Tipranavir Hiv [104110

Country of

US

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Originator

Pharmacia &

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Upjohn

First

US

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Introduced by

Boehringer

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Ingelheim

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Trade name

Aptivus

CAS registry No

174484-414191150-83-1

Molecular

602.66

weight

(Disodium salt = 646.64)

Tipranavir, an oral non-peptidic HIV protease inhibitor, was granted accelerated approval for use in combination with ritanovir and was subsequently launched the same month in 2005. The targeted patient population includes HIV-1 infected adults with evidence of viral replication and demonstrated resistance to multiple protease inhibitors. As with other protease inhibitors, binding at the HIV-1 protease's active site inhibits the virus-specific processing of the Gag and Gag-Pol polyproteins in HIV-1-infected cells resulting in the production of non-infectious virions. An effective regimen to reduce viral load and to preserve immune function typically consists of a cocktail of a protease inhibitor and at least one nucleoside reverse transcriptase inhibitor. It is believed that tipranavir has been effective where other protease inhibitors have encountered resistance because, as a non-peptidic inhibitor, it was designed by structure-based analysis to have increased flexibility making it acquiescent to conformational alterations at the binding site. Tipranavir is synthesized by a convergent route amenable to large-scale production. By splitting the molecule in half and constructing the C3-C4 bond of the dihydropyrone ring via a key aldol addition of a nitroaromatic ester to an aldehyde handle of the other half, the two stereocenters of the target can be set independently by prior enantiomeric resolution of each precursor. Furthermore, the shrewd selection of intermediates facilitates isolation and purification by crystallization. While, tip-ranavir has a K of <0.01 nM against HIV-1 and < 1 nM against HIV-2, its poor solubility, impaired bioavailability, and high-protein binding (>99%) initially resulted in a large pill burden, requiring between 4 and 8 capsules twice a day. Changing from the original 300 mg hard-filled capsule to a 250 mg self-emulsifying drug delivery system (SEDDS), significantly, improved the dissolution and bioavailability of tipranavir. A two-fold increase in systemic concentration was realized, thus, cutting the daily dose in half. Maximum plasma concentrations are, however, achieved with co-administration of ritonavir, particularly taken with a high-fat meal. Ritonavir inhibits CYP3A4, the predominant enzyme involved in tipranavir metabolism. The other factor responsible for the enhanced plasma levels is the fact that ritonavir also inhibits the P-glycoprotein efflux pump for which tipranavir is a substrate. Boosting with ritonavir (200 mg) increased tipranavir Cmin 4-fold and Cmax 20-fold. The primary route of excretion is through the feces (83%) with an effective mean elimination half-life of 4.8 h in healthy volunteers and 6.0 h in HIV-infected adults. The efficacy of tipranavir/ritonavir combination therapy has been evaluated in multiple clinical trials. The number of patients exhibiting < 50 or 400log10 copies/mL HIV RNA, change in viral load, and change in CD4 cell count were all considered primary endpoints. For example, the Phase III RESIST-2 trial enrolled more than 800 patients in Europe and South America. These patients had advanced HIV disease and were experiencing virologic failure. In addition, they had already endured a multiple drug regimen with documented protease inhibitor resistance. The results from the co-administration of tipranavir/ ritonavir (tipranavir/r, 500 mg tipranavir (2 x 250mg) + 200mg ritonavir (2 x 100 mg)) were compared to a marketed protease inhibitor/ritonavir (CPI/r) combination. A decrease in viral load from baseline of 1 log10 or greater was achieved in 41% of patients who received tipranavir/r compared to 14.9% of patients in the CPI/r group. Furthermore, patients receiving tipranavir/r therapy experienced greater increases in CD4+ cell counts compared to the CPI/r group —31 cells/mm3 and 1 cell/mm3, respectively. While the adverse events were comparable between the two groups, the tipranavir/r patients displayed a higher rate of liver enzyme and lipid elevations; however, no observable symptoms resulted from these abnormal laboratory measurements. In general, the adverse events included nausea, vomiting, and diarrhea. While tipranavir is a CYP3A4 inducer and substrate, as previously stated, its co-administration with the CYP3A4 inhibitor ritonavir results in net inhibition; therefore, patients should avoid the concomitant use of drugs highly dependent on CYP3A4 for clearance. The complete list of contraindicated drugs can be found in the package insert, but the general classes include antiar-rhythmics, antihistamines, antimycobacterials, neuroleptics, sedatives, ergot derivatives, GI motility agents, and the herbal supplement St. John's wort. Finally, as the elevated liver enzyme levels suggest, tipranavir should not be taken by patients with severe liver disease. Patients with clinical symptoms of hepatitis should immediately discontinue use of tipranavir. It is highly recommended that liver function tests be performed prior to treatment and throughout the course of therapy.

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