Stephen C. Piscitelli, PharmD

Disclosures

February 04, 2000

Question

I am interested in dosing delavirdine (Rescriptor) twice daily for some of my patients, particularly those who will also be on amprenavir (Agenerase). Can you comment on this type of dosing?

Mark Netherda, MD

Response from Stephen C. Piscitelli, PharmD

One of the disadvantages of using delavirdine (DLV) to treat HIV infection is having to administer DLV 3 times daily. However, the pharmacokinetics of this agent, combined with the available clinical information, suggest that twice-daily dosing may be an option. Pharmacokinetic studies in healthy volunteers and HIV-infected patients, as well as computer simulations, suggest that the overall exposure and trough concentrations of DLV 600 mg bid are similar to those of the standard 400-mg tid regimen.[1,2] In addition, DLV possesses nonlinear pharmacokinetics, meaning that an increase in dose results in a proportionally larger increase in the plasma concentration. Thus, a 600-mg bid regimen might be expected to provide even higher concentrations than a tid regimen with the same total daily dose. To date, however, a straightforward pharmacokinetic study evaluating 400 mg tid vs 600 mg bid in volunteers has not been performed.

Two clinical studies have evaluated twice-daily dosing of DLV in combination with other antiretrovirals. Gatell and colleagues reported on regimens containing bid DLV at the 1999 ICAAC meeting.[3] Protease inhibitor- and NNRTI-naive patients were randomized into 1 of 4 arms, 3 of which included DLV 600 mg bid and nelfinavir 1250 mg bid with either d4T, ddI, or both nucleoside analogues. At week 24, available data from 45 patients demonstrated that 81% had HIV RNA below 400 copies/mL, and 67% had HIV RNA below 50 copies/mL. As expected, the most commonly reported adverse effects were rash, diarrhea, and nausea, and 80%-90% of patients remained on the triple-therapy regimens.

ACTG 359 was a 6-arm study examining the combination of DLV 600 mg bid, adefovir, or both with a dual protease inhibitor regimen containing saquinavir and either ritonavir or nelfinavir.[4,5] Patients had previously failed an indinavir-based regimen. Of 254 patients enrolled in the trial, 30% had viral loads less than 500 copies/mL at 16 weeks. For those patients with a virologic response at 16 weeks, 59% had viral loads < 500 copies/mL at week 48. The patients in the DLV treatment arms had a significantly lower viral load compared with the adefovir arms. Examination of the pharmacokinetic interactions between DLV and protease inhibitors confirmed DLV's inhibitory effects on cytochrome P450-mediated drug metabolism of protease inhibitors, increasing the AUC of saquinavir-sgc, ritonavir, and nelfinavir by > 50%. Although data are not available for amprenavir, based on these data and other DLV interactions[6] it is likely that amprenavir AUC would be expected to be significantly increased by concomitant DLV.

Two other studies with twice-daily DLV are currently ongoing. One is a study comparing DLV 600 mg bid versus DLV 400 mg tid in combination with indinavir and zidovudine. The second is a 4-arm trial evaluating saquinavir-sgc either tid or bid with 3TC plus either DLV 400 mg tid, DLV 600 mg bid, zidovudine 200 mg tid, or ZDV and DLV bid.[6] Data from these studies are not yet available.

In summary, the pharmacokinetic data for delavirdine and the limited clinical trial information suggest that twice-daily delavirdine may be effective as part of a combination regimen. DLV also is a potent inhibitor of CYP450 metabolism and can markedly increase concentrations of concomitant protease inhibitors.

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