Prediction of CYP Down Regulation after Tusamitamab Ravtansine Administration (a DM4-Conjugate), Based on an In Vitro-In Vivo Extrapolation Approach.

Tusamitamab ravtansine is an antibody-drug conjugate (ADC) composed of a humanized monoclonal antibody (IgG1) and DM4 payload. Even if DM4 and its main metabolite methyl-DM4 (Me-DM4) circulate at low concentrations after ADC administration, their potential as perpetrators of cytochrome P450 mediated drug-drug interaction was assessed. In vitro studies in human hepatocytes indicated that Me-DM4 elicited a clear concentration-dependent down regulation of cytochrome P450 enzymes (CYP3A4, 1A2, and 2B6).

Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Focus on Downregulation, CYP2C Induction, and CYP2B6 Positive Control.

The European Medicines Agency (EMA), the Pharmaceutical and Medical Devices Agency (PMDA), and the Food and Drug Administration (FDA) have issued guidelines for the conduct of drug-drug interaction studies. To examine the applicability of these regulatory recommendations specifically for induction, a group of scientists, under the auspices of the Drug Metabolism Leadership Group of the Innovation and Quality (IQ) Consortium, formed the Induction Working Group (IWG). A team of 19 scientists, from 16 of the 39 pharmaceutical companies that are members of the IQ Consortium and two Contract Research Organizations reviewed the recommendations, focusing initially on the current EMA guidelines.

Effect of deuteration on metabolism and clearance of Nerispirdine (HP184) and AVE5638.

Replacing hydrogen with deuterium as a means of altering ADME properties of drug molecules has recently enjoyed a renaissance, such that at least two deuterated chemical entities are currently in clinical development. Although most research in this area aims to increase the metabolic stability, and hence half-life of the active species, experience has shown that prediction of the in vivo behaviour of deuterated molecules is difficult and depends on multiple factors including the complexity of the metabolic scheme, the enzymes involved and hence the mechanism of the rate-determining step in the biotransformation. In an effort to elucidate some of these factors we examined the metabolic behaviour of two molecules from the Sanofi portfolio in a range of in vitro and in vivo systems.