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FDA Approval: Darunavir
Darunavir has substantial activity against PI-resistant viruses and offers several advantages over tipranavir.
Background:
The FDA granted accelerated approval for the PI darunavir (Prezista) on June 23, 2006. Darunavir has in vitro activity against many PI-resistant viruses and must be coadministered with ritonavir to achieve therapeutic drug levels.
Indications:
Darunavir is indicated for the treatment of HIV infection in treatment-experienced adults, such as those with strains resistant to more than one PI. Its approval was based on favorable 24-week results from the POWER studies, which have been presented at several meetings over the past 2 years (ACC Mar 21 2005, Sep 14 2005 and Feb 1 2006). In these studies, triple-class–experienced patients with viral loads >1000 copies/mL and at least one major PI-associated mutation were randomized to receive an optimized background regimen plus either ritonavir-boosted darunavir or a comparator PI. More than half of the patients had three or more major PI mutations. At 24 weeks, the proportion of patients with viral loads <400 copies/mL was 63% in those receiving darunavir at a twice-daily dosage of 600 mg plus 100 mg of ritonavir versus 19% in those receiving comparator PIs. As in other studies of investigational agents in heavily treatment-experienced patients, the use of additional active agents (notably, T-20) increased overall response, especially in patients with more advanced HIV disease as defined by a lower CD4-cell count.
Pharmacology and dosing:
Like other PIs, darunavir is hepatically metabolized by cytochrome P450 3A (CYP3A); hence, drug levels are significantly increased by the required co-dosing with ritonavir. Both darunavir and ritonavir inhibit CYP3A, so the drug–drug interactions seen with most other boosted PIs are expected with this one as well. Because darunavir does not induce P-glycoprotein as tipranavir does, it has fewer and more-predictable drug–drug interactions than this agent.
The recommended dose is 600 mg (two 300-mg tablets) of darunavir plus 100 mg of ritonavir, both administered twice daily with food. The type of food does not affect absorption of darunavir as it does other PIs, such as nelfinavir. No dose adjustment is required in renal insufficiency; dose adjustments in patients with hepatic impairment have not been studied.
A clinical trial in treatment-naive patients is ongoing, using a dose of 800 mg of darunavir (two 400-mg tablets) with 100 mg of ritonavir. The 400-mg tablets are not yet commercially available, and darunavir is not approved for this indication.
Adverse effects:
In the POWER studies, the most commonly reported adverse effects with darunavir were gastrointestinal (nausea and diarrhea); however, these effects did not occur more frequently than in the control arm. Similarly, rates of elevated transaminases and lipids were comparable to those seen with comparator PIs. Because darunavir contains a sulfonamide moiety (as do fosamprenavir and tipranavir), it should be used with caution in patients with sulfonamide allergies. A mild-to-moderate rash occurred in 7% of patients receiving the drug in clinical trials; it did not usually require drug cessation, but severe rashes (including Stevens-Johnson syndrome) have been reported.
Cost and availability:
As of June 26, 2006, the wholesale acquisition cost of daily darunavir was US$25. A 1-month supply will therefore cost $750. Patients taking darunavir will also incur the cost of ritonavir and other components of their combination regimens. Darunavir is expected to be in pharmacies this week.
Comment: Darunavir joins tipranavir as an approved PI with substantial activity against PI-resistant viruses. However, it has several notable advantages over tipranavir:
• fewer drug–drug interactions
• a lower required dose of ritonavir (100 mg twice daily vs. 200 mg twice daily)
• rates of abnormal liver function tests and lipid elevations that are comparable to those seen with comparator PIs
• a tablet formulation with more heat stability
In addition, if clinical studies confirm preliminary results from the resistance analyses of the POWER studies (ACC Mar 15 2006), then patients who do not respond to darunavir may still respond to tipranavir. Given these advantages, most clinicians will probably select darunavir as the PI of choice for patients with multiple PI mutations.
— Paul E. Sax, MD
Published in AIDS Clinical Care June 28, 2006