Nr

Abbreviations: NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, HIV protease inhibitor; AUC, area under the plasma concentration-time curve; T, increase, ¿, decrease; no change; NR, not reported.

^Reported mean change in the AUC of the standard dose of the affected drug by the standard dose of the affecting drug; studies using modified dosing regimens were dose-normalized. ^Parameters reported for the saquinavir soft-gel capsule formulation. ^Lopinavir is only available in a coformulation with ritonavir.

Abbreviations: NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, HIV protease inhibitor; AUC, area under the plasma concentration-time curve; T, increase, ¿, decrease; no change; NR, not reported.

^Reported mean change in the AUC of the standard dose of the affected drug by the standard dose of the affecting drug; studies using modified dosing regimens were dose-normalized. ^Parameters reported for the saquinavir soft-gel capsule formulation. ^Lopinavir is only available in a coformulation with ritonavir.

to diminish these complications. Indinavir frequently causes unconjugated hyperbilirubinemia, which is generally asymptomatic and not associated with long-term sequelae. Because indinavir is less soluble at higher pH, antacids or other buffering agents should not be coadministered. Rifampin lowers the indinavir AUC by 90% and is contraindicated, while the dose of rifabutin should be reduced by 50% when coadministered with indinavir.

Nelfinavir Nelfinavir is a nonpeptidic protease inhibitor that is active against HIV-1 and HIV-2. It is absorbed more slowly after oral administration than the other HIV-1 protease inhibitors and is very sensitive to food effects. It undergoes extensive hepatic metabolism, primarily by CYP2C19, to an active metabolite M8. Concomitant use of drugs that induce CYP2C19 may be contraindicated (e.g., rifampin) or may require an increase in the nelfinavir dose (e.g., rifabutin). Although liver disease may prolong the t1/2 of the drug, it has been used in HIV-infected patients with significant hepatic dysfunction without evidence of untoward toxicity.

Fosamprenavir Fosamprenavir is a prodrug that is converted to amprenavir, a nonpeptide HIV protease inhibitor; the increased aqueous solubility of the prodrug markedly improves bioavailability. The drug is active against both HIV-1 and HIV-2. Amprenavir is the HIV protease inhibitor that is most likely to produce rash, possibly because it contains a sulfonamide moiety. It generally is combined with ritonavir.

Lopinavir Lopinavir is a peptidomimetic HIV protease inhibitor that is structurally similar to ritonavir and inhibits both HIV-1 and HIV-2. It is only administered in combination with ritonavir, and should be taken with food because oral bioavailability is increased by 50% with a high fat meal.

Atazanavir Atazanavir is a peptide protease inhibitor that is active against both HIV-1 and HIV-2. Absorption is increased by food and it is recommended that the drug be administered with a meal. Absorption may be pH dependent, because proton pump inhibitors substantially reduce drug concentration after oral dosing. Like indinavir, atazanavir frequently causes unconjugated hyperbilirubinemia. The drug may be less likely than other HIV protease inhibitors to cause lipodystrophy.

Tipranavir The FDA recently granted approval for tipranavir, the first member of a new class of nonpeptide inhibitors of the HIV-1 protease, in combination therapy. Although it also binds to the active site of the HIV-1 protease, tipranavir differs in structure from previously available pep-tidomimetic protease inhibitors and retains activity against HIV-1 isolates that are resistant to other HIV protease inhibitors. Tipranavir, coadministered with ritonavir, is approved for the treatment of HIV-1-infected adults with evidence of viral replication and who have received multiple treatment regimens or have HIV-1 strains resistant to multiple protease inhibitors. As noted in a "black box"

Table 50-5

Drug Interactions Amongst HIV Protease Inhibitors*

Drug Affected (Change in Plasma AUC)

Drug Exerting Effect

Saquinavir*

Indinavir

Ritonavir

Nelfinavir

Amprenavir

Fosamprenavir

Lopinavir*

Atazanavir

Saquinavir*

o

o

Tl8%

¿32%

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