Rifampicin protease inhibitors

RIFAMPICIN PROTEASE INHIBITORS 1 levels of protease inhibitor. Risk of hepatotoxicity with saquinavir Induction of metabolism Avoid co-administration... 

Most ARVs available for adults are also available for children with specific child formulations including dosages that are based on either body surface area or weight. First-line treatment options for children include ZDV/3TC plus either a non-nucleoside (NVP or EFV) or ABC. EFV cannot be used in children under the age of 3 years due to lack of appropriate dosing information. However, EFV would be the non-nucleoside of choice in children on rifampicin, in case ARV needs to start before anti-tuberculous therapy is completed. Second-line therapy for children in the event of first-line regimen failure would include a change in nucleoside backbone (e.g., from ZDV + 3TC to d4T + ddl) plus a protease inhibitor. 

Protease inhibitors Use in combination with rifampicin Comments... 

It is similar to rifampicin and shows significant activity against M. tuberculosis, M. avium complex and M. fortuitum. Rifabutin is both substrate and cytochrome 450 enzyme inducer. Because it is less potent inducer, rifabutin is used (in place of rifampicin) for the treatment of tuberculosis in HIV-infected patients, who are on concurrent antiretroviral therapy with a protease inhibitor. It is used alone or in combination with pyrazi-namide. 

Cardiac depressant effects may occur when verapamil or diltiazem is combined with a (p-adrenoceptor antagonoist or a cardiac glycoside. Nifedipine and verapamil are metabolised by cytochrome P-450 3A4. Inhibitors of this enzyme, e.g. HIV-protease inhibitors, cimetidine, fluoxetine, ketoconazole, erythromycin, will increase plasma levels and the dose should be carefully monitored. Conversely, enzyme inducers, e.g. carbamazepine, rifampicin, phenytoin, will decrease their plasma concentrations. 

Interactions. Involvement of protease inhibitors with the cytochrome P450 system provides scope for interaction with numerous substances. Agents that induce P450 enzymes (e.g. rifampicin, St John s wort) accelerate their metabolism, and reduce plasma concentration enzyme inhibitors (e.g. ketoconazole, cimetidine) raise their plasma concentration competition with other drugs for the cytochrome enzymes can lead to variable results. Ritonavir is itself a powerful inhibitor of CYP 3A4 and CYP 2D6. This effect is utilised when ritonavir in small quantity is combined (in capsules) with lopinavir to inhibit its metabolism and increase its therapeutic efficacy. The present account should be sufficient to warn the physician, and thereby the patient, to take particular heed when seeking to co-administer any drug a with protease inhibitor. 

The recommendations of the Center for Disease Control and Prevention in Atlanta regarding the use of antituberculosis drugs in combination with antiretroviral drugs have been published (98). In general, the use of rifampicin in patients taking protease inhibitors is contraindicated, except in the following circumstances ... 

The use of rifampicin with the protease inhibitors indinavir, nelfinavir, and amprenavir is contraindicated. However, these agents can be used with rifabutin after appropriate dosage reduction. Failure to reduce the dosage of rifabutin can result in toxic manifestations, such arthralgia and uveitis. 

CYP3A4 alprazolam, calcium channel blockers, cisapride, clarithromycin, cyclosporin A, erythromycin, HIV protease inhibitors, lidocaine, midazolam, simvastatin, terfenadine carbamazepine, dexamethsone, phenobarbital, phenytoin, rifampicin, St John s wort cimetidine, erythromycin, grapefruit juice, HIV protease inhibitors, itraconazole, ketoconazole... 

Remember some of those drugs that are key enzyme inducers (e.g. phenytoin, barbiturates, rifampicin, etc) or enzyme inhibitors (e.g. azole antifungals, HIV-protease inhibitors, erythromycin, SSRIs). 

The pharmacokinetic interactions with efavirenz and rifampicin are likely to be clinically important. The reduction in maraviroc plasma levels seen could result in decreased efficacy and the development of viral resistance. Doubling the dose of maraviroc overcame this interaction, and this is the suggested approach of the manufacturer when maraviroc is used in the absence of protease inhibitors. Efavirenz appears to halve the increase in maraviroc levels seen with ritonavir-boosted protease inhibitors. 

Rifampicin (rifampin) bioavaiiabiiity is increased by indinavir, but amprenavir has no effect. Rifampicin markedly reduces the bioavailability of amprenavir, atazanavir/ritonavir, indinavir, indinavir with ritonavir, iopinavir/ritonavir, nelfinavir and saquinavir, but oniy modestiy reduces that of ritonavir. The effects of rifampicin on iopinavir/ritonavir and saquinavir/ritona-vir can be overcome by increasing the protease inhibitor dose, but this appears to increase adverse effects (hepatotoxicity). 

Rifampicin is a potent inducer of the cytochrome P450 isoenzyme CYP3A4, by which the protease inhibitors are at least partially metabolised, and therefore it markedly reduces protease inhibitor levels. Rifabutin is a weak inducer of CYP3A4. The protease inhibitors are inhibitors of CYP3A4, with ritonavir being the most potent, and can therefore increase the levels of the rifamycins. 

Rifampicin markedly reduces the levels of many of the protease inhibitors, and its use with unboosted protease inhibitors should be avoided, because of the risk of reduced antiviral efficacy and emergence of resistant viral strains. There are limited data to suggest that ritonavir as the sole protease inhibitor, or ritonavir used as a pharmacokinetic enhancer with other protease inhibitors such as saquinavir, can be used with rifampicin. However, further study has shown a high incidence of hepatotoxicity with saquinavir/ritonavir 1000/100 mg twice daily and rifampicin, and the manufacturers of ritonavir and saquinavir advise that these drugs should not be given together with rifampicin. Current UK guidelines state that, until more data are available, ritonavir-boosted protease inhibi-... 

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