Rescriptor (delavirdine) Treatment Increases Norvir (ritonavir) Concentrations

Delavirdine treatment results in increased systemic exposure to ritonavir, presumably by inhibiting its metabolism, according to a report in the May issue of Antimicrobial Agents and Chemotherapy.

Delavirdine is known to inhibit CYP3A4, the authors explain, an enzyme that both metabolizes ritonavir and is potently inhibited by ritonavir. In contrast, most nonnucleoside reverse transcriptase inhibitors besides delavirdine are known to be enzyme inducers.

Dr. Gene D. Morse from University of Buffalo, New York and associates evaluated the pharmacokinetics of ritonavir and delavirdine in 12 HIV-infected patients who had delavirdine mesylate (400 mg every 8 hours) added to their existing antiretroviral regimens that already included ritonavir.

Addition of delavirdine to the antiretroviral regimen was associated with a mean 51% increase in systemic exposure to ritonavir (as measured by AUC(0-12), the authors report. Eleven of 12 patients experienced increases, and the changes ranged from a 29% decrease to a 214% increase in ritonavir AUC.

Maximum and minimum ritonavir concentrations were also significantly increased by delavirdine treatment, the report indicates, but the time to maximum serum concentration (Tmax) was not influenced by delavirdine.

In contrast, delavirdine pharmacokinetics did not appear to be changed by its coadministration with ritonavir-containing antiretroviral regimens, the researchers note.

"At present," the investigators write, "delavirdine appears to be the only antiretroviral agent that inhibits the metabolism of ritonavir to a clinically significant extent."

"Based upon the results of this study," the authors conclude, "ritonavir doses should probably be reduced for patients taking both full-dosage ritonavir and delavirdine, given the poor tolerance for higher ritonavir doses and presumably for higher exposure."

The researchers add, "Extrapolation of these results to patients receiving delavirdine with lower doses...of ritonavir as a pharmacologic enhancer of a second protease inhibitor will require further investigation to determine the net pharmacokinetic outcome of these three- or four-way interactions in HIV-infected patients during salvage therapy."

06/16/03

Antimicrob Agents Chemother 2003;47:1694-1699.