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

“In genotoxicity studies, quizartinib was mutagenic in a bacterial reverse mutation assay. Quizartinib was not genotoxic in the following assays: mouse lymphoma thymidine kinase mutation assay, chromosome aberration assay in human peripheral blood lymphocytes, and rat bone marrow micronucleus assay (tested to the maximum tolerated dose, MTD).”

“No carcinogenicity studies were conducted or are required to support the marketing of quizartinib for the current indication.”

“In an embryo-fetal development (EFD) study in rats, quizartinib at doses resulting in exposures approximately 3 times the exposure at the maximum recommended human dose (MRHD) was associated with adverse developmental outcomes including structural abnormalities (anasarca and edema) and alterations to growth (lower fetal weights and effects on skeletal ossification).”

“However, quizartinib and the major metabolite AC886 did not inhibit hERG, INa, INa-L, or ICa-L currents at clinically relevant concentrations. In vivo, a single dose of quizartinib administered to monkeys induced a dose-dependent increase in corrected QT interval (QTc) with sustained prolongation over 24 hours.”

“In genotoxicity studies, quizartinib was mutagenic in a bacterial reverse mutation assay.”

“Quizartinib was not genotoxic in the following assays: mouse lymphoma thymidine kinase mutation assay, chromosome aberration assay in human peripheral blood lymphocytes, and rat bone marrow micronucleus assay (tested to the maximum tolerated dose, MTD).”

“Of note, an equivocal result (positive genotoxicity but within the range of historical control data) at a dose approximating the MTD was obtained in the micronucleus assessment in a 28-day rat toxicology study. An additional genotoxicity study was conducted in transgenic F344 homozygous Big Blue rats, and the results were negative.”

“The lack of dedicated carcinogenicity studies is acceptable.”

“No carcinogenicity studies were conducted or are required to support the marketing of quizartinib for the current indication.”

“In summary, quizartinib showed IKs current inhibition at clinically relevant physiologic concentrations based on free drug concentration. However, quizartinib and the major metabolite AC886 did not inhibit hERG, INa, INa-L, or ICa-L currents at clinically relevant concentrations. In vivo, a single dose of quizartinib administered to monkeys induced a dose-dependent increase in corrected QT interval (QTc) with sustained prolongation over 24 hours.”