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Clin Pharmacol Ther. 2015 Nov;98(5):551-9. doi: 10.1002/cpt.178. Epub 2015 Aug 4.

Toxicity of a novel therapeutic agent targeting mitochondrial complex I.

Author information

1
Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, USA.
2
CPC Clinical Research, Aurora, Colorado, USA.
3
Department of Anesthesia, University of Colorado School of Medicine, Aurora, Colorado, USA.
4
Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus School of Medicine, Aurora, Colorado, USA.

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.

PMID:
26108785
DOI:
10.1002/cpt.178
[Indexed for MEDLINE]

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