Chapter 25 Tipranavir

INTRODUCTION

The availability of potent antiretroviral drugs, including protease inhibitors (PI), and their use in combination regimens–highly active antiretroviral therapy (HAART)–has led to a dramatic decline in the morbidity and mortality associated with human immunodeficiency (HIV) infection.^1,² However, despite the success of HAART, there is a growing concern over the development of resistance to antiretroviral drugs. Treatment experienced patients with HIV-1 variants resistant to one or more antiretroviral agents comprise an ever larger proportion of the HIV-infected population. These patients typically have multiple PI resistance mutations conferring some level of resistance to most available PIs, including lopinavir. Furthermore, transmission of single or multidrug resistant viruses has been well documented.³ Thus, there is an urgent need to develop new PIs with a substantial activity against resistant variants.

Tipranavir (TPV), a nonpeptidic PI with unique resistance characteristics, demonstrated potent inhibitory activity in vitro against variants resistant to currently available PIs, suggesting that it may offer potential therapeutic advantages in PI-experienced patients with uncontrolled viral replication.

CHEMICAL STRUCTURE

TPV is a nonpeptidic PI belonging to the class of 4-hydroxy-5, 6-dihydro-2-pyrone sulfonamides (Fig. 25-1). The chemical name of TPV is 2-pyridinesulfonamide, N-3-(1R-1-(6R)-5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-propyl-2H-pyran-3-ylpropyl)phenyl-5-trifluoromethyl). It has a molecular weight of 602.7. It has been suggested that TPV binds to the active site of the protease enzyme with fewer hydrogen bonds than peptidic PI, resulting in increased flexibility that allows the drug to adjust to amino acid changes in the active site.⁴ Other studies propose that the strong hydrogen bonding interaction with the amide backbone of the protease site Asp30 is responsible for the favorable antiviral activity of TPV against isolates with multiple PI-associated mutations.⁵

Figure 25-1 Chemical structure of tipranavir.

It is a white to slightly yellow solid that is freely soluble in dehydrated alcohol and propylene glycol and insoluble at pH 7.5 in aqueous buffer.

The marketed formulation of TPV (Aptivus) is a soft gelatin capsule for oral administration. Each capsule contains TPV 250 mg.

IN VITRO ACTIVITY

TPV is a potent and selective inhibitor of HIV protease. In general, it has exhibited potent antiviral activity with 90% inhibitory concentration (IC₉₀) ranging from 0.03 to 0.18 μM.⁶ When tested in human serum, protein binding decreases the activity of TPV by 3.75-fold. TPV retains in vitro antiviral activity against both laboratory and patient-derived isolates resistant to multiple other PIs with an IC₉₀ of 0.18–0.45 μM.^7,⁸ TPV is also active against HIV-2.

PHARMACOKINETICS AND METABOLISM

TPV has a low solubility, resulting in limited absorption in humans. The capsules were formulated with a self-emulsifying drug delivery system (SEDDS) to achieve maximum absorption. TPV pharmacokinetics were characterized alone and in combination with ritonavir (RTV) in 95 healthy volunteers, which demonstrated that the minimum concentrations for TPV did not exceed the target threshold expected to be necessary to treat PI-resistant virus without RTV boosting.⁹ TPV 500 mg bid given with RTV 200 mg bid results in close to a 50-fold increase in the morning trough of TPV concentrations compared with TPV administered without RTV, allowing to obtain levels exceeding the IC₅₀ for resistant virus by 27- to 50-fold. TPV should be taken with a standard or high-fat meal, which increases the area under the curve (AUC) by ∼30% and improves the gastrointestinal tolerability.¹⁰ TPV is extensively bound to plasma proteins (>99.9%). Based on molecular weight and high protein binding, TPV is not expected to penetrate the central nervous system to an appreciable extent.

Cytochrome P450 (CYP)-3A is the major isoform that is involved in TPV metabolism in vivo. CYP-3A is induced by TPV and inhibited by RTV. The RTV inhibition predominates when the two drugs are co-administered. TPV metabolism is then minimal, with only trace metabolites detected and >98% of TPV remaining in the unchanged form through the dosing interval. TPV is a substrate for a weak inhibitor and a potent inducer as well of P-glycoprotein (P-gp). This is an important issue in antiretroviral therapy because P-gp can pump PIs out of cells and thus decrease antiviral efficacy. On the other hand, RTV is an inhibitor of P-gp. The clinical significance of TPV/RTV co-administration and of their interaction with P-gp is difficult to predict. Data suggest that the net effect of TPV/RTV at the proposed dose regimen (500/200 mg) is P-gp induction at steady state.¹¹

About 80% of TPV is excreted in the feces. Renal clearance is negligible. TPV exhibits linear pharmacokinetics with a mean elimination half-live of 6 h at steady state.

For patients with renal impairment, no clinically significant difference in TPV clearance is expected. Close clinical and laboratory monitoring of patients with mild or moderate hepatic impairment is important. TPV is contraindicated in severe hepatic impairment.

EFFICACY

The in vivo antiviral efficacy of TPV in antiretroviral-naive patients was evaluated in study BI 1182.3.¹² The median change from baseline in HIV-1 RNA value over 14 days was −0.77 log₁₀ when TPV was given alone at a dose of 1200 mg twice daily, and was significantly better when TPV was co-administered with RTV: −1.43 log₁₀ and −1.64 log₁₀ with TPV/RTV 300/200 mg and TPV/RTV 1200/200 mg twice daily, respectively.

