title: Toxicity of a novel therapeutic agent targeting mitochondrial complex I.
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.
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, USA.|CPC Clinical Research, Aurora, Colorado, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Low Wang
authors.affiliation: CPC Clinical Research, Aurora, Colorado, USA.|Department of Anesthesia, University of Colorado School of Medicine, Aurora, Colorado, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Galinkin
authors.affiliation: CPC Clinical Research, Aurora, Colorado, USA.|Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, USA.
authors.forename: W R
authors.initials: WR
authors.lastname: Hiatt
mesh_terms: D000293:Adolescent; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D015507:Drugs, Investigational / Q000008:administration & dosage* / Q000009:adverse effects*; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000097:blood; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000097:blood; D008297:Male; D009325:Nausea / Q000139:chemically induced / Q000175:diagnosis
chemical_list: D015507:Drugs, Investigational; D019344:Lactic Acid; D042967:Electron Transport Complex I