HIV protease inhibitor impresses in preclinical trials
inhibitor that has demonstrated cross-resistance profile and
multi-drug resistant strains of HIV-1 compared to other HIV
protease inhibitors, which are fast becoming ineffective against
emergent strains.
PPL-100 is a phosphorylated pro-drug of Procyon's PL-100 protease inhibitor. PL-100 is the active antiviral agent that is potent, specific and non-cytotoxic with a favorable cross-resistance profile in drug and multi-drug resistant strains of HIV-1.
PL-100 has been shown activity against several HIV-1 strains specifically selected for key mutations that render these strains resistant to currently marketed protease inhibitors.
Due to the limited number of new HIV/AIDS therapies and increasing resistance exhibited by the virus to drugs already on the market, the need for an effective protease inhibitor that maintains activity against most protease inhibitor (PI)-resistant strains of HIV remains a high priority.
Over 50 per cent of HIV patients on drug therapy are experiencing drug or multi-drug resistance and 10-20 per cent of the newly diagnosed patients are now presenting resistance.
Preclinical studies, which included safety and toxicity evaluations in 28-day repeated oral dose studies, were demonstrated in rats as well as 14-day repeated oral dose studies in beagle dogs.
No Observed Adverse Effect Level (NOAEL) was seen in rats at a dose of 1000 mg/kg/day (equivalent to a total dose of 10 grams/day in a 65 Kg. adult human), demonstrating an equal or better safety profile in animals for PPL-100 when compared to several commercially available HIV protease inhibitors.
In a similar study with a combination of PPL-100 and Ritonavir (a "boosting" agent), the NOAEL was observed at a ratio of 6:1 for the drugs (1000:167 mg/kg/day), being well within acceptable limits for these compounds.
Results from the dog study were similar to those in the rat study, showing a NOAEL at 300 mg/kg/day (equivalent to a 10 grams/day in a 65 kg. adult human).
Additional studies for cardiac safety pharmacology and genotoxicity have also confirmed the safety of the drug.
"We are pleased with the solid safety profile of our PPL-100 HIV protease inhibitor as this is a critical issue in the development of such compounds," said Hans Mader, president and CEO of Procyon Biopharma.
"Together with the favourable cross-resistance profile, increased bioavailability through the Pro-drug approach, we believe PPL-100 to be a promising therapy for the treatment of HIV-infection and we are on track to begin clinical trials by year end," he added.
A prodrug is a pharmacological substance (usually a drug) which is administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolised in the body (in vivo) into the active compound.
The rationale behind the use of a prodrug is generally for ADME optimisation. Prodrugs are usually designed to improve oral bioavailability - poor absorption from the gastrointestinal tract is usually the limiting factor, and is often due to the chemical properties of the drug.
In rational drug design, the knowledge of chemical properties likely to improve absorption and the major metabolic pathways in the body allows the modification of the structure of new chemical entities for improved bioavailability.
Protease inhibitors are extremely powerful antiviral agents and are a key component of the polytherapy that is commonly used to treat HIV/AIDS.
However, they are associated with complex dosage schedules, viral resistance, a multitude of potentially harmful drug interactions and serious side effects such as abnormal fat deposit, diabetes and coronary heart disease.
GlaxoSmithKline's Amprenavir (Agenerase), Merck & Co's Indinavir (Crixivan) and Abbot Laboratories' Lopinavir and Ritonavir (Kaletra) are examples of drugs in this class.
