Atazanavir pharmacokinetics

Pharmacology Atazanavir is an azapeptide HIV-1 protease inhibitor. The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1-infected cells, thus preventing formation of mature virions. Pharmacokinetics ... 

Effect of food - Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. 

Atazanavir is an azapeptide PI with a pharmacokinetic profile that allows once-daily dosing. It should be taken with a light meal to enhance bioavailability. Atazanavir requires an acidic medium for absorption and exhibits pH-dependent aqueous solubility therefore, separation of ingestion from acid-reducing agents by at least 12 hours is recommended. Atazanavir is able to penetrate both the cerebrospinal and seminal fluids. The plasma half-life is 6-7 hours, which increases to approximately 11 hours when -administered with ritonavir. The primary route of elimination is biliary atazanavir should not be given to patients with severe hepatic insufficiency. 

Bruce RD, Altice FL. Three case reports of a clinical pharmacokinetic interaction with buprenorphine and atazanavir plus ritonavir. AIDS (2006) 20, 783-4. 

Atazanavir, given for 14 days, had little effect on the steady-state pharmacokinetics of methadone in 16 patients treated for opiate addiction, and symptoms of opiate withdrawal or excess were not detected. ... 

Buffered didanosine decreases the AUC of indinavir, and the drugs shouid be given one hour apart. Buffered didanosine interacts simiiarly with atazanavir. Tipranavir with low-dose ritonavir modestly reduced the AUC of abacavir and zidovudine, and such combinations are not recommended in the UK. The changes in pharmacokinetics seen when giving other combinations of protease inhibitors with NRTIs do not appear to be clinically significant. Protease inhibitors do not affect the intracellular activation of NRTIs. 

Lamivudine metabolism does not involve the cytochrome P450 isoenzyme CYP3A4. Therefore it is unlikely that it will interact with drugs, such as the protease inhibitors, whieh are metabolised by this system. No pharmacokinetic interaction appears to oeeur between lamivudine and amprenavir, - atazanavir, -" indinavir, and nelfinavir. The manufacturer of lopinavir/ritonavir notes that lamivudine did not alter the pharmacokinetics of lopinavir, - and tipranavir plus low-dose ritonavir did not cause a signifieant ehange in the AUC of lamivudine. - ... 

The manufacturer of atazanavir -" notes that there was no pharmacokinetic interaction with stavudine. 

The pharmacokinetics of atazanavir 400 mg daily were not affected by the concurrent use of ketoconazole 200 mg daily for 7 days. ... 

Bristol-Myers Squibb Company. Re Reyataz (atazanavir sulfate) with or without Norvir (ritonavir) and proton pump inhibitors should not be coadm inister important new pharmacokinetic data, December 2004. Available at htq> //www. fda.gov/oashi/aids/listserv/ 2004/reyataz.pdf (accessed 21/08/07). 

Kiser JJ, Lichtenstein Anderson PL, Fletcher CV. Effects of esomeprazole on the pharmacokinetics of atazanavir and fosamprenavir in a patient with human immunodeficiency virus infection. Pharmacodierapy (200Q 26, 511-14. 

Food increases the 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 the bioavailability of amprenavir, fosamprenavir, lopinavir/ritonavir tablets and ritonavir. Mixing ritonavir with enteral feeds does not affect the pharmacokinetics of ritonavir. 

Nelfinavir approximately doubles the sierum levels of azithromycin, but the ciinical significance of this is uncertain. Single doses of azithromycin have no effect on the levels of indinavir and nelfinavir. Ritonavir and atazanavir increase clarithromycin leveis. Amprenavir, indinavir and saquinavir do not have a clinically significant effect on clarithromycin pharmacokinetics. Clarithromycin has no important effect on the pharmacokinetics of amprenavir, atazanavir, darunavir, indinavir or ritonavir, but it increases tipranavir levels. Although both clarithromycin and erythromycin markedly raise saquinavir levels, this is not considered clinically important for short courses of these antibacteriais. 

MummaneniV,RandallD,ChabuelD,GeraldesM,0 MaraE Steady-state pharmacokinetic interaction study of atazanavir with cl ithromycin in healthy subjects Intersci Conf Antimicrob Agents Chemoffier (2002) 42,275. 

Quinidine sulphate 200 mg was given to 10 healthy subjects, followed 1 hour later by a single 400-mg dose of indinavir. Quinidine had no clinically significant effects on the pharmacokinetics of indinavir. However, indinavir is predicted to increase quinidine levels, and the US manufacturer recommends caution and monitoring of quinidine ieveis. Lopinavir/ritonavir is also predicted to increase quinidine levels, and the combination should be monitored. Similarly, atazanavir/ritonavir, darunavir/ritonavir, amprenavir and fosamprenavir ate predieted to increase quinidine levels, and the UK manufacturers contraindieate the combinations "" while the US manufacturers recommend monitoring quinidine concentrations. Conversely, for saquinavir/ritonavir, the UK manufacturer recommends caution and monitoring quinidine levels, and the US manufacturer eontraindicates the combination. Both the UK and US manufacturers contraindicate the use of quinidine with nelfinavir, ritonavir or tipranavir/ritonavir. ... 

Various dual combinations of proteas e inhibitors have been tried, or are us ed, to boos t the levels and cons equently the efficacy of one of the proteas e inhibitors . Ritonavir is the mos t potent at boos ting levels of the other proteas e inhibitors , and current guidelines recommend the us e of low-dos e ritonavir in combination with atazanavir, darunavir, fos amprenavir, lopinavir, s aquina-vir, or tipranavir. Some proteas e inhibitor combinations may re-s ult in additive toxicity (indinavir and ritonavir or atazanavir). Although this monograph s ummaris es the pharmacokinetic interactions and dos ing recommendations current guidelines should be consulted when choosing protease inhibitor combinations. 

