title: Tipranavir: a protease inhibitor from a new class with distinct antiviral activity.
abstract: Tipranavir (TPV) is the first of a new class of non-peptidic protease inhibitors (NPPIs). It is a sulphonamide-containing dihydropyrone, which is highly selective for the HIV protease enzyme and demonstrates potent in vitro activity against wild-type HIV-1 and HIV-2. The IC90 for TPV was 0.1 microM against clinical HIV isolates. Since CYP3A is the major cytochrome P450 isoform for the phase I metabolism of TPV, its exposure is markedly enhanced in the presence of ritonavir (RTV). In one clinical study, using the new self emulsifying drug delivery system (SEDDS) formulation of TPV, plasma concentrations in excess of 20 microM were maintained for 12 hours, allowing for twice-a-day dosing following administration of TPV 300 mg/RTV(r) 200 mg twice a day. The 20 microM target represents 10-fold the IC90 for multiple protease inhibitor (PI)-resistant strains. Both in vitro data and pharmacokinetic results indicate that TPV will be active in vivo against PI-resistant viruses, when given twice a day in combination with low dose RTV. Of 105 HIV viral isolates taken from patients who had been heavily pretreated with PI-based regimens: 90% were fully susceptible to TPV; 8% exhibited intermediate resistance; and 2% were more than 10-fold resistant. In patients who had failed at least two PI-based regimens, only 12.2% of the HIV isolates exhibited four to 10-fold reduced susceptibility to TPV after one year of treatment with a regimen containing the NPPI (Study BI1182.2). A reduction of approximately 1.5 log10 copies/mL in the plasma viral load (pVL) was observed in treatment-naive patients after 15 days of monotherapy with TPV (300 or 1200 mg twice a day) co-administered with RTV (200 mg twice a day) (TPV/r) in a dose-ranging study (Study BI1182.3). The safety and efficacy of TPV (500 or 1250 mg) plus ritonavir (100 mg twice a day) plus two new nucleoside reverse transcriptase inhibitors (NRTIs) was studied in patients failing their first PI-containing regimen (Study BI1182.4). Similar decreases in pVLs (1.44-1.79 log10 copies/mL) were observed after 16 weeks of treatment with either dose of TPV/r. Two doses of TPV/r plus efavirenz (EFV) and a new NRTI have been studied in non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive patients who had failed two or more PI-containing regimens (BI1182.2). Between 50% and 78.9% of patients maintained a pVL < 50 copies/mL for 48 weeks. Clinical studies have shown that TPV/r-associated adverse events are generally gastrointestinal-associated, transient and mild. A phase II study will define the optimal dose of TPV/r for highly treatment-experienced patients. The safety and efficacy of this dose of TPV/r will be evaluated in two phase III studies that will enroll more than 1300 patients worldwide. Tipranavir's robust activity against PI-resistant strains results from its molecular flexibility, which allows it to fit into the active pocket of the protease enzyme in viruses that have become resistant to other PIs.
authors.affiliation: CHU Bichat-Claude Bernard, 46, rue Henri-Huchard, 75877 Paris Cedex 18, France. patrick.yeni@bch.ap-hop-paris.fr
authors.forename: Patrick
authors.initials: P
authors.lastname: Yeni
mesh_terms: D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D066298:In Vitro Techniques; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011753:Pyrones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides
chemical_list: D017320:HIV Protease Inhibitors; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; C107201:tipranavir