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| |  ICDCD: Rescriptor May Result In Protease Inhibitor Dose Reduction, Simpler Dosing Schedule BRIDGEWATER, NJ -- Dec. 16, 1998 -- The preliminary results of two studies of Pharmacia & Upjohn’s anti-HIV drug, Rescriptor(R) (delavirdine mesylate tablets), a non-nucleoside reverse transcriptase inhibitor (NNRTI), in combination with protease inhibitors, show that Rescriptor, when added to various antiretroviral combinations, allows for a dose reduction of indinavir (IDV) by 25 to 50 percent and a simpler dosing schedule (twice daily) for Rescriptor and nelfinavir (NFV) in NFV-containing combinations. These findings were presented today at the International Conference on the Discovery and Clinical Development of Antiretroviral Therapies (ICDCD) in St. Thomas, U.S. Virgin Islands. "The complexity of antiretroviral combination therapy, as well as numerous side effects reported with protease inhibitors, make this type of regimen fine-tuning crucial," said Jeffrey Goodgame, M.D., principal investigator, Central Florida Research Initiative. "These studies indicate that adding Rescriptor to two different protease inhibitor combinations has an overall beneficial effect on viral load and CD4 cells, and they also address crucial adherence issues such as the need for simpler dosing schedules and lower doses of certain medications." Investigators based their study of Rescriptor (DLV) on an earlier finding that concomitant use of Rescriptor with indinavir increases blood levels of indinavir two-fold. Pilot study 0063, Rescriptor (DLV, 400 mg) + zidovudine (also known as AZT or ZDV, 200 mg) + indinavir (IDV, 400 mg and 600 mg), was conducted to determine if reduced doses of indinavir could be taken in this combination while maintaining antiretroviral potency. Forty-four NNRTI and protease inhibitor naive HIV-1 infected patients participated in this open label study. Participants were divided among three treatment arms: Rescriptor (DLV 400 mg TID) + AZT (200 mg TID) + IDV (400 mg TID); Rescriptor (400 mg TID) + AZT (200 mg TID) + IDV (600 mg TID); AZT (200 mg TID) + 3TC (lamivudine 150 mg BID) + IDV (800 mg TID); control arm. The participants' mean baseline CD4 cell count at the initiation of the study was 350 cells/mL and mean HIV RNA level was 4.9 log10. After 24 weeks of therapy, 50 to 62 percent of patients in all three groups achieved HIV RNA below quantifiable levels (BQL) (less than 400 copies per/mL) using the Roche Amplicor assay and patients in all three groups demonstrated at least a 2 log10 decrease -- or 41 percent decrease -- in viral load. An interim analysis of this study showed that patients in all three treatment arms achieved the following results (HIV RNA BQL): Rescriptor + AZT + IDV (400 mg) achieved 50 percent BQL; Rescriptor + AZT + IDV (600 mg) achieved 52 percent BQL and AZT + 3TC + IDV (800 mg) achieved 57 percent BQL. All three regimens were well tolerated. The most commonly reported side effects were nausea (28 percent) and rash (18 percent). There were no grade three or grade four rashes reported. Researchers from this multi-centre study concluded that after six months of therapy, the two treatment regimens containing Rescriptor + IDV (400 mg) and Rescriptor + IDV (600 mg) have immunological and virological effects that are comparable to the standard regimen of AZT + 3TC + IDV (800 mg). Data Researchers also presented results of an open label triple and quadruple combination study investigating twice daily (BID) dosing of both Rescriptor and nelfinavir (NFV). Eighty NNRTI and protease inhibitor naive HIV-1 infected patients were enrolled and randomised to one of four treatment arms: Rescriptor (600 mg) + NFV (1250 mg) + d4T (stavudine 40 mg); Rescriptor (600 mg) + NFV (1250 mg) + ddI (didanosine 200 mg) NFV (1250 mg) + ddI (200 mg) + d4T (40 mg); Rescriptor (600 mg) + NFV (1250 mg) + ddI (200 mg) + d4T (40 mg) Study participants had a median baseline viral load of 4.9 log10 and CD4 cell count of 356 cells/mL. Antiretroviral results were rapidly achieved. The following results were observed across all drug regimens: -- Within two weeks of initiating therapy, patients experienced a 1.2 log10 mean reduction on the Roche RNA PCR assay in viral load from baseline, or a 25 percent decrease. -- After four weeks, patients experienced a 1.8 log10 mean reduction in viral load from baseline, or a 39 percent decrease. -- After 12 weeks on therapy, participants in the three BID triple-drug arms had experienced at least a 2.5 log10 mean reduction in viral load from baseline, or 51 percent decrease and those patients on BID quadruple therapy had a mean reduction of greater than 2.9 log10. -- Overall, individuals had mean increases in CD4 cell count of 105-178 cells/mm3 across all four treatment arms. All therapies were well-tolerated. The most commonly reported side effects were diarrhea (14 percent) and rash (10 percent). There were no grade three or grade four reported adverse events. These study results suggest that twice-daily dosing of Rescriptor (600 mg BID) in combination with nelfinavir (1,250 mg BID) plus d4T and/or ddI may result in a rapid and significant decrease in viral load within four weeks of initiating therapy. The changes in viral and immunological status seen in these patients suggest that these BID regimens are efficacious. Rescriptor, an NNRTI, received accelerated approval in the US on April 7, 1997. It is also marketed in Brazil, Mexico, Argentina, Peru, Australia and Canada and marketing authorisation applications have been submitted in the European Union and Switzerland. Rescriptor tablets are indicated for the treatment of HIV-1 infection in combination with appropriate anti-retroviral agents when therapy is warranted. The indication is based on surrogate marker changes in clinical studies. Rescriptor can be used to treat HIV-infected patients, including newly infected asymptomatic patients as well as those patients who have AIDS. Clinical benefit was not demonstrated for Rescriptor based on survival or AIDS-defining clinical events in a completed trial comparing Rescriptor plus ddI with ddI monotherapy. Rescriptor has been shown to be well tolerated. The most commonly reported side effect attributable to Rescriptor was a skin rash that occurred in 18 percent of patients. In most cases, the rash disappeared within three to 14 days without dosage reduction or interruption of treatment. In two pivotal clinical trials, 4.3 percent of patients treated with the recommended dose of Rescriptor discontinued treatment due to skin rash. The recommended dose for Rescriptor is 400 mg, taken three times daily with or without food. Rescriptor should always be administered in combination with appropriate anti-retroviral therapy. The tablets are 100 mg each and are dispersible in water to make consumption easier. Related Links: Rescriptor, Pharmacia & Upjohn
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