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

“Lonafarnib was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using human whole blood lymphocytes, or the in vivo mouse micronucleus assay.”

“The Applicant will be required to conduct a carcinogenicity study postapproval.”

“In pregnant rats, post-implantation loss (resorptions) was seen at plasma drug exposures approximately equal to that achieved in humans. In pregnant rabbits, skeletal malformations were seen at plasma drug exposures lower than human exposures.”

“The hERG IC50 was 1.3 µM (0.83 µg/mL), which is approximately 3 times below the clinical Cmax (2.64 µg/mL).”

“Lonafarnib was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using human whole blood lymphocytes, or the in vivo mouse micronucleus assay.”

“Lonafarnib was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using human whole blood lymphocytes, or the in vivo mouse micronucleus assay.”

“Lonafarnib was not mutagenic or clastogenic in the Ames test, the in vitro chromosomal aberration test using human whole blood lymphocytes, or the in vivo mouse micronucleus assay.”

“The Applicant will be required to conduct a carcinogenicity study postapproval.”

“As agreed at the pre-IND meeting held on August 22, 2018 (PIND 139923), the Applicant will conduct a carcinogenicity study postapproval.”

“However, when considering the plasma protein binding of lonafarnib, which was very high (>99%), the free fraction concentration in the patient (0.01 x 2.64 µg/mL = 0.026 µg/mL) is 32 times lower than the hERG IC50.”