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

“Pitolisant and its metabolites were not mutagenic in the in vitro bacterial reverse mutation assay (Ames), or clastogenic in the in vitro mammalian chromosomal aberration assay. Pitolisant was negative in the in vivo mouse micronucleus assay.”

“A two-year carcinogenicity study of pitolisant was conducted in rats and a 6-month carcinogenicity study was conducted in tgRasH2 mice. The executive carcinogenicity assessment committee concluded that these studies were adequate and that there were no drug-related neoplasms in either study.”

“At the maternally toxic doses, fetal toxicity included stillbirths, postnatal pup mortality (due to lack of milk or failure to nurse) and decreased pup length and weight. Pitolisant was teratogenic at 22 times the MRHD based on mg/m2 , causing major malformations including cleft palate and abnormal limb flexure.”

“In safety pharmacology studies, pitolisant was a moderate hERG channel inhibitor with an IC50 of 1.32 µM. However, in in vivo studies in rat, rabbit and dog, pitolisant had minimal to no effect on QTc intervals and no pro-arrhythmic potential.”