Pharmacokinetics and milk discard times of pirlimycin after intramammary infusion: a population approach

A population pharmacokinetic approach was used to analyse milk concentration data to determine whether milk discard times and the clearance of intramammary infusions of pirlimycin could be adequately predicted by readily available demographic variables. Milk samples were collected at 12 hourly milking intervals after dosing with pirlimycin during product development from both normal cows (primary data) and cows with naturally occurring mastitis (validation data) and pirlimycin concentration was determined by microbial inhibition assay. The data were analysed by the conditional estimation/maximum likelihood population approach within the computer program PPharm and fitted a two compartment open model. Bayesian estimates of individual parameters allowed solutions for each cow, predicting the time after last dosing by which milk concentration reached the target safe concentration. From this population of times, the 95% confidence interval of the 99th percentile was defined as the milk discard time. After elimination of one very low producing outlier, the calculated discard time agreed with the label recommendation of 36 h (3 milkings, USA) after the last dose. Milk pirlimycin clearance was strongly and positively correlated to the logarithm of the kilograms of milk produced in 24 h at time of dosing ( r 2  = 0.939). Agreement was strong at most time points between predicted and measured pirlimycin concentrations in milk from cows with mastitis. This alternative method for determining milk discard times was compared to existing recommendations.