Toxicity of a novel therapeutic agent targeting mitochondrial complex I. Issue 5 (4th August 2015)

• Record Type: Journal Article
• Authors: Low Wang, CC; Galinkin, JL; Hiatt, WR
• Is Part Of: Clinical pharmacology & therapeutics. Volume 98:Issue 5(2015:Nov.)
• Page Start: 551
• Page End: 559
• Publication Date: 2015-08-04
• Subjects: Pharmacology -- Periodicals; Therapeutics -- Periodicals; 615.5
• DOI: 10.1002/cpt.178
• Languages: English
• ISSNs: 0009-9236

Abstract

Abstract : R118 is an experimental compound that completed preclinical development as a potential medical therapy for the exercise limitation in peripheral artery disease. Animal studies established that R118 provided partial and reversible mitochondrial complex I inhibition with consequent increases in adenosine monophosphate (AMP) kinase activation in liver and skeletal muscle. After demonstration of improved exercise performance in a mouse model and safety in rodent and primate models, a phase I trial was performed in 24 subjects randomized to R118 vs. placebo (5:1) in escalating doses. Plasma lactic acid levels were transiently elevated in 20% of subjects at the lowest dose and in 100% of subjects using a different formulation at the highest dose, which was associated with hospitalization in all subjects and severe metabolic acidosis requiring prolonged intubation in two subjects. Thus, inhibition of mitochondrial complex I with R118 resulted in severe lactic acidosis, representing unacceptable toxicity from this mechanism of action.