reference number 4). Further study is needed.

Borin MT,Chambers JH, Carel BJ, Freimuth WW, Aksentijevich S, Piergies AA. Pharmacokinetic study of the interaction between rifabutin and delavirdine mesylate in HIV-1 infected patients. Antiviral Res (1997) 35, 53–63.

Borin MT,Chambers JH, Carel BJ, Gagnon S, Freimuth WW. Pharmacokinetic study of theinteraction between rifampin and delavirdine mesylate. Clin Pharmacol Ther (1997) 61, 544–

53.

Cox SR,Herman BD, Batts DH, et al. Delavirdine and rifabutin: pharmacokinetic evaluationin HIV-1 patients with concentration-targeting of delavirdine [abstract no. 344]. 5(See reference number th) Conference on Retroviruses and Opportunistic Infections, Chicago, 1998.

Centers for Disease Control and Prevention. Updated guidelines for the use of rifamycins forthe treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR (2004) 53,37.

Rescriptor (Delavirdine mesylate). Pfizer Inc. US Prescribing information,June 2006.

Benedek IH,Fiske WD, White SJ, Stevenson D, Joseph JL, Kornhauser DM. Pharmacokinetic interaction between multiple doses of efavirenz and rifabutin in healthy volunteers [abstract no. 461]. Clin Infect Dis (1998) 27, 1008.

Weiner M,Benator D, Peloquin CA, Burman W, Vernon A, Engle M, Khan A, Zhao Z; theTuberculosis Trials Consortium. Evaluation of the drug interaction between rifabutin and efavirenz in patients with HIV infection and tuberculosis. Clin Infect Dis (2005) 41, 1343–9.

Spradling P,Drociuk D, McLaughlin S, Lee LM, Peloquin CA, Gallicano K, Pozsik C, Onorato I, Castro KG, Ridzon R. Drug-drug interactions in inmates treated for human immunodeficiency virus and Mycobacterium tuberculosis infection or disease: an institutional tuberculosis outbreak. Clin Infect Dis (2002) 35, 1106–12.

López-Cortés LF,Ruiz-Valderas R, Viciana P, Alarcón-González A, Gómez-Mateos J, León-Jimenez E, Sarasa-Nacenta M, López-Pua Y, Pachón J. Pharmacokinetic interactions between efavirenz and rifampicin in HIV-infected patients with tuberculosis. Clin Pharmacokinet (2002) 41, 681–90.

Benedek I,Joshi A, Fiske WD, et al. Pharmacokinetic interaction between efavirenz and rifampin in healthy volunteers. 12(See reference number th)World AIDS Conference, Geneva, June 28-Jul 3 1998. 829.

Sustiva (Efavirenz). Bristol-Myers Squibb Pharmaceuticals Ltd. UK Summary of productcharacteristics,May 2007.

Brennan-Benson P,Lyus R, Harrison T, Pakianathan M, Macallan D. Pharmacokinetic interactions between efavirenz and rifampicin in the treatment of HIV and tuberculosis: one sizedoes not fit all. AIDS (2005) 19, 1541–3.

Manosuthi W,Sungkanuparph S, Thakkinstian A, Vibhagool A, Kiertiburanakul S, Rattanasiri S, Prasithsirikul W, Sankote J, Mahanontharit A, Ruxrungtham K. Efavirenz levels and24-week efficacy in HIV-infected patients with tuberculosis receiving highly active antiretroviral therapy and rifampicin. AIDS (2005) 19, 1481–6.

Manosuthi W,Kiertiburanakul S, Sungkanuparph S, Ruxrungtham K, Vibhagool A, Rattanasiri S, Thakkinstian A. Efavirenz 600 mg/day versus efavirenz 800 mg/day in HIV-infectedpatients with tuberculosis receiving rifampicin: 48 weeks results. AIDS (2006) 20, 131–2.

Maldonado S,Lamson M, Gigliotti M, Pav JW, Robinson P. Pharmacokinetic interaction between nevirapine and rifabutin. Intersci Conf Antimicrob Agents Chemother (1999) 39, 21.

Viramune (Nevirapine anhydrate). Boehringer Ingelheim Ltd. UK Summary of product characteristics,January 2007.

Viramune (Nevirapine). Boehringer Ingelheim Pharmaceuticals,Inc. US Prescribing information, June 2007.

Ribera E,Pou L, Lopez RM, Crespo M, Falco V, Ocaña I, Ruiz I, Pahissa A. Pharmacokineticinteraction between nevirapine and rifampicin in HIV-infected patients with tuberculosis. J Acquir Immune Defic Syndr (2001) 28, 450–3.

Oliva J,Moreno S, Sanz J, Ribera E, Pérez Molina JAÒ, Rubio R, Casas E, Mariño A. Coadministration of rifampin and nevirapine in HIV-infected patients with tuberculosis. AIDS (2003) 17, 637–8.

Dean GL,Back DJ, de Ruiter A. Effect of tuberculosis therapy on nevirapine trough plasmaconcentrations. AIDS (1999) 13, 2489–90.

Manosuthi W,Sungkanuparph S, Thakkinstian A, Rattanasiri S, Chaovavanich A, Prasithsirikul W, Likanonsakul S, Ruxrungtham K. Plasma nevirapine levels and 24-week efficacyin HIV-infected patients receiving nevirapine-based highly active antiretroviral therapy withor without rifampicin. Clin Infect Dis (2006) 43, 253–5.

Ramachandran G,Hemanthkumar AK, Rajasekaran S, Padmapriyadarsini C, Narendran G,Sukumar B, Sathishnarayan S, Raja K, Kumaraswami V, Swaminathan S. Increasing nevi-rapine dose can overcome reduced bioavailability due to rifampicin coadministration. J Acquir Immune Defic Syndr (2006) 42, 36–41.

Khakoo S,Glue P, Grellier L, Wells B, Bell A, Dash C, Murray-Lyon I, Lypnyj D, FlanneryB, Walters K, Dusheiko GM. Ribavirin and interferon alfa-2b in chronic hepatitis C: assessment of possible pharmacokinetic and pharmacodynamic interactions. Br J Clin Pharmacol (1998) 46, 563–70.

Glue P,Rouzier-Panis R, Raffanel C, Sabo R, Gupta SK, Salfi M, Jacobs S, Clement RP. Adose-ranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis C. TheHepatitis C Intervention Therapy Group. Hepatology (2000) 32, 647–53.