Darunavir Atazanavir

This class of agents affects a later part of the HIV cycle, by inhibiting the protease enzyme and leading to impaired assembly of mature HIV virions. Examples include amprenavir, atazanavir, darunavir, fosampre-navir indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir. There have been no published reports of AKI or other direct kidney toxicity due to amprenavir, darunavir, fosamprenavir, and lopinavir. 

Amprenavir, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir, Saquinavir, Tipranavir... 

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. 

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. 

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. 

Zidovudine Didanosine Stavudine Lamivudine Abacavir Tenofovir Emtricitabine Nevirapine Efavirenz TMC125 Saquinavir Indinavir Lopinavir Fosamprenavir Atazanavir Tipranavir Darunavir Raltegravir Elvitegravir Enluvirtide Maraviroc Vicriviroc Bevirimat... 

TC Lamivudine ABC Abacavir d4T Stavudine ddC Zalcitabine ddl Didanosine TDF Tenofovir ZDV Zidovudine, also abbreviated as AZT FTC Emtricitabine NVP Nevirapine DLV Delavirdine EFV Efavirenz RTV, r Ritonavir Pl/r Ritonavir boosted protease inhibitor SQV Saquinavir IDV Indinavir LPV Lopinavir NEV Nelfinavir APV Amprenavir ATV Atazanavir DRV Darunavir... 

Clinically important, potentially hazardous interactions with atazanavir, azithromycin, bosentan, cholestyramine, clarithromycin, cyclosporine, darunavir, delavirdine, erythromycin, exenatide, fenofibrate, fosamprenavir, gemfibrozil, grapefruit juice, imatinib, itraconazole, red rice yeast, tacrolimus, telithromycin, tipranavir, tolvaptan, verapamil... 

Clinically important, potentially hazardous interactions with amprenavir, aprepitant, atazanavir, carbamazepine, chlorpheniramine, cimetidine, clarithromycin, clorazepate, CNS depressants, darunavir, delavirdine, dexamethasone, efavirenz, erythromycin, esomeprazole, fluconazole, fluoxetine, fosamprenavir, grapefruit juice, griseofulvin, imatinib, indinavir, itraconazole, ivermectin, ketoconazole, lopinavir, nelfinavir, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, ritonavir, roxithromycin, saquinavir, St John s wort, telithromycin, tipranavir... 

Clinically important, potentially hazardous interactions with amphetamines, aprepitant, astemizole, atazanavir, azithromycin, azole antifungals, clarithromycin, darunavir, dirithromycin, erythromycin, fluoxetine, fosamprenavir, grapefruit juice, imatinib, indinavir, itraconazole, ketoconazole, methylphenidate, nefazodone, nelfinavir, nilotinib, pemoline, phenothiazines, protease inhibitors, quinidine, ritonavir, saquinavir, sertraline, sparfloxacin, sulpiride, telithromycin, thioridazine, tipranavir, tricyclic antidepressants, troleandomycin, voriconazole, zileuton, ziprasidone... 

Clinically important, potentially hazardous interactions with amiodarone, amprenavir, anisindione, antacids, anticoagulants, aprepitant, atazanavir, atovaquone, beclomethasone, buprenorphine, corticosteroids, cortisone, cyclosporine, cyproterone, dabigatran, dapsone, darunavir, delavirdine, dexamethasone, dicumarol, digoxin, eszopiclone, flunisolide, fosamprenavir, gadoxetate, gestrinone, halothane, imatinib, isoniazid, itraconazole, ketoconazole, lapatinib, lorcainide, methylprednisolone, midazolam, nelfinavir, nifedipine, oral contraceptives, phenylbutazone, prednisone, protease inhibitors, pyrazinamide, ramelteon, ritonavir, saquinavir, solifenacin, sunitinib, tacrolimus, telithromycin, temsirolimus, tipranavir, tolvaptan, trabectedin, triamcinolone, triazolam, voriconazole, warfarin, zaleplon... 

