Brukinsa: genotox, carcinogenicity and repro: done or skipped?

“Zanubrutinib was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in either the in vitro chromosomal aberrations assay or in the in vivo bone marrow micronucleus assay in rats.”

“No carcinogenicity studies have been conducted or are required to support marketing of zanubrutinib for the current indication.”

“In an embryo-fetal development study in female rats, once daily administration of zanubrutinib at 30, 75, or 150 mg/kg/day on GD 6-17 resulted in fetal heart malformations in the form of 2- or 3-chambered hearts.”

“Zanubrutinib had no toxicologically-significant effects on cardiovascular function in a cardiovascular study in telemetered dogs, and had no effects on neurobehavioral function, temperature, or respiratory function in CNS and respiratory studies conducted in male rats.”

“Zanubrutinib was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in either the in vitro chromosomal aberrations assay or in the in vivo bone marrow micronucleus assay in rats.”

“BGB-3111 did not induce chromosome aberrations in Chinese Hamster Ovary cells with or without metabolic activation.”

“BGB-3111 did not increase the frequency of micronucleated polychromatic erythrocytes in rats after oral administration.”

“No carcinogenicity studies have been conducted or are required to support marketing of zanubrutinib for the current indication.”

“No carcinogenicity studies have been conducted or are required to support marketing of zanubrutinib for the current indication.”

“In the GLP-study (2017), IC50 for BGB-3111 was determined to be 9.11 µM and 50 nM for the positive control terfenadine. Based on this study, the risk of hERG inhibition is low considering the Cmax at steady state being approximately 1 µM.”