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

by Selleckchem | Sep 03 2023

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.

Comments:

Title: Impact of Food Intake and Circadian Rhythms on the Pharmacokinetics of Mavacamten in Rats

Abstract: This study aimed to investigate the influence of food intake and circadian rhythms on the pharmacokinetics of mavacamten, a novel drug. A sensitive bioanalytical method was developed and validated to quantify mavacamten in rat plasma. The method was then utilized to assess the effect of chronopharmacology and food intake on the pharmacokinetics of mavacamten in rats. The results showed significant changes in the volume of distribution, clearance, and time of maximum plasma concentration of mavacamten due to circadian variation at two doses (p < 0.05). However, food intake had only a negligible impact on the pharmacokinetic parameters, except for the time of maximum plasma concentration (p < 0.05). These findings suggest that considering circadian rhythms and chronotype variations in humans may be crucial for optimizing the dosing time of mavacamten.

Keywords: mavacamten, pharmacokinetics, circadian rhythms, food intake, chronopharmacology, dosing time

1. Introduction: Mavacamten is a promising drug currently under investigation for its therapeutic potential in the treatment of certain conditions. Understanding its pharmacokinetics, including the effects of circadian rhythms and food intake, is essential for optimizing its dosing regimen. Circadian rhythms, regulated by the body's internal clock, influence various physiological processes, including drug metabolism and disposition. Food intake can also affect drug absorption, distribution, metabolism, and elimination. Therefore, assessing the impact of these factors on mavacamten pharmacokinetics is crucial for ensuring its safe and effective use.

2. Materials and Methods:

2.1. Bioanalytical Method Development and Validation: A sensitive bioanalytical method was developed to quantify mavacamten concentrations in rat plasma. The method involved [provide details of the analytical technique, such as liquid chromatography coupled with mass spectrometry (LC-MS)]. Validation of the method was performed according to regulatory guidelines to ensure its accuracy, precision, selectivity, sensitivity, linearity, and stability.

2.2. Experimental Design: Male rats were used in the study and were subjected to different dosing regimens of mavacamten. The animals were divided into groups based on their circadian rhythms (chronotypes) and food intake conditions. Mavacamten was administered orally or intravenously at two different doses. Blood samples were collected at predetermined time points, and plasma mavacamten concentrations were quantified using the validated bioanalytical method.

3. Results: The pharmacokinetic analysis revealed significant changes in mavacamten's volume of distribution, clearance, and time of maximum plasma concentration due to circadian variation at the two doses administered (p < 0.05). These findings indicate that the body's internal clock affects mavacamten's distribution and elimination processes. However, food intake had an insignificant impact on most pharmacokinetic parameters, except for the time of maximum plasma concentration, which showed a statistically significant difference (p < 0.05).

4. Conclusion: This study demonstrates that circadian rhythms significantly influence the pharmacokinetics of mavacamten in rats, while food intake has a limited impact. The observed changes in volume of distribution, clearance, and time of maximum plasma concentration suggest that considering the circadian variation in humans may be crucial for optimizing the dosing time of mavacamten. These findings contribute to a better understanding of mavacamten's pharmacokinetic profile and provide valuable insights for future clinical studies and dosing regimen optimization in humans.

Further research is warranted to confirm these results in human subjects and investigate the potential implications of chronopharmacology on mavacamten's therapeutic efficacy and safety.