Pharmacology Update

Darunavir Tablets (Prezista™)

By William T. Elliott, MD, FACP, and James Chan, PhD, PharmD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationships to this field of study.

The FDA has given an accelerated approval for a new protease inhibitor (PI) for the treatment of HIV infections. Darunavir (TMC114) is approved for patients who have shown resistance to more than one protease inhibitor. It is marketed by Tibotec Therapeutics, a Division of Ortho Biotech, as Prezista™.

Indications

Darunavir is indicated for the treatment of HIV infections in antiretroviral treatment-experienced adult patients with HIV-1 strains that are resistant to one or more protease inhibitors.1

Dosage

The recommended dose is 600 mg (2 x 300 mg) twice daily with ritonavir 100 mg. Darunavir should be taken with food.1

Darunavir is supplied as 300 mg tablets.

Potential Advantages

In treatment-experienced patients with HIV-1 RNA > 1000 copies/mL, darunavir/ritonavir plus optimized background regimen (OBR) produced virologic response in 69.5% of patients compared to 21% who received an investigator selected PI plus OBR. Darunavir has shown activity against viruses resistant to other PIs.1-4

Potential Disadvantages

Darunavir is an inhibitor of CYP3A and can have significant drug-drug interactions with many drugs. Most common adverse events include diarrhea, nausea, and headache. Fat redistribution or accumulation of body fat may occur. Mild-to-moderate rash has been reported (7%); in some cases the rash is severe or life-threatening. As with other PIs, hyperglycemia, increase in bleeding, and immune reconstitutional syndrome may occur. Darunavir resistant viruses are generally not susceptible to other protease inhibitors.

Darunavir has a sulfonamide moiety and should be used with caution in patients allergic to sulfonamides.1

Comments

The accelerated approval of darunavir was based on two randomized controlled studies. Treatment-experienced subjects with a baseline HIV-1 RNA > 1000 copies/mL and prior treatment with PIs, NNRTIs and NRTIs, who had one primary PI mutation at screening, and were on a stable PI-containing regimen at screening for at least 8 weeks were randomized to darunavir plus ritonavir and ORB or a PI of choice by the investigator plus OBR. At week 24, 69.5% of the subjects randomized to darunavir had virologic response (1 log10 decline below baseline) and 45% had viral load < 50 copies/mL compared to 21% and 12.1% respectively for the PI control group. The replacement of PIs in non-suppressive regimen with darunavir/ritonavir in patients who had taken multiple PIs has resulted in significant reduction in HIV-1 RNA.4 The activity declines with increased numbers of PI mutations present in the viruses. Darunavir is active against PI resistant viruses.1-4 It may have a high genetic barrier to the development of resistance.2

The addition of enfuvirtide to darunavir/ritonavir demonstrated improved efficacy compared to darunavir/ritonavir alone.5

Clinical Implications

Darunavir provides an alternative to treatment-experienced patients with viruses resistant to other protease inhibitors.

References

1. Prezista product information. Tibotec Therapeutics. June 2006.

2. De Meyer S, et al. TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. Antimicrob Agents Chemother. 2005;49:2314-2321.

3. Poveda E, et al. Successful rescue therapy with darunabir (TMC114) in HIV-infected patients who have failed several ritonavir-boosted protease inhibitors. AIDS. 2006;20:1558-1560.

4. Arasteh K, et al. TMC114/ritonavir substitution for protease inhibitor(s) in a non-suppressive antiretroviral regimen: a 14-day proof-of-principle trial. AIDS. 2005;19:943-947.

5. Youle M, et al. Concomitant use of an active boosted protease inhibitor with enfuvirtide in treatment-experienced, HIV-infected individuals: recent data and consensus recommendations. HIV Clin Trials. 2006;7:86-96.