Safety Assessment of D‐β‐Hydroxybutyrate: A Novel Formulation for the Treatment of Long‐Chain Fatty Acid Oxidation Disorders

ABSTRACT

Long‐chain fatty acid oxidation disorders (LC‐FAODs) represent a group of rare, life‐threatening, inborn errors of metabolism that prevent the body from converting long‐chain fatty acids into energy during periods of fasting and physiological stress. β‐D‐Hydroxybutyrate (D‐BHB) may provide an alternative energy source and noncanonical signaling to alleviate symptoms of various LC‐FAODs. A study‐enabling toxicity package with D‐BHB in a novel equimolar blend of sodium salt D‐BHB and arginine salt D‐BHB was conducted, which is reported here. D‐BHB is not mutagenic nor clastogenic/aneugenic. However, single doses of D‐BHB administered by oral gavage to the minipig induced dose‐dependent but transient increases of arterial blood pressure from 1000 mg/kg and of heart rate from 500 mg/kg. Diarrhea was observed in all minipigs receiving D‐BHB at 3000 mg/kg. When the QT is corrected for heart rate, a lengthening was observed at the three doses. D‐BHB administered to the minipig daily for 90 days at doses of 150 or 500 mg/kg BID was well tolerated, with effects limited to increases in urea concentrations at 500 mg/kg BID. D‐BHB was not tolerated at 1250 mg/kg BID, due to clinical signs of liquid feces. In addition, slight seminiferous tubular vacuolation in the testes, seen at the end of the treatment period in all males at this dose level, was considered to be adverse. The no observed adverse effect level (NOAEL) was 3500 mg/kg/day in the rat; however, the NOAEL in the more sensitive and clinically relevant minipig was 500 mg/kg BID (1000 mg/kg total/day) over 90 days, and it is this value that will be used for future development.