Delavirdine with protease inhibitors

Many of the drugs likely to be taken by patients with HIV have a strong potential to interact with the protease inhibitors. In particular, the non-nucleoside reverse transcriptase inhibitors are also metabolised by CYP450 and have been shown to interact with protease inhibitors. Delavirdine is an inhibitor of CYP3A4 but nevirapine and efavirenz are inducers of CYP3A4. The protease inhibitors also interact with each other, and these interactions are being explored for their potential therapeutic benefits. 

By inhibiting their metabolism, ritonavir potentiates the actions of other protease inhibitors. The addition of delavirdine instead of another NNRTI in three patients taking protease inhibitors plus ritonavir further increased the exposure to the protease inhibitors (6). Combining delavirdine with indinavir removes the food restrictions during indinavir administration (4). The superior virological response observed in antiretroviral regimens containing delavirdine and protease inhibitors has been attributed in part to the pharmacokinetic interaction. 

Lipemia retinalis and pancreatitis have been reported in a 39-year-old man with HIV infection associated with protease inhibitor therapy (13). He developed lipemia retinahs after switching to an antiretroviral regimen including ritonavir and saquinavir (together with zalci-tabine and delavirdine). He had previously been taking zidovudine, lamivudine, and indinavir. 

The NNRTis are extensively metabolised by the cytochrome P450 isoenzyme system, particularly by CYP3A4. They are also inducers (nevirapine, efavirenz) or inhibitors (delavirdine) of CYP3A4. NNRTis would therefore be expected to interact with each other, and with protease inhibitors, but not with NRTIs (see below). They also have the potential to interact with other drugs metabolised by CYP3A4, and are affected by CYP3A4 inhibitors and inducers. Delavirdine and efavirenz may also inhibit some other P450 isoenzymes. For a summary, see Table 21.2 , (p.773). 

In general, efavirenz and nevirapine decrease the levels of protease inhibitors, whereas delavirdine increases them. Ritonavir is sometimes used to elevate the levels of other protease inhibitors when efavirenz or nevirapine are required. Amprenavir and nelflnavir decrease the levels of delavirdine. Most protease inhibitors do not appear to affect the levels of efavirenz or nevirapine. There is some evidence of increased adverse effects with antiviral doses of ritonavir and efavirenz, or saquinavir and delavirdine, including raised liver enzymes. Note that NNRTIs are not given with protease inhibitors in current first-line regimens for HIV infection either an NNRTI or protease inhibitors are combined with dual NRTIs. 

Therapies not recommended for initial treatment due to poor potency or significant toxicity include delavirdine, nevirapine in patients with moderate to high CD4+ T-cell counts, indinavir or saquinavir used without ritonavir ( unboosted ), ritonavir used without another protease inhibitor, and tenofovir plus didanosine with an NNRTI. 

Delavirdine mesylate is a member of the /7w(heteroaryl)piperazine (BHAP) class of nonnucleoside HIV-1 reverse transcriptase inhibitors (Adams et al., 1998 Romero et al., 1993 Romero, 1994). This class of compounds was discovered by Upjohn scientists from a computer-directed dissimilarity analysis of the Pharmacia Upjohn chemical library to select compounds for screening against HIV-1 RT. The result of the in vitro assay (Deibel et al., 1990) is an IC50 of 0.260 p,M, which is comparable to AZT. In accordance with the previous NNRTIs, delavirdine is a noncompetitive inhibitor of reverse transcriptase, and has a synergistic effect with nucleoside transcriptase and protease inhibitors (Chong et al., 1994). 

Delavirdine should not be used in combination with drugs that are CYP3A4 substrates such as pimozide, midazolam, triazolam, amiodarone, propafenone and ergot derivatives. Inducers of the hepatic P-450 system, rifampin, rifabutin, pheno-barbital, phenytoin or carbamazepine, should not be used in combination with delaviridine. It also increases the plasma levels of HIV protease inhibitors. 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

Saquinavir is subject to extensive first-pass metabolism by CYP3A4, and functions as a CYP3A4 inhibitor as well as a substrate thus, it should be used with the same precautions regarding drug-drug interactions as the other protease inhibitors. Coadministration with the CYP3A4 inhibitor ritonavir has been adopted by clinicians because inhibition of first-pass metabolism of saquinavir by ritonavir can result in higher—and thus more efficacious—levels of saquinavir (see Table 49-3 and Table 49-4). Liver function tests should be monitored if saquinavir is coadministered with delavirdine. 

Clinically important, potentially hazardous interactions with antihistamines, azole antifungals, benzodiazepines, carbamazepine, cimetidine, delavirdine, diazepam, erythromycin, HIV protease inhibitors, ketorolac, macrolide antibiotics, neuroleptics, phenobarbital, phenytoin, rifampin, ritonavir... 

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... 

Delavirdine, a nonnucleoside reverse transcriptase inhibitor, is used as part of antiretroviral therapy. Because of its moderate efficacy and inconvenient dosing (three times a day) as well as interaction with other protease inhibitors, delavirdine is currently rarely used (see footnote 1). 

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