Abstract
Understanding drug-drug interactions (DDI) is a key component of clinical practice ensuring patient safety and efficacy of medicines. The role of drug metabolites in DDIs is a developing area of science, and has been recently highlighted in draft regulatory guidance. The guidance states that metabolites representing ≥25% of parent drug's area under the plasma concentration/time curve and/or >10% exposure of total drug-related material should trigger in vitro characterization of metabolites for cytochrome P450 (CYP) inhibition and propensity for DDIs. The relationship between in vitro CYP inhibitory potency, systemic exposure and DDI potential of drug metabolites was examined using the Pfizer development database to identify compounds with preexisting in vivo biotransformation data, where circulating metabolites were identified in human. The database yielded 33 structurally diverse compounds with collectively 115 distinct circulating metabolites. Of these, 52% (60/115) achieved exposures >25% of parent drug levels as judged from mass balance/metabolite identification studies. It was noted that 14 metabolite standards for 12 parent drugs had been synthesized, monitored in clinical studies, and examined for CYP inhibition. For the 14 metabolite/parent drug pairs no clinically relevant DDIs were expected to occur against the major human CYP isoforms. A review of the literature for parent/metabolite DDI information was also conducted in order to examine trends using a larger data set. Leveraging the analysis of both internal and literature-based datasets, an algorithm was devised for use in drug discovery/early development to assess CYP inhibitory potential of drug metabolites and the propensity to cause a clinically relevant DDI.
- cytochrome P450
- drug interactions
- enzyme inhibitors
- in vitro-in vivo prediction
- inhibition
- metabolite kinetics
- The American Society for Pharmacology and Experimental Therapeutics