HIV Protease Inhibitors Saquinavir, Ritonavir, Indinavir, Nelfinavir, Amprenavir, Lopinavir, Atazanavir, Fosamprenavir, Tipranavir and Darunavir as Drugs against HIV Infection... 

Atazanavir (BMS-232632) and fosamprenavir (phosphate prodrug of amprenavir)followed in 2003, as well as tipranavir (PNU-140690) and darunavir (TMC-114) ° in 2005 and 2006 respectively. Therefore, there are currently 10 FDA approved HIV protease inhibitors on the market. After the X-ray structure of HIV protease was published in 1989 by several labora-... 

Figure 5.4 Structures of marketed HIV protease inhibitors. Saquinivir (top left), ritonavir (top middle), indinavir (top right), nelfinavir (second row left), lopinavir (second row middle), tipranavir (second row right), atazanavir (third row left), darunavir (third row middle), fosamprenavir (third row right) and amprenavir (bottom).

Proton pump inhibitors (marked effect) and H2-receptor antagonists (modest effect) reduce atazanavir levels. Other drugs that increase gastric pH are also predicted to reduce plasma levels of atazanavir. Fosamprenavir may be similarly affected (moderate effects seen with ranitidine), although antacids and esomeprazole had little effect in one study. Omeprazole decreases indinavir levels and an antacid modestly decreased tipranavir levels. Neither ranitidine nor omeprazole had any effect on darunavir/ritonavir or lopinavir/ritonavir levels. In contrast, cimetidine, ranitidine and omeprazole have been shown to increase saquinavir levels. 

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. ... 

The manufacturer notes that combining atazanavir 300 mg once daily with darunavir/ritonavir 400/100 mg twice daily did not significantly alter the AUC and minimum level of darunavir. In addition, the AUC and minimum level of atazanavir were not significantly changed, when compared with atazanavir/ritonavir 300/100 mg once daily alone, although the minimum level was increased by 52%. ... 

Atazanavir/ritonavir, darunavir/ritonavir and lopinavir/ritonavir modestly increased the levels of tenofovir, and there is at least one case report of nephrotoxicity with the combination of tenofovir, didanosine, and lopinavir/ritonavir. Saquinavir/ritonavir, ti-pranavir/ritonavir, and probably also fosamprenavir/ritonavir, have little effect on tenofovir levels. Tenofovir modestly decreased atazanavir levels, and this was minimised when ritonavir was also given. Tenofovir had no important effect on ritonavir-boosted darunavir, lopinavir, and tipranavir levels, and modestly increased those of ritonavir-boosted saquinavir in one of two studies. Indinavir and nelfinavir do not interact pharmacokineti-cally with tenofovir. 

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. Unboosted atazanavir should be used with caution or not given with tenofovir because of the potential for reduced etficacy 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 the 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. 

Eehinaeea purpurea and darunavir-l-ritonavir, 463 efavirenz arul atazanavir, 461 efavirenz arul... 

Drug-drug iuteractions Atazanavir Hyperbilirubinemia and jaundice occurred during administration of atazanavir in all 23 healthy volunteers taking part in a 30-day follow-up study there was a 52% increased minimum plasma concentration with coadministration of darunavir [178 ]. 

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. 

The use of boceprevir with ritonavir boosted HIV-1 protease inhibitors (Pis) (atazanavir or ATV, lopinavir or LPV and darunavir or DRV) were investigated in 39 healthy individuals and demonstrated reduced effectiveness in both coadministered drugs [73 ]. 

Deeks ED. Cobicistat areviewofits use asapharmacokinetic enhancer of atazanavir and darunavir in patients with HIV-1 infection. Drugs... 

Capel E, Auclair M, Caron-Debarle M, Capeau J. Effects of ritonavir-boosted darunavir, atazanavir and lopinavir on adipose functions and insulin sensitivity in murine and human adipocytes. Antivir Ther 2012 17(3) 549-56. 

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