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FDA Approval: Tipranavir
Background:
Tipranavir (Aptivus), a nonpeptidic PI with activity against many PI-resistant viruses, was given accelerated approval by the FDA on June 22, 2005. The drug must be coadministered with low-dose ritonavir to achieve adequate blood levels.
Indications:
Tipranavir is indicated for use in treatment-experienced patients with virologic failure and evidence of resistance to multiple PIs. In two pivotal, phase III clinical trials — RESIST-1 (ACC Jan 1 2005) and RESIST-2 (7th International Congress on Drug Therapy in HIV Infection, Nov 2004, Abstract PL14.3) — patients with substantial resistance to existing PIs were randomized to receive an optimized background regimen with either ritonavir-boosted tipranavir or another boosted PI. Patients who received tipranavir + ritonavir had a better virologic response as measured by both absolute viral-load reduction and the proportion of patients who achieved an undetectable viral load. Response to tipranavir + ritonavir was enhanced when other active agents — in particular T-20 — were also used (ACC Mar 21 2005). Increased resistance to tipranavir correlates with a higher number of baseline PI-resistance mutations.
Pharmacology and dosing:
Tipranavir is hepatically metabolized, predominantly by cytochrome P450 3A4 (CYP3A4). The drug’s effect on P-glycoprotein and CYP3A4 is opposite that of ritonavir, acting as an inducer of both. When tipranavir is coadministered with ritonavir, the net effect is P-glycoprotein induction at steady state and inhibition of CYP3A4. As a result, tipranavir + ritonavir has a somewhat more complex pattern of drug interactions than other PIs. For example, in one study evaluating coadministration of tipranavir + ritonavir with other PIs, tipranavir significantly lowered blood levels of lopinavir, amprenavir, and saquinavir (ACC Sep 1 2004). Prescribers should consult the package insert carefully regarding possible drug interactions.
The recommended dose of tipranavir is 500 mg (two 250-mg soft-gelatin capsules) with 200 mg of ritonavir, both administered twice daily with food. The drug must be refrigerated prior to dispensing and then maintained at 77º F or lower. No dose adjustment is required for patients with renal insufficiency.
Adverse effects:
Like other PIs, tipranavir might induce gastrointestinal symptoms, such as diarrhea, nausea, vomiting, and abdominal pain. In clinical trials, hepatitis and elevated lipid levels were more common with tipranavir than with other PIs. Because of hepatotoxicity, careful monitoring of liver function tests is recommended, especially in patients with chronic hepatitis B or C. Tipranavir contains a sulfonamide moiety, making rash another potential adverse effect.
Cost:
As of June 29, 2005, the wholesale acquisition cost of daily tipranavir is $29.80; a 1-month supply will therefore cost $894. Patients taking tipranavir will also incur the cost of ritonavir, as well as the other components of their combination regimen.
Comment: Tipranavir clearly has more in vitro activity than existing PIs against viruses with high-level PI resistance, and clinical trials show that this activity translates into increased antiviral activity. The FDA approval of tipranavir therefore offers an important new option for salvage therapy in treatment-experienced patients, particularly those who have viruses harboring multiple PI-resistance mutations. As with many new drugs, tipranavir’s effectiveness can be enhanced with coadministration of other active agents. Because many patients with PI-resistant viruses also have resistance to NRTIs and NNRTIs, clinicians will have a strong inducement to use T-20 in tipranavir-containing regimens. Monitoring tipranavir’s adverse-effect and drug-interaction profiles in clinical practice will be important.
As part of the accelerated FDA approval for tipranavir, the manufacturer (Boehringer Ingelheim) has agreed to conduct further studies in pediatric patients, women, patients coinfected with hepatitis, and treatment-naive patients. Additional drug-interaction studies are also planned.
— Paul E. Sax, MD
Published in AIDS Clinical Care June 29, 2005