Nevirapine interactions

The NNRTIs efavirenz and nevirapine interact with a number of drugs metabolized in the liver. The doses of protease inhibitors may need to be increased when they are given with efavirenz or nevirapine. Nevirapine is associated with a high incidence of... 

The identification of the HIV-1-specific non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a separate class of HIV inhibitors was heralded by the discovery of the tetrahydroimidazo[4,5,1 -// .][ 1,4]benzo-diazepin-2(l //)-onc and -thione (TIBO) derivatives (Fig. 7) [58,59] and 1 -(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) derivatives (Fig. 8) [60,61]. The first TIBO derivatives (R82150, R82913) were the first NNRTIs [58] postulated to act as inhibitors of HIV-1 RT [59], For the HEPT derivatives it became evident that they also interact specifically with HIV-1 RT after a number of derivatives (i.e., E-EPU, E-EBU, and E-EBU-dM) had been synthesized that were more active than HEPT itself [62,63]. Following HEPT and TIBO, several other compounds, i.e., nevirapine, pyridinone, and bis(heteroaryl)piperazine (BHAP), were... 

The HEPT and TIBO derivatives were discovered as the result of a systematic evaluation for anti-HIV activity in cell culture. They were later found to achieve their anti-HIV-1 activity through an interaction with the HIV-1 RT. In contrast, nevirapine, pyridinone, and BHAP emerged from a screening program for HIV-1 RT inhibitors. The anti-HIV-1 activity of these compounds was subsequently confirmed in cell culture. Like the HEPT and TIBO derivatives, the 2, 5 -bis-0-(tert-butyldimethylsilyl)-3 -spiro-5" -(4" -amino-1", 2" -oxathiole-2", 2" -dioxide)-pyrimidine (TS AO) derivatives (Fig. 9) [65,66] and a-anilinophenylacetamides (a-APA) (Fig. 10) [67] were discovered through the evaluation of their anti-HIV activity in cell culture. Subsequently, they were found to act as specific inhibitors of HIV-1 RT. 

Shown below are snapshots of structures from our simulations of native RT with Sustiva and nevirapine. No crystal structure had been reported for RT with Sustiva when the calculations were performed however, confidence in the computed structure comes from the quantitative accord for the inhibition penalties and because Matador yielded docked structures for nevirapine, MKC-442, and 9-C1-TIBO that are virtually identical to the crystal structures.57 Sustiva hydrogen bonds with the backbone of K101, as do MKC-442 and 9-chloro-TIBO, and it has hydrophobic interactions in the Y181-Y188 pocket, also typical of NNRTIs. 

The following drug classes may have a potential drug interaction with nevirapine Antiarrhythmics, anticonvulsants, antifungals, calcium channel blockers, cancer chemotherapy (cyclophosphamide), ergot alkaloids, immunosuppressants, motility agents, opiate agonists. 

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. 

Nevirapine induces and is metabolized by CYP3A4 therefore, coadministration of drugs that induce or are metabolized by this isoenzyme may result in interactions. Nevirapine may decrease the effectiveness of ethinyl estradiol-based contraceptives and can lower plasma concentrations of methadone. Nevirapine should not be administered with ketoconazole, rifampin, or rifabutin. 

Lopinavir/Ritonavir (Kaletra) [Anrirelroviral/Protease Inhibitor] Uses HIV Infxn Action Protease inhibitor Dose Adults. Tx naive 2 tab PO daily or 1 tab PO bid Tx experiencedpt 1 tab PO bid (T dose if w/ amprenavir, efavirenz, fosamprenavir, nelfinavir, nevirapine) Peds. 7-15 kg 12/3 mg/kg PO bid 15-40 kg 10/2.5 mg/kg PO bid >40 kg Adult dose w/ food Caution [C, /-] Numerous interactions Contra w/drugs dependent on CYP3A/CYP2D6 (Table VI-8) Disp Tab, soln SE Avoid disulfiram (soln has EtOH), metronidazole GI upset, asthenia, T cholesterol/triglycerides, pancreatitis protease metabolic synd Interactions T Effects Wl clarithromycin, erythromycin T effects OF amiodarone, amprenavir, azole andfungals, bepridil, cisapride, cyclosporine, CCBs, ergot alkaloids, flecainide, flurazepam, HMG-CoA reductase inhibitors, indinavir, lidocaine, meperidine, midazolam, pimozide, propafenone, propoxyphene, quinidine, rifabutin, saquinavir, sildenafil, tacrolimus, terfenadine, triazolam, zolpidem 1 effects Wl barbiturates, carbamazepine, dexamethasone, didanosine, efavirenz, nevirapine, phenytoin, rifabutin, rifampin, St. John s wort 1 effects OF OCPs, warfarin EMS Use andarrhythmics and benzodiazepines... 

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. 

Nonnucleoside Inhibitors Nevirapine and efavirenz are active inhibitors of reverse transcriptase, that is, they do not require phosphorylation. Adverse reactions include rashes and interactions involving cytochrome P450 isozymes (CYP). 

NEVIRAPINE SAQUINAVIR Possible 1 efficacy, risk of treatment failure of saquinavir t CYP3A4-mediated metabolism of saquinavir Clinical significance unclear. Different formulations of saquinavir may have different magnitudes of interaction... 

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