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

“Pirtobrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay. Pirtobrutinib was aneugenic in in vitro micronucleus assays using human peripheral blood lymphocytes. Pirtobrutinib was not genotoxic in an in vivo rat bone marrow micronucleus assay at doses up to 2000 mg/kg.”

“No carcinogenicity studies with pirtobrutinib were submitted as these studies are not warranted for advanced cancer indications (ICH S9).”

“Doses ≥ 375 mg/kg twice daily caused decreased fetal body weights and increased incidence of malformations and variations in the urinary tract (including absent or abnormal ureters and kidneys), reproductive tract (malpositioned ovaries and misshapen uterus), and bone (misshapen sternebrae).”

“Safety pharmacology studies did not point to any toxicities of concern in the CNS, respiratory, or cardiovascular systems.”

“Pirtobrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay but was aneugenic in in vitro micronucleus assays using human peripheral blood lymphocytes”

“Pirtobrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay but was aneugenic in in vitro micronucleus assays using human peripheral blood lymphocytes (at approximately 37-fold the unbound human Cmax (unbound) at the recommended human dose).”

“Pirtobrutinib was not genotoxic in the rat bone marrow micronucleus assay at doses up to 2000 mg/kg.”

“The absence of carcinogenicity studies is in line with ICH guideline S9 and the assessment relied on the lack of hyperplastic changes in chronic studies (up to 3 months).”

“No carcinogenicity studies with pirtobrutinib were submitted as these studies are not warranted for advanced cancer indications (ICH S9).”

“In this in vitro GLP study, pirtobrutinib inhibited the hERG channel with an IC50 of 32 μM (15 μg/mL). This is 55-fold higher than the preliminary unbound or free human Cmax at 200 mg with 95.4% protein binding, 0.27 μg/mL, in humans.”