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New Data on Pharmacokinetics and Safety of Dual-Boosted Tipranavir

Pressmeddelande   •   Jul 14, 2004 09:01 CEST

First HIV drug development program to examine dual-boosted PI therapy in very highly treatment-experienced patients
14 July 2004

Bangkok/Thailand, 14 July 2004 - Today, new findings from an interim analysis of a Phase IIb study of tipranavir in HIV-positive patients with very limited treatment options were presented at the 15th International AIDS Conference (IAC) in Bangkok. This is a major study conducted in the most heavily pretreated population who had screened for participation in the two Phase III RESIST studies. The four-week results demonstrate that tipranavir, a non-peptidic protease inhibitor, boosted with low-dose ritonavir (tipranavir/r) is safe and well tolerated when used both alone and in a regimen with another protease inhibitor (PI) boosted by ritonavir.

Although the study was not specifically designed to examine efficacy, the two-week data demonstrate that treatment with tipranavir/r alone had a significantly larger virologic reduction than ritonavir-boosted regimens lopinavir/r, amprenavir/r and saquinavir/r, even in this advanced patient population. At enrollment, patients in the study had been previously treated with an average of six PIs and had very high levels of PI resistance, including a median fold resistance of 100 to lopinavir.

A pharmacokinetic analysis of the tipranavir/r in combination with another PI-regimen boosted with ritonavir demonstrated that blood levels of the second PI decreased in the presence of tipranavir/r, which was added to these treatment arms at week two. The clinical relevance of the reductions has not been definitively established yet. Pharmacokinetics describes the way a drug or drugs are handled by the body.

“Interim results from the 1182.51 study demonstrate that tipranavir is highly potent, safe and well tolerated over four weeks in a patient population with very limited treatment options,” said Douglas Mayers, M.D., Therapeutic Area Head of Virology at Boehringer Ingelheim. “We are looking forward to analyzing the 24-week data to fully understand the utility of dual-boosted PIs in these very highly treatment-experienced patients.”

Four-Week Interim Analysis: Safety and Pharmacokinetics
Data from this interim analysis presented today at IAC were derived from 296 of 315 randomized patients who had reached week four by the interim report cutoff date. All dual-boosted protease inhibitor combinations with tipranavir were well tolerated and the frequency of adverse events was similar among all four treatment arms. The safety data were comparable in the first two weeks when all patients were taking single ritonavir-boosted PI regimens, and were comparable between weeks two and four when the dual-boosted PI regimens were being taken. The incidence of laboratory abnormalities was also similar in all four arms, with triglyceride elevations being the most frequent abnormality observed.

Substantial reductions in plasma PK parameters of saquinavir, amprenavir and lopinavir were observed when these boosted PIs were co-administered with tipranavir/r. The minimum drug levels (Cmin) of saquinavir, amprenavir and lopinavir decreased by 81%, 56% and 55%, respectively, from weeks two to four with the addition of TPV/r. The clinical relevance of these reductions is not yet established and recommendations for dosing adjustments cannot be made at this time.

Eight-Week Interim Analysis: Efficacy
Although study 1182.51 was designed primarily to evaluate safety and pharmacokinetics, preliminary data on efficacy were presented at the 5th International Workshop on Clinical Pharmacology of HIV Therapy in Rome in April 2004. This analysis demonstrated that for the first two weeks, the tipranavir/r control arm had a highly superior viral load response (1.2 log10 decrease) compared with the other single-boosted PI arms (