PNU-140690 (tipranavir) is a novel , nonpeptidic inhibitor of the HIV protease enzyme which exhibits high enzymatic inhibition (Ki = 8 pM) and potent in vitro antiviral activity (IC₉₀ = 100 nM in cell culture) [1]. In vitro, it has a high degree of activity against a variety of laboratory and clinical isolates [2]. Specifically, the IC₉₀ against a panel of wild-type and zidovudine- and delavirdine-resistant strains was 0.03-0.32 µM (except for a single strain with an IC₉₀ of 0.8 µM) in a PBMC-based model. It is of note that the IC₉₀ remained in the sub-micromolar range when isolates resistant to other protease inhibitors (ritonavir, indinavir, nelfinavir and saquinavir) were evaluated. Using standard laboratory models, the combination of tipranavir and ritonavir has been shown to be additive or synergistic against ritonavir-sensitive and -resistant isolates [3].

In order to better define the parameters of drug administration, 900 mg tipranavir was administered in a randomized cross-over study to 12 healthy volunteers. The volunteers were given six 150 mg capsules in a fasting state, after a high-fat breakfast, and after administration of an antacid [4]. Total drug exposure was two-fold higher post-prandially than in the fasting state, while antacids decreased exposure by about 33%. Multiple dose studies were then conducted, once again in healthy volunteers [5]. Doses of 300-2000 mg tid were evaluated over 12 days. Neurologic toxicity was observed in some individuals at the 2000 mg dose, while trough levels exceeded 1 µM for doses of 900 mg tid and higher. In a first phase I/II trial in HIV-infected patients, tipranavir was given at doses of 900-1500 mg tid to 24 PI-naive patients on stable NRTI therapy. At the two higher doses, a 90% (1.0 log₁₀) decrease in plasma viral load was measured over 4 weeks. At steady state, the mean (±SD) trough tipranavir concentration at the 1200 mg dose (the dose being proposed for use in subsequent trials) was 1.9 ± 1.2 µM-well above the levels required to inhibit wild-type viruses. In this short study, there was no evidence of tipranavir resistance [6].

One of the main proposed advantages of tipranavir is its potential activity against viruses that have become resistant to other PI, due to its novel non-peptidic structure and its flexible binding to the protease active site. To evaluate this potential, in vitro studies were conducted using 107 isolates broadly resistant to all currently available PI and 28 other isolates resistant to one of these agents [7]. The results are summarised in the table below.

N	Indinavir	Nelfinavir	Ritonavir	Saquinavir	Tipranavir
107	R	R	R	R	96S, 8I, 3R*
13	R	S	R	S	S
10	S	R	S	S	S
5	S	S	S	S	HS**

R = resistant
S = sensitive
I = intermediate resistance
*Resistance is associated with 82T/84V or 84V/90M. Isolates with 48V/82A/90M remain susceptible to tipranavir.
**Hypersensitivity (2.5x IC₅₀ vs. wild-type isolates) is associated with 48V/82A.

In vitro, it appears that tipranavir has the potential to retain activity against the majority of isolates that have become resistant to the majority of other protease inhibitors, though no data have yet been generated on isolates that are resistant to amprenavir. However, these data must be confirmed in clinical trials to determine the in vivo activity of tipranavir, that is, when drug pressure is applied in a more complex model. At the present time, one of the major drawbacks to further study of tipranavir is practical; the drug must be administered as eight large capsules three times a day with a heavy meal. Preliminary data suggest that it may be possible to address this issue by co-administering ritonavir, allowing for convenient twice daily dosing. If this is correct, tipranavir will be among the first of the "second generation" protease inhibitors (specifically designed for use against drug-resistant isolates) to prove its worth where it counts… in real patients. Preliminary data allow us to be cautiously optimistic in this regard.

Related HIVresistanceWeb articles:

New Antiretroviral Drugs (Report From the 3rd International Workshop on HIV Drug Resistance). (Charles Boucher, Sept/Oct 1999)