title: N-vinylpyrrolidone dimer (VPD), a novel excipient for oral drugs: repeat-dose oral toxicity in Sprague-Dawley rats.
abstract: N-vinylpyrrolidone dimer (VPD), a novel vehicle for preclinical toxicity studies, was evaluated in a standard 28-day oral toxicity study in rats including a 4 week recovery period. In addition, a subgroup of animals was dosed for 13 weeks. In the 28-day study arm, daily dosages of 0 (saline control, 3mL/kg), 300, 1000 or 3000mg/kg at respective dose volumes of 0.3, 1 and 3mL/kg were administered. In the 13 week study arm, animals received daily doses of 0 or 300mg/kg. No test item related mortality or changes in body weight, food consumption, ophthalmology and clinical pathology parameters were observed after 28-days or 13 weeks of administration. VPD induced transient salivation at all tested dose levels after each dose and increased water consumption at doses ≥1000mg/kg (28-day arm). After 28-days of administration, urinalysis revealed slightly higher mean specific gravity in all treated groups. Relevant organ weight changes consisted of increased mean liver weights. Histopathology revealed hepatocellular centrilobular hypertrophy at a dose-related incidence and severity, minimal to slight follicular cell hypertrophy in male thyroids, hypertrophy of basophil/chromophobe cells in pituitaries and an increase in kidney hyaline droplets consistent with α(2μ)-globuline immunohistochemistry. After a 4-week recovery, all changes were partially or completely reversible. Administration of VPD at 300mg/kg for 13 weeks caused similar histopathological findings observed after 28-days dosing. Overall, in rats, repeated high oral doses of VPD produced changes in the liver, thyroid and pituitary, most likely secondary to hepatic microsomal enzyme induction and stimulation of the thyroid via disruption of the hypothalamic-pituitary-thyroid axis. In conclusion, our data suggest that VPD is a promising vehicle for preclinical studies. However, in rats, findings secondary to hepatic microsomal enzyme induction and stimulation of the thyroid need to be taken into consideration, depending on dose and study duration. In order to develop VPD as a preclinical excipient, additional preclinical toxicity studies (non-rodents, different administration routes, chronic and reproductive toxicity) would be beneficial.
authors.affiliation: Abbott GmbH & Co. KG, Global Preclinical Safety, Development Sciences, 67061 Ludwigshafen, Germany. silke.weber@abbott.com
authors.forename: S
authors.initials: S
authors.lastname: Weber
authors.forename: S
authors.initials: S
authors.lastname: Halm
authors.forename: M
authors.initials: M
authors.lastname: Du Vall
authors.forename: K
authors.initials: K
authors.lastname: Whitney
authors.forename: G
authors.initials: G
authors.lastname: Blaich
authors.forename: D
authors.initials: D
authors.lastname: Bury
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D005079:Excipients / Q000633:toxicity*; D005260:Female; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D011760:Pyrrolidinones / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013961:Thyroid Gland / Q000187:drug effects / Q000473:pathology
chemical_list: D005079:Excipients; D011760:Pyrrolidinones; C042670:N-vinyl-2-pyrrolidinone