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

“Pexidartinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in either the in vitro chromosomal aberrations assay in peripheral human lymphocytes or the in vivo bone marrow micronucleus assay in rats.”

“The Applicant also conducted a two-year (104-week) carcinogenicity study in rats and a 26-week carcinogenicity study in transgenic mice. Pexidartinib was negative for carcinogenicity in these studies.”

“Oral administration of pexidartinib to pregnant animals during the period of organogenesis resulted in malformations, post-implantation loss, and abortion at maternal exposures that were approximately equal to the human exposure at the recommended dose (see Data ) .”

“There were no pexidartinib-related adverse effects on the central nervous system or respiratory function following a single dose up to 200 mg/kg. Pexidartinib inhibited the hERG potassium channel with an IC50=0.7 μM, suggesting some potential for QTc prolongation; however, there were no effects on QTc or other electrocardiogram parameters in in vivo animal studies”

“Pexidartinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in either the in vitro chromosomal aberrations assay in peripheral human lymphocytes or the in vivo bone marrow micronucleus assay in rats.”

“Pexidartinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in either the in vitro chromosomal aberrations assay in peripheral human lymphocytes or the in vivo bone marrow micronucleus assay in rats.”

“Pexidartinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test or clastogenic in either the in vitro chromosomal aberrations assay in peripheral human lymphocytes or the in vivo bone marrow micronucleus assay in rats.”

“The Applicant also conducted a two-year (104-week) carcinogenicity study in rats and a 26-week carcinogenicity study in transgenic mice. Pexidartinib was negative for carcinogenicity in these studies.”

“The Applicant conducted a two-year (104-week) carcinogenicity study with pexidartinib in rats and a 26-week carcinogenicity study in rasH2 transgenic mice (See Appendix 19.3 for full review).”

“Pexidartinib inhibited the hERG potassium channel with an IC50=0.7 μM, suggesting some potential for QTc prolongation; however, there were no effects on QTc or other electrocardiogram parameters in in vivo animal studies and no evidence of QT prolongation occurring in humans at the 800 mg dose, likely due to the high protein binding of pexidartinib in human plasma”