title: Four-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of TS-DP2, a Novel Human Granulocyte Colony Stimulating Factor in Rats.
abstract: TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of 1000 μg/kg/day. Rats received TS-DP2 intravenously at doses of 250, 500, and 1000 μg/kg/day once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 500 μg/kg/day and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was 250 μg/kg/day, and no observed adverse effect level (NOAEL) in females was 250 μg/kg/day in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures (AUC0-24h and C0) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats.
authors.affiliation: Bio Business Department, TS Corporation, Korea; Department of Molecular Bioscience, College of Bio Medical Science, Kangwon National University, Korea.
authors.forename: JooBuom
authors.initials: J
authors.lastname: Lee
authors.affiliation: R&D Center, TS Corporation, Korea.
authors.forename: Kyungsun
authors.initials: K
authors.lastname: Lee
authors.affiliation: Bio Business Department, TS Corporation, Korea; R&D Center, TS Corporation, Korea.
authors.forename: Keunbum
authors.initials: K
authors.lastname: Choe
authors.affiliation: R&D Center, TS Corporation, Korea.
authors.forename: Hyunseob
authors.initials: H
authors.lastname: Jung
authors.affiliation: R&D Center, TS Corporation, Korea.
authors.forename: Hyunseok
authors.initials: H
authors.lastname: Cho
authors.affiliation: R&D Center, TS Corporation, Korea.
authors.forename: Kiseok
authors.initials: K
authors.lastname: Choi
authors.affiliation: R&D Center, TS Corporation, Korea.
authors.forename: Taegon
authors.initials: T
authors.lastname: Kim
authors.affiliation: R&D Center, TS Corporation, Korea.
authors.forename: Seojin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Nonclinical Research Institute, Chemon Inc., Korea.
authors.forename: Hyeong-Seok
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Nonclinical Research Institute, Chemon Inc., Korea.
authors.forename: Mi-Jin
authors.initials: MJ
authors.lastname: Cha
authors.affiliation: Nonclinical Research Institute, Chemon Inc., Korea.
authors.forename: Si-Whan
authors.initials: SW
authors.lastname: Song
authors.affiliation: Nonclinical Research Institute, Chemon Inc., Korea.
authors.forename: Chul Kyu
authors.initials: CK
authors.lastname: Lee
authors.affiliation: Department of Molecular Bioscience, College of Bio Medical Science, Kangwon National University, Korea.
authors.forename: Gie-Taek
authors.initials: GT
authors.lastname: Chun
keywords: Lenograstim; Neutropenia; Rats; TS-DP2; Toxicity; Toxicokinetics; rhG-CSF