Effect of chronopharmacology and food on in vivo pharmacokinetic profile of mavacamten.

Aim: This study investigated the impact of food intake and circadian rhythms on the pharmacokinetics of mavacamten. Materials & methods: A sensitive bioanalytical method for quantifying mavacamten in rat plasma was developed and validated. This method was applied to assess the effect of chronopharmacology and food intake on the pharmacokinetics of mavacamten in rats. Results: A circadian variation at two doses resulted in significant changes in the volume of distribution, clearance and time of maximum plasma concentration of mavacamten (p < 0.05). In addition, food intake had an insignificant impact on the pharmacokinetic parameters except for the time of maximum plasma concentration (p < 0.05). Conclusion: These pharmacokinetic changes and human chronotype findings will help optimize dosing time.

Aldehyde oxidase mediated drug metabolism: an underpredicted obstacle in drug discovery and development.

Aldehyde oxidase (AO) has garnered curiosity as a non-CYP metabolizing enzyme in drug development due to unexpected consequences such as toxic metabolite generation and high metabolic clearance resulting in the clinical failure of new drugs. Therefore, poor AO mediated clearance prediction in preclinical nonhuman species remains a significant obstacle in developing novel drugs. Various isoforms of AO, such as AOX1, AOX3, AOX3L1, and AOX4 exist across species, and different AO activity among humans influences the AO mediated drug metabolism. Therefore, carefully considering the unique challenges is essential in developing successful AO substrate drugs. The in vitro to in vivo extrapolation underpredicts AO mediated drug clearance due to the lack of reliable representative animal models, substrate-specific activity, and the discrepancy between absolute concentration and activity. An in vitro tool to extrapolate in vivo clearance using a yard-stick approach is provided to address the underprediction of AO mediated drug clearance. This approach uses a range of well-known AO drug substrates as calibrators for qualitative scaling new drugs into low, medium, or high clearance category drugs. So far, in vivo investigations on chimeric mice with humanized livers (humanized mice) have predicted AO mediated metabolism to the best extent. This review addresses the critical aspects of the drug discovery stage for AO metabolism studies, challenges faced in drug development, approaches to tackle AO mediated drug clearance's underprediction, and strategies to decrease the AO metabolism of drugs.