Approaches of validation of a 2-week combined repeated oral dose toxicity study with plasma micro sampling toxicokinetics (PMS-TK) in common marmosets

Abstract

We investigated the viability of a combined repeated dose toxicity study, including toxicokinetics (TK), in common marmosets according to the ICH-S4, ICH-S3A and ICH-S7A Guidelines using valsartan as test article whose non-clinical repeated dose toxicity studies had been conducted using this species for regulatory purpose. Valsartan was administered orally to 3 animals/sex at 200 mg/kg/day for 2 weeks. In addition to the routine parameters in repeated dose toxicity studies, safety pharmacology parameters (examinations of the central nervous, respiratory and cardiovascular systems) were also evaluated. The Plasma Micro Sampling Toxicokinetics (PMS-TK) method required ultrasensitive quantitation, was employed to evaluate the relationship between toxic changes and plasma concentrations as well as the effects of frequent blood sampling in individual animals. In valsartan, toxic findings (a deteriorated physical condition; moribundity of one male and one female on Day 14; sporadic vomitus; decreases in body weights and food consumption; decreases in erythrocytic parameters; and renal changes such as an increase in urea nitrogen, dilation of the tubules and hypertrophy of the tubular epithelium) were similar and plasma concentrations comparable to the results in the approval information. Furthermore, no side effects caused by frequent blood sampling were confirmed in the negative control group. Consequently, a combined repeated dose toxicity study including TK analysis using the PMS-TK method is viable in common marmosets and contributes to animal welfare.