A Randomized, Double-Blind, Crossover Study to Investigate the Pharmacokinetics of Extended-Release Melatonin Compared to Immediate-Release Melatonin in Healthy Adults

Abstract

Exogenous melatonin can be helpful for treatment of some sleep disorders. However, immediate-release formulations are rapidly absorbed and cleared from the body making it difficult to provide coverage for an entire sleep period. Extended-release melatonin formulations can better mimic the naturally occurring melatonin profile and increase efficacy, but few studies have reported on their pharmacokinetics. To assess the pharmacokinetics of extended-release melatonin, we conducted a randomized, double-blind, crossover study of extended-release melatonin (4 mg) compared to immediate-release melatonin (4 mg) in 18 healthy adults, ages 18–65 years. Participants received immediate-release or extended-release melatonin in clinic after an 8 h fast, and blood samples were taken over a 10-h period. After a 7-day washout period, the same procedures were repeated with the melatonin form not previously received. Extended-release melatonin had a longer time to peak concentration (1.56 vs 0.6 h) and elimination half-life (1.63 vs 0.95 h) compared with immediate-release melatonin. Maximum concentration was lower for extended-release melatonin compared with immediate-release melatonin (7581 pg/mL vs 13120 pg/mL). Extended-release melatonin raised melatonin levels in as little as 15 min and sustained elevated melatonin levels (>300 pg/mL) for 6 h before falling below 50 pg/mL by 9 h. No clinically relevant adverse events were observed, and safety parameters remained within normal ranges for both formulations. The pharmacokinetic profile of this extended-release melatonin formulation suggests that it could be used for future efficacy studies of melatonin and sleep outcomes. This trial is registered at ClinicalTrials.gov, NCT04067791.

Keywords:

• Extended-release
• melatonin
• pharmacokinetics
• prolonged-release

Acknowledgements

We thank Ann G. Liu, PhD for assistance with the preparation of this report.

Disclosure statement

JGM, DW, DLDF, MF, SJG, RWG, and SHM are employees of Pharmavite, LLC.

Author contributions

JGM, DW, DLDF, and SHM conceived of and designed the study. JGM, DW, MF, SJG performed key procedures and acquired data. JGM, RWG, SHM contributed to the analysis and interpretation of the data. All authors critically reviewed the manuscript and approved the final version.

Additional information

Funding

This research was funded by Pharmavite, LLC.

Notes on contributors

Jonathan G. Mun

Jonathan Mun, PhD is a Principal Nutrition Scientist at Pharmavite, a dietary supplements company dedicated to quality products that help people lead healthier lives. He holds a PhD in Nutritional Sciences from the University of Illinois at Urbana-Champaign, and his areas of expertise include plant science, nutritional biochemistry, neuroscience, and sleep. His interest is in translating preclinical and clinical research into affordable products that improve public health and quality of life.

Dan Wang

Dan Wang, PhD is Product Research and Development Scientist of Pharmavite. He has contributed to the growth of the dietary supplement industry for past 30 years. He is an inventor of two patented technology/products, and developer of over 50 dietary supplement products. His major research interests included therapeutic nutrition of cereal dietary fiber for hypercholesterolemia and the genetics of the nutrition quality of cereal grain.

Denise L. Doerflein Fulk

Denise Doerflein Fulk, BS currently holds the position of Senior Product Development Manager at Pharmavite, a dietary supplements company. She has more than 20 years of experience in the food/supplement industry, providing technical and strategic leadership in the areas of product development, research, quality assurance and production. She has developed a multitude of innovative products in both the food and supplement industries.

Mina Fakhary

Mina Fakhary, MS, she serves as Principal Scientist at Pharmavite. She obtained her master’s degree in chemistry from California State University Northridge. She possesses over 16 years of experience in pharmaceutical and nutraceutical industry. She has extensive experience on developing and validating analytical methods for identification and measurement of actives in finished products and raw materials.

Scott J. Gualco

Scott Gualco, MSc currently holds the position of Verification Programs Manager at Pharmavite. He obtained a Master of Science in Agriculture with a specialization in Dairy Products Technology from California Polytechnic State University, San Luis Obispo, and has over 10 years of experience in Quality Assurance in the food industry. His areas of expertise include new product development, GMP systems auditing, and manufacturing process control.

Ryan W. Grant

Ryan Grant, PhD is the Senior Manager of Nutrition Science at Pharmavite. He received his PhD in Nutritional Sciences from the University of Illinois at Urbana-Champaign. Ryan’s team provides technical and strategic leadership for developing the science-supported benefits of Pharmavite’s supplements. Ryan applies his broad background in nutrition and specific expertise in metabolism, immunology and inflammation to tackle scientific questions from proof-of-concept research to clinical trials supporting commercialized products.

Susan Hazels Mitmesser

Susan Hazels Mitmesser, PhD, is a creative and dynamic research scientist with nutritional biochemistry experience in various industries, academia, and clinical settings. Her multidisciplinary training in basic, applied, and human clinical sciences, with extensive experience in biomedical research, experimental design, statistical analyses, and abstract/manuscript preparation sets her apart as a visionary in strategic research planning, implementation, and execution. Dr. Mitmesser has 20 years of leadership experience and currently serves as the VP of Science and Technology at Pharmavite. At Pharmavite, she provides scientific and technical leadership on pre-clinical and clinical research, innovation, product development, medical education with a focus on the safety, effectiveness, and biological activity of compounds found in foods. Additionally, physical research is emphasized to determine the best way to deliver compounds to improve consumer compliance and satisfaction. Dr. Mitmesser serves on the Editorial Board of four peer-reviewed journals, has published in numerous peer-reviewed journals and is a contributing author for book chapters relating to nutrition in adult and pediatric populations. She is an active member of the American Society of Nutrition, the American Association for the Advancement of Science, and serves on the Senior Scientific Advisory Council for the Council for Responsible Nutrition. Dr. Mitmesser holds two adjunct professorships at the University of Connecticut and Tufts University.