In study BI 1182.52, three doses of TPV/RTV (500/100, 300/200, and 750/200 bid) were evaluated in patients who had previously failed at least two PI-based regimens and had one or more primary mutations. In the first 2 weeks, the current PI was replaced by TPV/RTV but the background regimen was held constant. During this 2-week functional monotherapy phase, the median HIV reductions from baseline in 216 patients were 0.9, 1.0, and 1.2 log₁₀ copies/mL for TPV/RTV 500/100, 500/200 and 750/200 mg, respectively.¹³ HIV-1 RNA reductions at week 24 across the doses were dependent on the number of baseline viral PI mutations. Patients in the two higher dose groups required more than one baseline viral mutation before TPV activity started to decrease. A dose–response relationship was noted for adverse events with the highest incidence of grade 3–4 gastrointestinal symptoms in the group receiving the highest dose; the grade 3–4 aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were also more common in the 750/200 mg group, with almost 13% of patients experiencing this degree of elevation in ALT. Although the 750/200 mg twice-daily dose had slightly more activity, the 500/200 mg twice-daily dose was selected for further evaluation in phase III trials.

BI 1182.51 study enrolled patients who had three or four mutations at codons 33, 82, 84, and 90. The initial phase of the study was a randomized comparison of optimized background therapy and one of the four following PI regimens: TPV/RTV 500/200 mg bid, lopinavir/RTV 400/100 mg bid, amprenavir/RTV 600/100 mg bid or saquinavir/RTV 1000/100 mg bid. After day 14, TPV/RTV was added to treatment of subjects initially randomized to receive one of the three currently available PIs, with the objective of evaluating pharmacokinetic interactions between TPV/RTV 500/200 mg and a second RTV boosted PI. The first part of the study allowed a randomized 14-day comparison of TPV/RTV versus three other boosted PI regimens given as functional monotherapy. Over 14 days, plasma HIV RNA levels decreased by 1.2 log₁₀ copies/mL in patients taking TPV/RTV, compared with reductions <0.4 log₁₀ copies/mL in each of the other boosted PI arms.¹⁴

The 24-week results from the two pivotal randomized, controlled, open-label studies, ‘Randomized Evaluation of Strategic Intervention in multidrug resistant Subjects with Tipranavir’ (RESIST) I and II led to FDA approval of TPV. RESIST I was conducted in North America and Australia while RESIST II recruited patients from Europe and Latin America. These two multicenter studies compared TPV/RTV 500/200 mg bid with a comparator PI plus RTV as booster twice daily, administered in combination with an optimized background regimen chosen on the basis of genotypic resistance testing. Patients were triple class-experienced and had failed at least two PI-based regimens. They were receiving PI treatment at the time of screening. The presence of at least one primary protease mutation at 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, and 90 and no more than two protease mutations at codons 33, 82, 84, and 90 was required for entry into the study. The primary endpoint of the RESIST trials was the proportion of patients with two consecutive viral load measurements >1 log₁₀ below baseline after 24 weeks of treatment.

There were 1483 subjects enrolled in the two RESIST trials. Characteristics of RESIST patients at baseline were as follows. Patients had received a median of four PIs, six nucleosides, and one non-nucleoside reverse transcriptase inhibitor (NNRTI). Mean baseline HIV RNA levels was 4.73 log₁₀ copies/mL and mean CD4+ T-lymphocyte counts ∼195/mm³. Patients had a median of 16 baseline, nonconsensus viral protease gene mutations, including resistance associated and polymorphism mutations. Almost 40% of patients began the trial with a viral load above 100 000 copies/mL.

The comparator PI was selected by study investigators based on screening viral resistance tests and included lopinavir/RTV (∼50% of patients), amprenavir/RTV (∼25% of patients), saquinavir/RTV, and indinavir/RTV. Overall, 25% of the patients in each arm used enfuvirtide. The comparator PI background regimen and enfuvirtide use were decided prior to randomization, which was stratified by comparator PI and enfuvirtide use.

Some issues need to be discussed. Although the optimal background antiretroviral therapy was predetermined before randomization, the number of subjects who had enfuvirtide predetermined as part of their optimized background treatment differed from the number of subjects who actually took enfuvirtide, due to a net loss of 25 subjects in the control arm. Some investigators, who wanted to save enfuvirtide for use with a known active PI, changed optimized background treatment once subjects were randomized in the control arm. Since there was difficulty in enrolling for the RESIST trials, the protocol was amended to allow subjects with no available active PI, as per their genotype, to enroll. Therefore, the control PI arm was not optimal for PI component in all patients.

The interim 24 week efficacy analysis contained 1159 patients of which 582 randomized to the TPV 500 mg/RTV 200 mg arm and 577 to the RTV-boosted comparator PI (CPI) arm. Week 24 results demonstrated that the proportion of treatment responders was significantly greater in the TPV group versus control group for both the RESIST studies. Treatment outcome details are shown in Table 25-1.^15,¹⁶ The proportion of treatment responders in the TPV/RTV group was similar across both RESIST I and RESIST II studies. There was no difference in the proportion of patients who developed AIDS in TPV/RTV and in CPI/RTV group.

Table 25-1 Selected 24-Week Treatment Outcome Data From the Combined RESIST Trials