Gamithromycin was rapidly absorbed after SC administration. Potentially therapeutic concentrations were achieved in PELF, BAL cells, and lung tissue within 30 minutes after administration and persisted for 7 (PELF) to > 15 (BAL cells and lung tissue) days after administration of a single dose.

The pharmacokinetics of afoxolaner in dogs was evaluated following either intravenous or after oral administration of NEXGARD(®), a soft chewable formulation. Afoxolaner is a member of one of the newest classes of antiparasitic agents, known as antiparasitic isoxazolines. The soft chewable formulation underwent rapid dissolution, and afoxolaner was absorbed quickly following oral administration of the minimum effective dose of 2.5mg/kg, with maximum plasma concentrations (Cmax) of 1,655 ± 332 ng/mL observed 2-6h (Tmax) after treatment. The terminal plasma half-life was 15.5 ± 7.8 days, and oral bioavailability was 73.9%. Plasma concentration-versus-time curves fit a 2-compartment model and increased proportionally with dose over the oral dose range of 1.0-4.0mg/kg, and over the oral dose range from 1.0 to 40 mg/kg. Following an intravenous dose of 1mg/kg, the volume of distribution (Vd) was 2.68 ± 0.55 L/kg, and the systemic clearance was 4.95 ± 1.20 mL/h/kg. Afoxolaner plasma protein binding was >99.9% in dogs. One major metabolite, formed following hydroxylation of afoxolaner, was identified in dog plasma, urine and bile. When afoxolaner is administered orally, there is a strong correlation between afoxolaner plasma concentration and efficacy with EC90 values of 23 ng/mL for Ctenocephalides felis and ≥ 100 ng/mL for Rhipicephalus sanguineus sensu lato and Dermacentor variabilis. The pharmacokinetic properties of afoxolaner are suited for a monthly administration product because the fast absorption and long terminal half-life support a rapid onset of action while ensuring month-long efficacy.

The pharmacokinetics (PK) and dose proportionality of gamithromycin (ZACTRAN), a novel azalide, after a single intravenous (i.v.) dose of 3 mg/kg or subcutaneous (s.c.) injection at 3, 6 and 9 mg/kg body weight were studied in 13 male castrate and 13 female Angus cattle. Following i.v. administration, the mean area under the curve extrapolated to infinity (AUC(inf)) was 4.28 +/- 0.536 microgxh/mL, and mean elimination half-life (t(1/2)) was 44.9 +/- 4.67 h, with a large volume of distribution (V(ss)) of 24.9 +/- 2.99 L/kg and a high clearance rate (Cl(obs)) of 712 +/- 95.7 mL/h/kg. For cattle treated with s.c. injection of 3, 6 or 9 mg/kg, mean AUC(inf) values were 4.55 +/- 0.690, 9.42 +/- 1.11 and 12.2 +/- 1.13 microgxh/mL, respectively, and the mean elimination half-lives (t(1/2)) were 51.2 +/- 6.10, 50.8 +/- 3.80 and 58.5 +/- 5.50 h. Gamithromycin was well absorbed and fully bioavailable (97.6-112%) after s.c. administration. No statistically significant (alpha = 0.05) gender differences in the AUC(Inf) or elimination half-life values were observed. Dose proportionality was established based on AUC(Inf) over the range of 0.5 to 1.5 times of the recommended dosage of 6 mg/kg of body weight. Further investigations were conducted to assess plasma PK, lung/plasma concentration ratios and plasma antibacterial activity using 36 cattle. The average maximum gamithromycin concentration measured in whole lung homogenate was 18 500 ng/g at first sampling time of 1 day ( approximately 24 h) after treatment. The ratios of lung to plasma concentration were 265, 410, 329 and 247 at 1, 5, 10 and 15 days postdose. The lung AUC(inf) was 194 times higher than the corresponding plasma AUC(inf). The apparent elimination half-life for gamithromycin in lung was 90.4 h ( approximately 4 days). Antibacterial activity was observed with plasma collected at 6 h postdose with a corresponding average gamithromycin plasma concentration of 261 ng/mL. In vitro plasma protein binding in bovine plasma was determined to be 26.0 +/- 0.60% bound over a range of 0.1-3.0 microg/mL of gamithromycin. The dose proportionality of AUC, high bioavailability, rapid and extensive distribution to lung tissue and low level of plasma protein binding are beneficial PK parameters for an antimicrobial drug used for the treatment and prevention of bovine respiratory disease.

The objectives of this study were to determine the plasma and pulmonary disposition of gamithromycin in foals and to investigate the in vitro activity of the drug against Streptococcus equi subsp. zooepidemicus (S. zooepidemicus) and Rhodococcus equi. A single dose of gamithromycin (6 mg/kg of body weight) was administered intramuscularly. Concentrations of gamithromycin in plasma, pulmonary epithelial lining fluid (PELF), bronchoalveolar lavage (BAL) cells, and blood neutrophils were determined using HPLC with tandem mass spectrometry detection. The minimum inhibitory concentration of gamithromycin required for growth inhibition of 90% of R. equi and S. zooepidemicus isolates (MIC(90)) was determined. Additionally, the activity of gamithromycin against intracellular R. equi was measured. Mean peak gamithromycin concentrations were significantly higher in blood neutrophils (8.35±1.77 μg/mL) and BAL cells (8.91±1.65 μg/mL) compared with PELF (2.15±2.78 μg/mL) and plasma (0.33±0.12 μg/mL). Mean terminal half-lives in neutrophils (78.6 h), BAL cells (70.3 h), and PELF (63.6 h) were significantly longer than those in plasma (39.1 h). The MIC(90) for S. zooepidemicus isolates was 0.125 μg/mL. The MIC of gamithromycin for macrolide-resistant R. equi isolates (MIC(90)=128 μg/mL) was significantly higher than that for macrolide-susceptible isolates (1.0 μg/mL). The activity of gamithromycin against intracellular R. equi was similar to that of azithromycin and erythromycin. Intramuscular administration of gamithromycin at a dosage of 6 mg/kg would maintain PELF concentrations above the MIC(90) for S. zooepidemicus and phagocytic cell concentrations above the MIC(90) for R. equi for approximately 7 days.

No abstract