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RITONAVIR (NORVIR™)
David Pizzuti, M.D. Abbott Laboratories
Ritonavir (Norvir™ or ABT-538) is Abbott's third HIV protease inhibitor introduced into humans. The company has filed a new drug application (NDA) of ritonavir for marketing approval with the FDA in December of 1995. Dr. Pizzuti mentioned that the time from ritonavir's first entry into the clinics to the NDA filing took only 25 months. Ritonavir is currently available through an expanded access program for selected patients.
Ritonavir is a potent HIV protease inhibitor with an EC50 of 27 nM against clinical isolates of HIV. It has an inhibitor constant (Ki) for HIV protease of 15 pM. Oral bioavailability of the compound exceeds 70% in animal models.
Results of two placebo-controlled phase II studies of ritonavir were recently published. One study (M93-112/M94-169) was designed to evaluate four different doses of ritonavir, 300, 400, 500 or 600 mg twice daily, in antiretroviral experienced patients with advanced HIV disease. Median CD4 counts increased by 150 to 200 cells/mm3 in patients receiving the highest dose (600 mg twice daily) after 36 weeks. Mean maximum decline of greater than 1 log in viral load was seen in all dose groups at week 2. Persistent viral load suppression was associated with the 500 and 600 mg twice daily regimens which maintained at least a 0.5 log reduction at week 36.
In this study, Chiron's first generation branched DNA (bDNA) test, which has a detection limit of 10,000 copies/ml, was used for determining viral load. Therefore, the apparent ritonavir-mediated antiviral response may not necessary reflect the true extent of viral load reduction due to the limited dynamic range of the test. The analysis of this study has led Abbott to the selection of 600 mg twice daily regimen, the current recommended dose, as the dose employed in the subsequent pivotal studies.
Ritonavir was generally well tolerated with occasional increases in liver function enzymes (SGOT/SGPT). However, SGOT/SGPT increases were thought to be associated with patients' pre-existing viral liver diseases (hepatitis B and C infection).
Another study (M93-134X) was designed to assess doses of 200 or 300 mg three times per day versus 200 or 300 mg four times per day in patients with advance HIV disease. A significant median rise in CD4 counts was noted during the first 12 weeks with an overall trend back towards baseline at week 32. All groups achieved peak reduction of about 1 log in viral load at week 2 from baseline. This initial decline, however, had rebounded back toward baseline at week 32.
Dr. Pizzuti echoed the statements made by previous speakers and others that protease inhibitors ultimately would have to be used in combination in order to derive the most benefit for patients. Toward that end, ritonavir was assessed in combination with AZT and ddC in 32 antiretroviral naive people with CD4 counts of between 50 and 250 cells/mm3. The study was conducted in France.
Patients were treated with ritonavir alone at 600 mg twice per day for 2 weeks followed by the addition of AZT at 200 mg three times per day and ddC at 0.75 mg three times per day for at least an additional 22 weeks. The mean increase in CD4 counts with the triple combination was about 100 cells/mm3 and was maintained at week 24. Viral load showed a sustained decrease of about 2.5 log over 20 weeks as measured by both PCR and total HIV infectious cells. There were a gradual increase in the proportion of patients on the triple drug regimen with viral loads below the limit of detection. In addition, there was also a gradual increase in the proportion of patients who had viral cultures with peak value between 30 and 40% at week 24. Dr. Pizzuti suggested that this may be the manifestation of emptying the body's viral reservoir. The true antiviral potential of prolonged treatment with ritonavir in combination with AZT and ddC is yet to be determined.
Most frequently seen mutations associated with ritonavir resistance were found at codons 82, 54, 71 and 36. Gradual increase in the accumulation of mutations was correlated with high level resistance (>10-fold) to ritonavir. For example, viruses with mutation at codons 82 and 54 or at codons 82, 54, 71 and 36 induced >15-fold decrease in sensitivity to ritonavir compared to <5-fold change with single mutation at codon 82. Dr. Pizzuti concluded that resistance mutations to ritonavir accumulate in a stepwise fashion.
Ritonavir resistant viruses have been demonstrated in cell culture to retain full sensitivity to saquinavir. This finding, together with recent results from preclinical studies, provides good rationale for combining ritonavir with saquinavir based on their complementary resistance profiles as a potential strategy to limit the emergence and spread of resistant viruses.
The mechanism by which ritonavir is metabolized via the cytochrome P450 3A4 pathway, a common pathway to most protease inhibitors, has led to the concept that it may effect the overall drug metabolism when administered concomitantly with other compounds. Indeed, plasma concentration of saquinavir was increased by 200-fold after oral administration of 10 mg/kg doses of ritonavir in rats. This enhancement effect was due to the inhibition of saquinavir metabolism by the presence of ritonavir. Dr. Pizzuti cautioned people in the community not to combine saquinavir with ritonavir outside of controlled studies due to the current lack of knowledge regarding the overall safety profile with the use of such combination. A pilot phase I/II study of the combined protease inhibitors in HIV+ individuals is now in progress.
The ritonavir NDA included data from two pivotal studies (M94-245 and M94-247). Protocol M94-245 was designed to assess virological effect of ritonavir in combination with AZT in previously untreated patients with CD4 counts of greater than 200 and HIV RNA of > 15,000 copies/ml. The other pivotal trial, protocol M94-247, was performed in patients witth advanced HIV disease with CD4 counts of less than 100 cells/mm3. Participants must have at least 9 months of prior treatment with AZT, ddI, ddC or d4T. The study objective was to determine the antiviral activity and clinical efficacy of ritonavir in this advanced, heavily pre-treated population.
Results of both pivotal studies are expected to be announced at the Third Conference on Retroviruses and Opportunistic Infections to be held in Washington, D.C. in late January.
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