The absolute bioavailability and lung tissue distribution of the triamilide antimicrobial, tulathromycin, were investigated in swine. Fifty-six pigs received 2.5 mg/kg of tulathromycin 10% formulation by either intramuscular (i.m.) or intravenous (i.v.) route in two studies: study A (10 pigs, i.m. and 10 pigs, i.v.) and study B (36 pigs, i.m.). After i.m. administration the mean maximum plasma concentration (C(max)) was 616 ng/mL, which was reached by 0.25 h postinjection (t(max)). The mean apparent elimination half-life (t(1/2)) in plasma was 75.6 h. After i.v. injection plasma clearance (Cl) was 181 mL/kg.h, the volume of distribution at steady-state (V(ss)) was 13.2 L/kg and the elimination t(1/2) was 67.5 h. The systemic bioavailability following i.m. administration was >87% and the ratio of lung drug concentration for i.m. vs. i.v. injection was > or =0.96. Following i.m. administration, a mean tulathromycin concentration of 2840 ng/g was detected in lung tissue at 12 h postdosing. The mean lung C(max) of 3470 ng/g was reached by 24 h postdose (t(max)). Mean lung drug concentrations after 6 and 10 days were 1700 and 1240 ng/g, respectively. The AUC(inf) was 61.4 times greater for the lung than for plasma. The apparent elimination t(1/2) for tulathromycin in the lung was 142 h (6 days). Following i.m. administration to pigs at 2.5 mg/kg body weight, tulathromycin was rapidly absorbed and highly bioavailable. The high distribution to lung and slow elimination following a single dose of tulathromycin, are desirable pharmacokinetic attributes for an antimicrobial drug indicated for the treatment of respiratory disease in swine.

Tulathromycin is a novel member of the triamilide class of antibiotics that was developed as a safe and effective single-dose treatment of bovine and porcine respiratory disease. An accurate and precise analytical method was developed for the extraction and measurement of tulathromycin in livestock plasma and lung homogenates. Analytes were solid-phase extracted onto a weak cation exchanger after aqueous dilution of samples and addition of heptadeutero-tulathromycin as an internal standard. Following HPLC with a narrow bore C8 column, quantitative detection of tulathromycin was accomplished by monitoring the transition of a doubly charged precursor ion to a singly charged product ion by tandem mass spectrometry using a triple quadrupole mass spectrometer. Procedures were validated for a dynamic range of 0.1 to 25 ng on column. Observed accuracies were between 90 and 110% of nominal and precision (RSD) varying 7% or less. Response and stability experiments showed that deuterated tulathromycin did not parallel the chemical behavior of tulathromycin. Applicability of the method to livestock studies was tested with plasma and lung samples from cattle and swine dosed with tulathromycin at multiple doses. The results demonstrated that the analytical method performed well in a range of sample concentrations spanning over 3 orders of magnitude and provided dose-exposure relationships for cattle and swine.

Plasma concentrations of doramectin in 40 cattle dosed by subcutaneous (sc) or intramuscular (i.m.) injection (200 micrograms/kg) were compared to assess the bioequivalence of the two routes of administration. Peak concentration (Cmax), and areas under the concentration curve (AUC0-infinity) were determined from plasma concentrations. Animals treated by the sc route showed a mean AUC0-infinity of 457 +/- 66 ng.day/mL (+/- SD) and a mean Cmax of 27.8 +/- 7.9 ng/mL. Results from the i.m. treatment group showed a mean AUC0-infinity of 475 +/- 82 ng.day/mL and a mean Cmax of 33.1 +/- 9.0 ng/mL. Absorption constants (ka) determined by modelling were 0.542 +/- 0.336 day-1 after sc administration and 0.710 +/- 0.357 day-1 after i.m. administration. The 90% confidence limits on the difference between mean AUC0-infinity values for the sc and i.m. groups fell within 20% of the mean value for the subcutaneous group. Cmax was somewhat greater for the i.m. route. The 90% confidence limits on the difference in mean In(Tmax +1) also fell within 20% of the mean sc value. Based on this analysis, bioequivalence of the sc and i.m. formulation has been established.