Delavirdine drug interactions

C. Delavirdine Drug interactions are a major problem with delavirdine, which is metabolized by both CYP3A4 and CYP2D6. Its blood levels are decreased by antacids, ddl. phenytoin. rifampin, and nelfinavir. Conversely, the blood levels of delavirdine are increased by azole anti-fiingals and macrolide antibiotics. Delavirdine increases plasma levels of several benzodiazepines, nifedipine, protea.se inhibitors, quinidine, and warfarin. Delavirdine causes skin rash in up to 20% of patients, and the drug should be avoided in pregnancy since it is teratogenic in animals. 

Delavirdine is extensively metabolized to inactive metabolites by the CYP3A and CYP2D6 enzymes and also inhibits CYP3A4 and 2C9. Therefore, there are numerous potential drug-drug interactions to consider (Tables 49-3 and 49-4). The concurrent use of delavirdine with fosamprenavir and rifabutin is not recommended because of decreased delavirdine levels. 

Saquinavir is subject to extensive first-pass metabolism by CYP3A4 and functions as a CYP3A4 inhibitor as well as a substrate thus, there are many potential drug-drug interactions (Table 49-4). A decreased dose of saquinavir is recommended when -administered with nelfinavir. Increased saquinavir levels when -administered with omeprazole necessitate close monitoring for toxicities. Digoxin levels may increase if co administered with saquinavir and should therefore be monitored. Liver function tests should be monitored if saquinavir is -administered with delavirdine or rifampin. There is no evidence of human teratogenicity from saquinavir there is short-term safety data for both mother and infant. 

Since indinavir is a substrate as well as an inhibitor of CYP3 A4, numerous and complex drug interactions can occur as described above. Indinavir levels decrease with concurrent use of rifabutin, fluconazole, St. John s wort, and rifampin. Caution is advised with other 3 A4 inducers also, including phenobarbital, phenytoin, carbamezepine, and dexamethasone. Dose reduction of indinavir should be considered if coadministered with delavirdine, ketoconazole, or itraconazole, while an increase in the dose of indinavir is indicated if the drug is coadministered with efavirenz or rifabutin. 

The advent of highly active antiretroviral therapy (HAART) to minimize the rapid development of viral resistance in the treatment of HIV infection may result in multiple drug interactions (110-113). Both the nonnucleoside reverse transcriptase inhibitors and the protease inhibitors are substrates and inhibitors of some CYP enzymes, and some act as inducers as well (110,111). The major effects are on the CYP3A isoforms, and this has been used to advantage to increase concentrations of some HIV drugs. For example, delavirdine is a mechanism-based irreversible inhibitor of CYP3A4, and thereby is used to increase exposure to protease inhibitors (114). Ritonavir is a protease inhibitor, but it is used primarily for its ability as a potent inhibitor of CYP3A4 to increase concentrations of other protease inhibitors (115). 

Tran JQ, Gerber JG, Kerr BM. Delavirdine clinical pharmacokinetics and drug interactions. Clin Pharmacokinet 2001 40 207-226. 

Medications in this class include delavirdine, efa-virenz, and nevirapine. Similar to the NRTls, these agents bind to viral reverse transcriptase and block DNA polymerase activity. A key difference is that NNRTIs do not require intracellular phosphorylation and are not incorporated into viral DNA. Clinically significant kidney toxicities or specific fluid-electrolyte complications have not been reported with this class of agents. In the rat model, efavirenz was associated wifh a species specific dependent kidney toxicity which occurred secondary to the development of a unique glutathione conjugate produced as a metabolite of efavirenz associated with renal tubular epifhelial cell necrosis [125-126]. This toxicity has not been observed in humans. One patient was recently reported to have reversible nephrotic-range proteinuria attributed to efavirenz use, in which a kidney biopsy showed diffuse podocyte foot process effacement [127]. Another report noted the development of rhabdomyolysis and acute tubular necrosis as a result of a drug interaction between delavirdine and atorvastatin [128]. Kidney toxicity due to nevirapine has not been reported. 

Clinically important, potentially hazardous interactions with amikacin, amphotericin B, delavirdine, drugs causing kidney toxicity, foscarnet, gentamicin, hydroxyurea, pentamidine, tobramycin... 

Groups of Antiretrovirals with Similar Drug Interactions PF/delavirdine/ Ergot alkaloids midazolam/triazolam/ Decreased metabolism of other agents Avoid... 

M, Jatiow P. Drug interactions between q>ioids and antiretroviral m ications interaction between metiiadone, LAAM, and delavirdine. (2006) 15,23-24. 

Ferry JJ, Herman BD, Carel BJ, Carlson GF, Batts DH. Pharmacokinetic drug-drug interaction study of delavirdine and indinavir in healthy volunteers. JAcquir launime... 

Cox SR, Schneck DW, Herman BD, Carel BJ, Gulloth BR, Kerr BM, Freimuth WW. Delavirdine (DLV) and nelfinavir (NFV) A pharmacokinetic (PK) drug-drug interaction study in healthy adult volunteers. 5th Conference on Retroviruses and Opportunistic Infections, Chicago, 1998. Abstract 345. 

Voorman, R.L., Payne, N.A., Wienkers, L.C., Hauer, M.J. and Sanders, P.E. (2001) Interaction of delavirdine with human liver microsomal cytochrome P450 inhibition of CYP2C9, CYP2C19, and CYP2D6. Drug Metabolism and Disposition, 29 (1), 41—47. 

Drugs that may interact with rifabutin include the following Anticoagulants, azole antifungal agents, benzodiazepines, beta blockers, buspirone, corticosteroids, cyclosporine, delavirdine, doxycycline, hydantoins, indinavir, rifamycins, losartan, macrolide antibiotics, methadone, morphine, nelfinavir, quinine, quinidine, theophylline, aminophylline, tricyclic antidepressants, and zolpidem. 

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. 

Buffering agents that are compounded with didanosine to counteract its degradation by gastric acid may interfere with the absorption of other drugs that require acidity (e.g., indinavir, delavirdine, ketoconazole, fluoroquinolones, tetracyclines, dapsone). An enteric-coated formulation Videx EC) that dissolves in the basic pH of the small intestine is not susceptible to these interactions. Ganciclovir and valganciclovir can increase blood levels of didanosine. The use of zalcitabine with didanosine is not recommended because that combination carries an additive risk of peripheral neuropathy. The combination of didanosine with stavudine increases the risk of pancreatitis, hepatotoxicity, and peripheral neuropa-... 

Delavirdine is a non-nucleoside reverse transcriptase inhibitor, which is dosed three times daily. No food restrictions apply. It is metabolized mainly by CYP3A, and so interactions with other drugs that use this metabolic pathway can occur. 

Absorption, Distribution, and Elimination These drugs are administered oraUy and rapidly absorbed. Food generally does not affect their absorption. They are metabolized primarily by hepatic CYPs 3A4 or 2B6. Thus, they are subject to multiple interactions with other drugs that are either substrates or inducers of these enzymes. Efavirenz and nevirapine are moderately potent inducers of CYP3A4, whereas delavirdine is an inhibitor. 

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). 

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