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

“While ISL induced chromosomal aberrations in an in vitro Chinese hamster ovary cell assay, this effect was mitigated by the addition of inosine, suggesting it may be related to a perturbation of nucleoside/nucleotide pools rather than direct DNA interaction. Negative results in both a bacterial reverse mutation (Ames) test and an in vivo rat micronucleus assay support this interpretation.”

“Consistent with this profile, ISL was non-carcinogenic in a 2-year study in rats and in a 26-week study in rasH2 transgenic mice.”

“ISL had no effect on the fertility of male or female rats at exposures ~1000 times the human exposure at the RHD. In rats, skeletal malformations were noted only at very high exposures (~5100 times the exposure at the RHD), with a developmental no-observed-effect level (NOEL) established at exposures ~500 times the human exposure at the RHD.”

“While high doses produced transient increases in heart rate (HR) and blood pressure (BP) in rats and monkeys, no QTc prolongation was observed, and effects occurred only at exposures (Cmax) >1,000-fold the clinical exposure at the RHD.”