Clinical Pharmacokinetics and Preclinical Pharmacodynamics of (+)‐Epicatechin on Cardiometabolic Endpoints

Abstract

We have previously reported on the capacity of the cacao flavanol (−)‐epicatechin to vigorously stimulate mitochondria biogenesis and beneficially impact metabolism. However, preliminary studies indicate that the (+) epimer form may be more potent. In the present study, we report on the pharmacokinetics (PK), partial pharmacodynamics (PD) and initial safety analysis of (+)‐epicatechin (Epi) using a Phase I study performed in pre‐diabetic subjects. Using a mouse model of diet‐induced obesity and insulin resistance we also provide PD evidence of the metabolic effects of (+)‐Epi vs. those of (+)‐catechin to determine if the effects observed correspond to class actions. For the Phase I PK study, subjects were provided a single incremental dose of (+)‐Epi using either 10, 30 or 100 mg in capsules. For the PD study, subjects were provided a single 30 mg dose/day for 7 days. In all subjects blood samples were collected and an assessment of standard safety measures were performed. Results indicate that incremental doses of (+)‐Epi increase the half life of blood metabolites ranging from ~2–6 h. Seven day dosing of prediabetic subjects leads to a trend in reducing blood glucose levels (p=0.053) and markers of inflammation. No adverse effects were reported and the compound was well tolerated. In obese‐insulin resistant animals, 2 weeks of dosing (0.003, 0.01, 0.03, 0.1 and 0.3 mg/kg/day by oral gavage) led to a dose dependent significant improvement in markers of metabolism (weight gain, glucose, cholesterol, triglycerides with doses as low as 0.01 mg/kg/day). (+)‐Catechin yielded no effects at 0.1 mg/kg/day. Overall results indicate that (+)‐Epi evidences a favorable PK and safety profile. The compound exerts a positive impact on metabolism which may link to enhanced mitochondrial bioenergetics. The effects noted are not due to antioxidant actions as (+)‐catechin yielded no effects.Support or Funding InformationNIH AT8310, DK9871, Cardero Therapeutics, Inc.