Pharmacokinetics of Osaterone Acetate after Repeated Oral Administration at 0.25 MG/KG/Day for 7 Days
A GLP study was performed on 6 non-fasted Beagle dogs to evaluate the pharmacokinetics of osaterone acetate (OSA) (YPOZANE, Virbac) after a 7-day oral repeated administration at the therapeutic dosage of 0.25 mg/kg/day. Blood samplings were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours after the 1st treatment, at 1, 2, 4, 6, 8, 12 and 24 hours after the 4th treatment, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours and 2, 3, 5, 8, 12, 15 days after the 7th treatment. OSA in plasma was quantified by validated Liquid Chromatography with Mass/Mass detection with a LOQ of 2.0ng/ml. According to a model for repeated administration, Tau (Interval between 2 administrations), Cmaxss (Maximal observed concentration at steady state during Tau), Tmaxss (Time for Cmaxss), Cmin (Minimal observed concentration at steady state during Tau), AUCss (Area Under the Curve at steady state during Tau), Cav (Mean concentration between 2 administrations: AUCss/Tau), Cmax1 (Cmax after the 1st administration) were calculated with Kinetica software (InnaPhase). Accumulation ratio (R1) was calculated as the ratio of Cmaxss to Cmax1. According to a non-compartmental analysis for extra-vascular administration, for single day of administration (1st, 4th and 7th administration), Cmax, Tmax, AUC0-t (AUC between t0 and time of the last quantifiable concentration), Lz (Constant of elimination rate, slope of the log-linear regression (ln concentration versus time) calculated for the last points to maximise the r coefficient), AUC0-24h (AUC from 0 to 24h after each administration) were calculated with Kinetica. Accumulation ratio (R2) was calculated as the ratio of AUC0-24h between 7th and 1st administration. The plasma concentration and the AUC of OSA were higher after the 7th dose than after the 1st dose (see table and figure). After 7-day oral administration, a bioaccumulation of OSA was demonstrated (R1 = 3.1 ± 1.0 and R2 = 4.2 ± 1.0) in correlation with a long elimination half-life.