Erschienen in:
01.07.2008 | Adis Drug Evaluation
Tipranavir
A Review of its Use in the Management of HIV Infection
verfasst von:
Jennifer S. Orman, Caroline M. Perry
Erschienen in:
Drugs
|
Ausgabe 10/2008
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Summary
Abstract
Tipranavir (Aptivus®) is a selective nonpeptidic HIV-1 protease inhibitor (PI) that is used in the treatment of treatment-experienced adults with HIV-1 infection. Tipranavir is administered orally twice daily and must be given in combination with low-dose ritonavir, which is used to boost its bioavailability.
The durable efficacy of tipranavir, in combination with low-dose ritonavir (tipranavir/ritonavir 500 mg/200 mg twice daily), has been demonstrated in well designed trials in treatment-experienced adults infected with multidrug-resistant strains of HIV-1. In treatment-experienced adults with HIV-1 infection receiving an optimized background regimen, viral suppression was greater and immunological responses were better with regimens containing tipranavir/ritonavir than with comparator ritonavir-boosted PI-containing regimens. The efficacy benefit appeared to be more marked in patients receiving two fully active drugs in the regimen, with the combination of tipranavir/ritonavir and enfuvirtide (for the first time) appearing to be the most successful. Although tipranavir is generally well tolerated, clinical hepatitis and hepatic decompensation, and intracranial haemorrhage have been associated with the drug. Tipranavir also has a complex drug-interaction profile. Thus, tipranavir, administered with ritonavir, is an effective treatment option for use in the combination therapy of adults with HIV-1 infection who have been previously treated with other antiretroviral drugs.
Pharmacological Properties
Tipranavir is a highly potent and selective nonpeptidic sulfonamide-containing dihydropyrone HIV-1 PI with good in vitro activity against a broad range of laboratory strains and clinical isolates of HIV-1. In vitro, resistance to tipranavir is slow to develop and the process is complex. On-treatment genotyping of viral isolates from treatment-experienced patients in clinical trials indicate that the mutations predominantly emerging with tipranavir treatment are L33F/I/V, V82T/ L and I84V. In vitro, mutations of the HIV-1 wild-type virus that confer resistance to tipranavir also confer resistance to most other commonly used PIs, with the exception of saquinavir and darunavir. The activity of tipranavir is reduced in the presence of human plasma proteins. Synergistic, additive and antagonistic effects have been observed with tipranavir and various other antiretroviral drugs in vitro.
Tipranavir is administered in combination with low-dose ritonavir (tipranavir/ ritonavir), which boosts its bioavailability resulting in the achievement of effective plasma/serum concentrations of tipranavir with a twice-daily regimen. Depending on the dose of tipranavir/ritonavir administered, maximum plasma tipranavir concentrations are reached within 1–5 hours and, in the majority of individuals, steady state is reached after approximately 7 days of twice-daily administration. At steady state, tipranavir pharmacokinetics are linear when tipranavir is boosted by low-dose ritonavir. The effect of tipranavir/ritonavir on cytochrome P450 (CYP) isoenzymes, particularly CYP3A, and on P-glycoprotein (P-gp) results in numerous pharmacokinetic interactions between tipranavir/ ritonavir and other drugs. At steady state, tipranavir/ritonavir shows moderate inhibitory effects on hepatic CYP3A4/5, strong inhibitory effects on intestinal CYP3A4/5 and a minimal effect on the activity of P-gp, according to preliminary results of a well designed drug interaction study in healthy volunteers.
Therapeutic Efficacy
The therapeutic efficacy of oral tipranavir/ritonavir 500 mg/200 mg twice daily versus that of a ritonavir-boosted comparator PI (CPI) [lopinavir, indinavir, saquinavir or amprenavir] has been evaluated in the similarly designed randomized, nonblind, multicentre RESIST (Randomized Evaluation of Strategic Intervention in multidrug reSistant patients with Tipranavir)-1 and RESIST-2 trials in highly antiretroviral-experienced, HIV-1-infected adult patients. All patients also received concurrent treatment with an optimized background regimen (with or without enfuvirtide).
Study participants were HIV-1-infected adult patients who had received ≥3 months of previous treatment with a nucleoside reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor and a PI. Included patients had also previously received at least two PI-based regimens. At baseline, all patients had a plasma HIV-1 RNA level of ≥1000 copies/mL.
Recipients of tipranavir/ritonavir experienced a sustained response to treatment, with a significantly larger proportion of patients achieving a confirmed viral load reduction of ≥1 log10 copies/mL at 48 weeks than recipients of CPIs (primary endpoint; pooled data). In addition, the tipranavir/ritonavir treatment group had a longer time to treatment failure than did patients treated with the CPIs (primary endpoint). Immunological responses, a secondary efficacy measure, were also significantly better in the tipranavir/ritonavir group than in the recipients of CPIs. Preliminary data indicate that the efficacy of tipranavir/ritonavir is sustained for up to 156 weeks.
Tolerability
In the RESIST trials, adverse events with tipranavir/ritonavir were typical of those seen with the ritonavir-boosted CPIs, despite the higher dosage of ritonavir received by patients in the tipranavir/ritonavir group. Gastrointestinal adverse events were the most common treatment-emergent events with tipranavir/ritonavir and were usually mild. The adverse event rate per 100 patient-exposure years of any adverse event was similar among patients receiving tipranavir/ritonavir and those receiving a CPI/ritonavir. Exposure-adjusted total rates of grade 3 or 4 laboratory abnormalities were also similar in the the two treatment groups. Grade 3 or 4 elevations in triglyceride levels, cholesterol levels and liver enzymes occurred significantly more frequently among patients receiving tipranavir/ritonavir than in the CPI/ritonavir recipients. However, the most highly treatment-experienced patients did not experience grade 3 or 4 AST or ALT elevations during 96 weeks of treatment with tipranavir/ritonavir in five phase IIb/III trials. When reported, grade 3 or 4 AST or ALT elevations were were asymptomatic in the majority of patients.
Reports of clinical hepatitis and hepatic decompensation, including some fatalities, have been associated with tipranavir/ritonavir treatment, usually in patients receiving multiple medications and with advanced HIV-1-infection. Caution is recommended and increased liver enzyme monitoring should be considered in patients with liver enzyme abnormalities or hepatitis receiving tipranavir. In addition, tipranavir has been associated with fatal and nonfatal intracranial haemorrhage and should be administered with caution in patients with an increased bleeding risk (see boxed warning in the manufacturer’s prescribing information). However, rates of intracranial haemorrage in a large cohort of US Medi-Cal recipients not taking tipranavir were similar to those observed in premarketing trials of tipranavir. Rashes have been reported in patients receiving tipranavir/ritonavir.