CRED Understanding Clinical Development 2024

 ADME studies in mice, rats and dogs that show that devostatin is readily absorbed after oral dosing with a bioavailability of approximately 20% in all species. Peak plasma levels were seen after approximately 5 hours and AUCs were dose proportional except at the highest dose. Steady state plasma levels were achieved in 2-3 days after repeated dosing. Terminal half-life was approximately 4 hours in the mouse and rat, and approximately 8 hours in the dog. Devostatin is extensively metabolised in the liver by a single metabolic pathway mediated by cytochrome P450 2D6. Two major metabolites and several minor metabolites have been identified which are inactive against HMG-CoA. Biliary excretion was the major route of elimination. After an oral dose, more than 90% of the drug was recovered from faeces with little or no unchanged drug recovered from urine. Tests on the Purkinje fibres and hERG channel receptors indicate that effects on the QT interval are unlikely to occur.  Single and repeated dose toxicity studies up to 3 months have been performed in a rodent and non-rodent species. The NOAEL (no observed adverse effect level) of devostatin was 60 mg/kg in mice and 20 mg/kg in dogs. The GI tract and kidney were the major target organs for devostatin-induced toxicity.

 Genotoxicity tests have shown that devostatin is not a mutagen.

Consider and answer the following questions based on the information you have been given above and information gained from presentations so far.

Question 1 Consider what phase 1 studies (pharmacokinetic and safety) should be conducted. Use the table format below to describe the design considerations for these studies and the rationale for your recommendations to the project team.

Parameter

Answer

Rationale/Comments

Main study objectives Starting dose selection Route of administration of study drug Considerations for dose levels Gender of subjects Study population & Key inclusion/exclusion criteria Age range Endpoints of interest Other clinical parameters of interest

2