Journal of Pharmacovigilance

CYP3A time-dependent inhibition risk assessment using inactivation rate

6^th Pharmacovigilance Congress

September 28-30, 2016 Toronto, Canada

Zimmerlin Alfred

Novartis Pharma, Switzerland

Posters & Accepted Abstracts: J Pharmacovigil

Abstract:

Time dependent inhibition (TDI) has become the focus of drug designers much more than reversible inhibition because of the higher safety risk this mode of inhibition carries with it. The IC50 shift is the most commonly used method to risk assess TDI because it can be easily tested with modification of the standard, readily automated, reversible CYP3A inhibition testing procedures. This particular inhibition mechanism was indeed the source of a few documented late stage failures and is strongly suspected to participate in the frequently disqualifying liver toxicities in pre-clinical species. We measured kinetic inactivation parameters KI and kinact for 63 known CYP3A inactivators using a single robust method and validated a miniaturised screening assay based on inactivation rate (kobs) at 10 μM test article concentration versus the current gold standard assay. The inactivation rate constant of a large set of registered drugs (400) has been used to highlight the specific advantages of this method versus the IC50 shift. Using an empirically defined positive/negative kobs bin of 0.02 min-1, 4% of registered drugs only were found positive. This proportion increased to more than 20% when in-house lead optimization molecules were considered, emphasizing the importance of filtering this property out when selecting promising drug candidates. Finally, we suggest that the data and technology described here may be a good basis for building structure activity relationships and in silico modelling.

Biography :

Email: alfred.zimmerlin@novartis.com