There are no pharmacokinetic data on the combination of atazanavir plus indinavir, but it is predicted that there may be an additive risk of hyperbi-lirubinaemia, so the combination is not recommended. " ... 

When atazanavir 300 mg once daily was given with ritonavir 100 mg once daily (as a pharmacokinetic booster), tenofovir disoproxil fumarate 300 mg once daily reduced the AUC of atazanavir by a similar amount (25%), but had less effect on the trough level (23% reduction), when compared with atazanavir/ritonavir alone. Similarly, the pharmacokinetics of atazanavir/ritonavir did not differ significantly between patients taking tenofovir and those not. Combined use increased the tenofovir AUC by 37% and the minimum level by 29%. - ... 

Hodder S, Bristol-Myers Squibb Company, Klein R, Struble K, FDA. Letter to health care providers. Re Important new pharmacokinetic data for REYATAZ (atazanavir sulfate) in combination with Viread (tenofovir disoproxil fumarate). August 8, 2003. Available at http //www.fda.gOv/oashi/aids/listserve/listserve2003.html (accessed 21/08/07). 

Atazanavir. A study in healthy subjects found that atazanavir 400 mg once daily given with diltiazem 180 mg once daily resulted in a two- to threefold increase in the bioavailability of diltiazem and its metabolite desacetyl-diltiazem. The pharmacokinetics of atazanavir were not affected by diltiazem. There was an increase in the maximum PR interval with combined use compared to that found with atazanavir alone. ... 

Although information is limited, these pharmacokinetic interactions are predictable, and potentially serious. To date, clinically relevant increases in calcium-channel blocker levels or effects have been shown for nelfinavir with nifedipine or felodipine, indinavir/ritonavir with amlodipine, diltiazem or nifedipine, and atazanavir with diltiazem. Caution would be required with any of these combinations, anticipating the need to use lower doses of the calcium-channel blocker. The manufacturers specifically recommend that if diltiazem is given with atazanavir the initial dose of diltiazem should be reduced by 50% with subsequent dose titration and ECG monitoring. They also note that verapamil levels may be raised and therefore advise caution. Similarly, the manufaeturers of nifedipine say that blood pressure monitoring is required and a reduction in nifedipine dose may be neeessary if it is given with HIV-protease inhibitors. However, some UK manufacturers (e.g. felodipine, lercanidipine, nimodipine ) recommend avoiding the concurrent use of ritonavir and other protease inhibitors if possible. 

Although information is limited, the pharmacokinetic interaction between the ethinylestradiol component of combined hormonal contraceptives and nelfinavir or ritonavir appears to be established and is likely to be clinically important. Similar decreases in plasma levels of ethinylestradiol caused by other drugs have resulted in reduced efficacy and reliability of combined oral contraceptives, and one retrospective report suggests that this has occurred with nelfinavir. It seem likely that the reduced contraceptive levels seen with fosamprenavir, lopinavir and tipranavir were due to the concurrent use of ritonavir (as would be common in practice). Similarly, although no interaction was reported with saquinavir, and raised contraceptive steroid levels were reported with amprenavir and atazanavir, in practice these drugs would be given with ritonavir (as a pharmacokinetic enhancer), and so the levels of combined hormonal contraceptives can reasonably be expected to be reduced. The Faculty ofFamily Planning... 

Klein CE, Chiu YL, Cai Y, Beck K, King KR, Causemaker SJ, Doan T, Esslinger HU, Podsadecki TJ, Hanna GJ. Effects of acid-reducing agents on the pharmacokinetics of lopinavir/ritonavir and ritonavir-boosted atazanavir. J Clin Pharmacol 2008 48(5) 553-62. 

Zhu L, Persson A, Mahnke L, Eley T, Li T, Xu X, Agarwala S, Dragone J, Bertz R. Effect of low-dose omeprazole (20 mg daily) on the pharmacokinetics of multiple-dose atazanavir with ritonavir in healthy subjects. J Clin Pharmacol 2011 51(3) 368-77. 

Zhu L, Butterton J, Persson A, Stonier M, Comisar W, Panebianco D, Breidinger S, Zhang J, Bertz R. Pharmacokinetics and safety of twice-daily atazanavir 300 mg and raltegravir 400 mg in healthy individuals. Antivir Ther 2010 15(8) 1107-14. 

Krishna G, Moton A, Ma L, Martinho M, Seiberling M, McLeod J. Effects of oral posaconazole on the pharmacokinetics of atazanavir alone and with ritonavir or with efevirenz in healthy adult volunteers. J Acquir Immune Defic Syndr 2009 51 437-44. 

McRae M, Clay PG, Anderson PL, Glaros AG. Pharmacokinetics of concurrent administration of fosamprenavir and atazanavir without ritonavir in human immunodeficiency virus-negative subjects. Pharmacotherapy 2009 29(8) 937-42. 

Sekar VI, Lefebvre E, De Marez T, Spinosa-Guzman S, De Pauw M, De Paepe E, Vangeneugden T, Hoetelmans RM. Pharmacokinetics of darunavir (TMC114) and atazanavir during coadministration in HIV-negative, healthy volunteers. Drugs R D 2007 8 (4) 241-8. 

Hulskotte EG, Feng HP, Xuan F, van Zutven MG, Treitel MA, Hughes EA, et al. Pharmacokinetic interactions between the hepatitis C virus protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, darunavir, and lopinavir. Qin Infect Dis 2013 56(5) 718-26. 

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