RESUMEN
BACKGROUND: A novel, high bioavailability oral, enteric coated tablet formulation of S-adenosylmethionine (MSI-195) has been developed for life science application. The present research reports on a Phase 1 study to (i) determine the safety of single doses of MSI-195 (ii) to determine the dose proportionality of MSI-195 at doses of 400, 800 and 1600 mg (iii) determine the pharmacokinetics of MSI-195 compared with a commercial reference product (SAM-e Complete™) over 24 h and (iv) to determine the effect of food on the pharmacokinetic profile of MSI-195 in human subjects. METHODS: This study was a pharmacokinetic and safety evaluation of MSI-195 and a commercial comparator broken into two stages. The first stage was an exploratory single ascending dose design of MSI-195 in 8 healthy normal male volunteers. The second stage was a single dose evaluation, targeting 26 male and female volunteers at set doses of MSI-195 and commercial comparator in a cross-over design followed by a food effect study on MSI-195. Plasma samples were collected and assayed for S-adenosylmethionine using a validated HPLC method with MS/MS detection. The main absorption and disposition parameters were calculated using a non-compartmental approach with a log-linear terminal phase assumption. Statistical analysis was based on an ANOVA model or t test as appropriate. RESULTS: MSI-195 was found to be generally well tolerated with an adverse event profile similar to the SAM-e Complete™ comparator product. The relative bioavailability of MSI-195 was approximately 2.8-fold higher than SAM-e Complete based on area under the curve (AUC) ratios for the two products and the MSI-195 formulation exposure based on AUC was found to be approximately dose proportional. There was a significant food effect for MSI-195 with a delayed time to maximum absorption Tmax, going from 4.5 h under fasted conditions to 13 h under fed conditions, and area under the curve with food reduced to 55% of that seen under fasting conditions. CONCLUSIONS: The overall conclusion was that MSI-195 was well tolerated and has markedly higher bioavailability compared with both the SAM-e Complete™ commercial product tested and, on a per mg basis, products reported in other literature. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT04623034 . Retrospectively registered Nov 9, 2020.