This HIV drug offers option when other therapeutics fail

July 25, 2005

Based on early data from clinical trials, the Food & Drug Administration's Antiviral Drugs Advisory Committee recommended tipranavir (Aptivus, Boehringer Ingelheim) for accelerated approval in May. The product was approved in June and is now available through wholesalers. Although not a first-line drug for HIV, tipranavir, a protease inhibitor (PI), could be an important option for a subset of patients with advanced disease.

Based on early data from clinical trials, the Food & Drug Administration's Antiviral Drugs Advisory Committee recommended tipranavir (Aptivus, Boehringer Ingelheim) for accelerated approval in May. The product was approved in June and is now available through wholesalers. Although not a first-line drug for HIV, tipranavir, a protease inhibitor (PI), could be an important option for a subset of patients with advanced disease.

Tipranavir has been approved for use with ritonavir (Norvir, Abbott) and is to be taken in addition to an established antiviral regimen. Ritonavir increases circulating levels of PIs, including tipranavir. "Boosting" PIs with small doses of ritonavir has become common in antiviral therapies. The tipranavir/ritonavir duo is indicated for HIV-1 infected adults who are highly treatment-experienced or have HIV-1 strains resistant to multiple PIs, and who have evidence of viral replication.

Tipranavir labeling will carry a warning that the drug can cause hepatitis and hepatic decompensation. In some cases, the latter has been fatal. The risk for hepatotoxicity is higher for patients with chronic hepatitis B or C. Boehringer Ingelheim cautions that patients with moderate to severe hepatic insufficiency should not take tipranavir. Close monitoring of liver function is recommended for all patients taking the drug.

The tipranavir/ritonavir regimen has extensive drug interaction potential. Tipranavir inhibits CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2D6. Ritonavir inhibits both CYP3A and CYP2D6. Furthermore, tipranavir and ritonavir have conflicting actions on P-glycoprotein (P-gp). It is important to note that while tipranavir interactions with other drugs have been studied, the effect ofthe tipranavir/ritonavir regimen on many of these same drugs has not.

Management of drug interactions will depend on the drugs involved. In some cases, the problem may be solved with dose adjustments. In others, changes in drug selection may be required. Because tipranavir inhibits CYP3A, drugs that are substrates for this enzyme can increase to dangerous levels when coadministered with the tipranavir/ritonavir combination. These drugs are contraindicated.

Tipranavir also interacts with several other drugs. The list in the prescribing information includes calcium-channel blockers, narcotic analgesics, and hypoglycemics. Dose adjustments or drug selection changes may be warranted when tipranavir is combined with any drug on the list.

Adding tipranavir to an established HIV therapy may be a bit tricky. At least one study found that tipranavir decreased concentrations of other PIs, in some cases to subtherapeutic levels. Tipranavir had a similar effect on nucleoside reverse transcriptase inhibitors. Adding tipranavir/ritonavir to abacavir (Ziagen, GlaxoSmithKline), zidovudine (Retrovir, GlaxoSmithKline), amprenavir (Agenerase, Glaxo-SmithKline), lopinavir (Kaletra, Abbott), or saquinavir (Invirase, Roche) is not recommended.

Despite the restrictions to tipranavir therapy, the drug remains a promising alternative for patients failing on their current regimens. Tipranavir trials will continue, and their results will show whether the drug is effective in slowing clinical progression of HIV. Additional safety data will be obtained, and efficacy in newly diagnosed, pediatric, and female HIV patients will be assessed.

Jillene Magill-Lewis, R.Ph. is a healthcare writer based in Washington State.