Metabolic Chiral Inversion of Brivanib and Its Relevance to Safety and Pharmacology

Abstract

ABSTRACT:Brivanib alaninate is an orally administered alanine prodrug of brivanib, a dual inhibitor of the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling pathways. It is currently in clinical trials for the treatment of hepatocellular carcinoma and colorectal cancer. Brivanib has a single asymmetric center derived from a secondary alcohol. The potential for chiral inversion was investigated in incubations with liver subcellular fractions and in animals and humans after oral doses of brivanib alaninate. Incubations of [ 14 C]brivanib alaninate with liver microsomes and cytosols from rats, monkeys, and humans followed by chiral chromatography resulted in two radioactive peaks, corresponding to brivanib and its enantiomer. The percentage of the enantiomeric metabolite relative to brivanib in microsomal and cytosolic incubations of different species in the presence of NADPH ranged from 11.6 to 15.8 and 0.8 to 3.1%, respectively. The proposed mechanism of inversion involves the oxidation of brivanib to a ketone metabolite, which is subsequently reduced to brivanib and its enantiomer. After oral doses of brivanib alaninate to rats and monkeys, the enantiomeric metabolite was a prominent drug-related component in plasma, with the percentages of area under the curve (AUC) at 94.7 and 39.7%, respectively, relative to brivanib. In humans, the enantiomeric metabolite was a minor circulating component, with the AUC <3% of brivanib. Pharmacological studies indicated that brivanib and its enantiomer had similar potency toward the inhibition of VEGF receptor-2 and FGF receptor-1 kinases. Because of low plasma concentration in humans, the enantiomeric metabolite was not expected to contribute significantly to target-related pharmacology of brivanib. Moreover, adequate exposure in the toxicology species suggested no specific safety concerns with respect to exposure to the enantiomeric metabolite.

An Animal Study to Compare Hepatoprotective Effects Between Fermented Rice Bran and Fermented Rice Germ and Soybean in a Sprague-Dawley Rat Model of Alcohol-Induced Hepatic Injury

“…The activity of ADH was measured using a spectrophotometry based on its indicator, the degree of the conversion of NAD (Sigma Chemical Co., Louis, MO, USA) to nicotinamide adenine dinucleotide dehydrogenase (NADH), as described previously [41,42]. In addition, the activity of ALDH was measured using the methods of Koivula and Koivusalo [43,44].…”

Pharmacokinetic Aspects of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors

“…Brivanib, applied in patients with advanced malignancies, has been found to be metabolized by various liver enzymes, such as CYP1A2, CYP3A4, and sulfotransferase to a high extent [108,[111][112][113]. When brivanib was administered as a radioactive-labeled dose, excretion occurred predominantly as its metabolites and 81.54 % of the radioactivity was detected in the feces, whereas renal excretion played only an insignificant role [108,111].…”

QSAR analysis of VEGFR-2 inhibitors based on machine learning, Topomer CoMFA and molecule docking

“…VEGFR-2 inhibitors are generally classified into the following categories according to their binding mode: (a) Type I kinase inhibitors, such as sunitinib and brivanib alaninate, whose heterocycles competitively occupy the hydrophobic cavity with hydrophobic forces, instead of ATP [ 11 , 12 ]. (b) Novel type I kinase inhibitors, including lenvatinib, fruquintinib and axitinib, each of which has an additional chemical fragment based on the structure of type I kinase inhibitor.…”