First pharmacokinetic results for HIV protease inhibitor

The first pharmacokinetics in-vivo results with Procyon Biopharma's PPL-100, a phosphorylated pro-drug of its protease inhibitor, PL-100 have indicated that PPL-100 is 1000-fold more water soluble than its precursor, PL-100.

More importantly, pharmacokinetics studies conducted in rats showed a two- to three-fold improvement in key pharmacokinetic parameters such as maximum plasma concentration (C_max) and oral bioavailability compared with PL-100. Plasma levels obtained with PPL-100 in rats suggest that PPL-100's previously-reported broad and favourable cross resistance profile will be supported in a clinical setting by encouraging pharmacokinetics results at this time. 'As oral bioavailability remains a challenge for the HIV protease inhibitor class, we are most happy to report significant progress with the development of PPL-100, a pro-drug of PL-100, which is much more water soluble as well as more bioavailable,' said Hans Mader, president and ceo of Procyon Biopharma Inc. 'PPL-100 presents the same favourable cross-resistance profile as the original molecule acquired from Pharmacor. However, its improved solubility and bioavailability should allow for the same therapeutic effect on drug-resistant HIV-infection but with potentially improved dosing characteristics,' he added.

Previously, the results of cross-resistance studies conducted at ViroLogic showed that PPL-100's median EC₉₅ (i.e. the concentration required to inhibit 95% of the viral replication of the diverse drug-resistant HIV-1 variants tested) was 72 to 83 ng/ml. When adjustments were made for protein binding, the median EC₉₅ was estimated to be 430 to 500 ng/ml. Oral dosing with 100 mg/kg of PPL-100 in conjunction with 17 mg/kg of ritonavir, used as a pharmacokinetic boosting agent, in rats showed that adequate plasma levels could be maintained above this level for up to 10 hours. On the basis of PPL-100's cross-resistance data and these pharmacokinetics results, it is expected that equivalent doses of PPL-100 in man will effectively inhibit replication of protease-resistant HIV strains. Moreover, this preliminary data also suggests that PPL-100 could be administered using a convenient twice-daily dosing regimen.

As reported in February 2005, a large viral cross-resistance study in collaboration with ViroLogic showed that PPL-100 and its back-up analogue PL-337 had a highly competitive and unique cross-resistance profile when compared with other commercially available protease inhibitors. PPL-100, its back-up compound, PL-337, and six commercially available protease inhibitors: amprenavir, atazanavir, indinavir, lopinavir, nelfinavir and saquinavir were tested for antiviral activity against 63 drug resistant HIV strains. On average, PPL-100 showed better cross-resistance profile than the approved protease inhibitors tested. Both median and mean fold-change in EC₅₀ for PPL-100 were significantly lower than the approved protease inhibitors tested. In addition the viral strains selected for the study also contained important resistant mutations for two other compounds currently in clinical studies by pharmaceutical companies. These strains were found to be susceptible to both PPL-100 and PL-337.

Procyon is planning to conduct additional pharmacokinetics studies in another animal species to confirm the results obtained in rodents. The company is also conducting 14 to 28 day GLP toxicology studies in two different animal species and is on track to file an Investigational New Drug (IND/CTA) submission and initiate a Phase I first-in-man trial with healthy volunteers during the second half of 2005.