Pharmacology Update: Tipranavir Capsules (Aptivus®)
Pharmacology Update
Tipranavir Capsules (Aptivus®)
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.
Tipranavir is a recently approved protease inhibitor for the treatment of HIV-1 infections. It is a selective non-peptide HIV-1 protease inhibitor for treatment-experienced adults with resistance to multiple protease inhibitors. Tipranavir is marketed by Boehringer Ingelheim as Aptivus®.
Indications
Tipranavir, given with ritonavir, is indicated for combination antiretroviral therapy in HIV-1 infected patients who show viral replication and are highly treatment-experienced or have viral strains resistant to multiple protease inhibitors.1
Dosage
The recommended dose is 500 mg (2 ´ 250 mg), taken with ritonavir 200 mg, twice daily with food. Administration of antacids or didanosine should be separated by at least 2 hours.1
Tipranavir is supplied as 250 mg capsules.
Potential Advantages
In vitro data suggest that most clinical strains of HIV-1 highly resistant to other protease inhibitors remain susceptible to tipranavir.2 Generally a few mutations lead to resistance with the traditional protease inhibitors, 16-20 protease gene mutations are needed to confer resistance to tipranavir. Evaluation of isolates from clinical trials, the presence of 3 protease inhibitor resistance-associated mutations have resulted in a 2.2 fold increase in wild-type IC50 for tipranavir compared to 17-422 fold increase for available protease inhibitors.
Potential Disadvantages
Serious hepatotoxicity has been associated with tipranavir/ritonavir. Liver function tests should be performed at baseline and frequently during therapy. Patients co-infected with hepatitis B or C are at greater risk. Tipranavir/ritonavir is an inhibitor of CYP3A and 2D6 and an inducer of P-glycoprotein.1 Ritonavir boosted tipranavir is not appropriate for treatment-naïve patients. Tipranavir contains a sulfonamide moiety and used be used with caution in patients with known sulfa allergy.1
Comments
Tipranavir is a non-peptide protease inhibitor that may allow for more flexible binding to the enzyme site compared to the larger peptide PIs. FDA approval was based on 2 unpublished randomized, controlled, open label studies (n = 1159). In these studies, patients on a failing protease inhibitor-based regimen, who have previously received at least two-PI based regimens, were randomization to ritonavir boosted tipranavir plus optimized background regimen (OBR) or another boosted PI regimen (lopinavir, amprenavir, saquinavir, or indinavir) plus OBR.1 Patients in the comparator arm generally had virus resistant as their selected PI. Virologic response (HIV-1 RNA < 50 copies/mL) at 24 weeks was 23% for tipranavir/ritonavir and 9% for the comparator. Forty percent achieved at least a 1 log10 decrease in viral load compared to 18% respectively. Tipranavir is synergistic with and appears to work best when combined with enfuvirtide.1,3 It has a < 4-fold decrease in susceptibility against 90% of isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, or saquinavir.1 Potential for hepatotoxicity and complex drug interactions are problematic. The wholesale cost for tipranavir (without ritonavir) is $869 per 30 days.
Clinical Implication
Tipranavir should be reserved for salvage therapy in antiretroviral-experienced patients who harbor HIV-1 virus resistant to other protease inhibitors.
References
1. Aptius Product Information. Boehringer Ingelheim Pharmaceutical, Inc. June 2005.
2. Plosker GL, Figgitt DP. Drugs. 2003;63:2317-2323.
3. FDA Information Sheet. www.aidsmeds.com/drugs/Aptivus.htm.
Tipranavir is a recently approved protease inhibitor for the treatment of HIV-1 infections. It is a selective non-peptide HIV-1 protease inhibitor for treatment-experienced adults with resistance to multiple protease inhibitors. Tipranavir is marketed by Boehringer Ingelheim as Aptivus®.Subscribe Now for Access
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