Pharmacology Update

Atazanavir Sulfate Capsules (Reyataz)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

The FDA has approved the first once-daily protease inhibitor (PI) for the treatment of HIV-1 infections. Atazanavir (Bristol-Myers Squibb) is the newest PI to enter this relatively crowded class. It is marketed under the trade name Reyataz.

Indication

Atazanavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infections.1

Dosing

The recommended dose is 400 mg (2 × 200 mg) capsules daily taken with food. If didanosine (buffered formulations) is included in the regimen, atazanavir should be taken with food 2 hours before or 1 hour after didanosine. If efavirenz is included in the regimen, atazanavir 300 mg, ritonavir 100 mg, and efavirenz 600 mg should taken together with food as a single dose. Food improves and reduces variability in the bioavailability of atazanavir.1

Atazanavir is available as 100-mg, 150-mg, and 200- mg capsules.

Potential Advantages

Atazanavir is dosed once daily with low pill burden and may improve compliance.2 The drug does not appear to be associated with clinically significant increases in total cholesterol, LDL-cholesterol, and triglycerides.1,3 In two 48-week studies the change in total cholesterol from baseline ranged from +2% to +9%, and triglycerides ranged from -9% to +1.5% for atazanavir.1,3 In contrast, changes in total cholesterol and triglycerides were +27.8% and +42.2% for nelfinavir and +21% and +23% for efavirenz. Hyperlipidemia is a common adverse effect of PIs with 50% or greater affected with hypertriglyceridemia being more common.4 However, it is not certain if the favorable lipid effects of atazanavir will result in a lower incidence of lipodystropy.6

Potential Disadvantages

Side effects include nausea, vomiting, diarrhea, headache, abdominal pain, somnolence, insomnia, and fever. Thirty-five to 47% of patients experience hyperbilirubinemia, and about 15-24% of patients show jaundice or scleral icterus.1 Atazanavir has been shown to prolong PR interval in some patients. Atazanavir is an inhibitor of cytochrome P450 isoenzyme 3A, 1A2, and 2C9 and may increase plasma levels of drugs metabolized via this metabolic pathway. Atazanavir is metabolized by CYP 3A, and drugs that are inhibitors of inducers of this isoenzyme may affect its drug levels. Co-administration of atazanavir with triazolam, midazolam, ergot-containing products, and pimozide is contraindicated, and co-administration with irinotecan, bepridil, indinavir, lovastatin, simvastatin, rifampin, St. John’s Wort, and antisecretory drugs is not recommended. Patients with hepatitis B, hepatitis C, or elevated liver transaminase levels may be at greater risk for further transaminase level elevation or hepatic decompensation.1

Comments

Atazanavir, the newest PI, offers the potential advantage of once-daily dosing and lower risk of lipid abnormalities. In antiretroviral treatment-naïve patients, atazanavir in combination with lamivudine and zidovudine has been shown to be similar in efficacy in a 48-week study to efavirenz and lamivudine and zidovudine.1 In another similar study the combination of atazanavir and lamivudine and stavudine was similar to nelfinavir and lamivudine and stavudine.1 In patients who have failed one or more prior PI-regimen the results were somewhat equivocal. In a 24-week study, patients who have failed only one prior PI-regimen, atazanavir 400 mg daily (plus 2 NNRTs) was less efficacious compared to lopinavir/ritonavir (plus 2 NNRTs). In another study of patients who have failed several drug therapies, however, atazanavir (300 mg daily) boosted with ritonavir (100 mg) appears to be comparable to lopinavir and ritonavir.5 All patients were also on tenofovir and a NRTI. The results of the latter study were submitted late to the FDA and were not reviewed in time before the user fee deadline. As with other PIs, various drug interactions can be problematic. The most common laboratory abnormality is reversible hyperbilirubinemia. In vivo resistant data indicate that 15% of isolates in treatment-naïve patients were susceptible to atazanavir, and 80% of these isolates develop mutation that keeps them susceptible to other PIs. In contrast, 51% of isolates from treatment-experienced patients were resistant to atazanavir.1,5 The wholesale cost of atazanavir is $662 per month.

Clinical Implications

Atazanavir offers another PI option. Once-daily dosing and current resistant data suggest a role in treatment-naïve patients. For treatment-experienced patients the role is not yet defined, as noninferiority has been established. Findings from the boosted atazanavir study may help clarify this issue as this regimen more closely reflects the future clinical use of atazanavir in this population.5  

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente, and Assistant Clinical Professor of Medicine, University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are associate editors of Internal Medicine Alert.

References

1. Reyataz Product Information. Bristol-Myers Squibb. June 2003.

2. Frank I. AIDS. 2002;31(1 Suppl):S10-S15.

3. Sanne I, et al. AIDS. 2003;32:18-29.

4. Prendergost BD. Heart. 2003;89:793-800.

5. FDC Report. "The Pink Sheet." 2003;65(20):10-11.

6. FDC Report. "The Pink Sheet." 2003;65(20):12-13.