Linearity and stationarity of the pharmacokinetics of tiludronate in horses

Two studies were conducted in order to assess the linearity and stationarity of the pharmacokinetics of tiludronate in horses. For each study, plasma concentrations of tiludronate were measured by HPLC-UV at regular intervals and noncompartmental analysis was performed. First, single intravenous administrations of 0.05 (group 1, n = 5), 0.1 (group 2, n = 5) and 0.2 mg/kg (group 3, n = 5) were performed in healthy male adult horses. A linear relationship between groups was found for C5min (C5min = 0.0726 + 11.8589 * dose) as well as for AUC0-inf (AUC0-inf = -0.632561 + 30.9649 * dose). Clearance ranged from 0.033 to 0.044 L/h/kg and was not significantly different between groups. MRT (h) were 3.96, 4.95 and 9.40 and VDss (L/kg) were 0.16, 0.19 and 0.28 for the 0.05, 0.1 and 0.2 mg/kg doses respectively. Second, 10 daily intravenous administrations at a dosage rate of 0.1 mg/kg were administered to 4 healthy horses. Plasma tiludronate concentrations were measured after the 1st and 10th dose as well as 8 hours after each dose. The mean plasma accumulation ratio between the 1st and the 10th dose was 1.31 ± 0.48. Medians of the tiludronate concentration values measured in plasma 8 hours post-dose were not statistically different between doses. Maximum and minimum concentrations of tiludronate (mg/L) following the last dose were 0.91 and 0.04 respectively. It was concluded that the pharmacokinetics of tiludronate in horses are linear from 0.05 to 0.2 mg/kg IV and stationary after 10 IV administrations of 0.1 mg/kg.