Pharmacokinetics of tildipirosin in bovine plasma, lung tissue, and bronchial fluid (from live, nonanesthetized cattle)

Abstract

The pharmacokinetics of tildipirosin (Zuprevo(®) 180 mg/mL solution for injection for cattle), a novel 16-membered macrolide for treatment, control, and prevention of bovine respiratory disease, were investigated in studies collecting blood plasma, lung tissue, and in vivo samples of bronchial fluid (BF) from cattle. After single subcutaneous (s.c.) injection at 4 mg/kg body weight, maximum plasma concentration (C(max)) was 0.7 μg/mL. T(max) was 23 min. Mean residence time from the time of dosing to the time of last measurable concentration (MRT(last)) and terminal half-life (T(1/2) ) was 6 and 9 days, respectively. A strong dose-response relationship with no significant sex effect was shown for both C(max) and area under the plasma concentration-time curve from time 0 to the last sampling time with a quantifiable drug concentration (AUC(last) ) over the range of doses up to 6 mg/kg. Absolute bioavailability was 78.9%. The volume of distribution based on the terminal phase (V(z)) was 49.4 L/kg, and the plasma clearance was 144 mL/h/kg. The time-concentration profile of tildipirosin in BF and lung far exceeded those in blood plasma. In lung, tildipirosin concentrations reached 9.2 μg/g at 4 h, peaked at 14.8 μg/g at day 1, and slowly declined to 2.0 μg/g at day 28. In BF, the concentration of tildipirosin reached 1.5 and 3.0 μg/g at 4 and 10 h, maintained a plateau of about 3.5 μg/g between day 1 and 3, and slowly declined to 1.0 at day 21. T(1/2) in lung and BF was approximately 10 and 11 days. Tildipirosin is rapidly and extensively distributed to the respiratory tract followed by slow elimination.

Overall Decrease in the Susceptibility of Mycoplasma bovis to Antimicrobials over the Past 30 Years in France

“…For fluoroquinolones, all strains are classified as intermediate. Breakpoints are not available for gamithromycin and tildipirosin, but the MIC 50 (128 µg/mL) is much greater than the maximum concentrations used for respiratory infections at therapeutic doses, 18 and 15 µg/g of lung homogenate, respectively [35], [36].…”

Pharmacokinetic and pharmacodynamic modeling of cyadox against Clostridium perfringens in swine

“…Due to the difficulty in determining the free drug concentration at the target site, the PK data in most previous PK-PD studies have often been obtained from plasma. It has been shown that the antibiotic concentration time-course in plasma is significantly different from that in biophase at the infection site, including the interstitial fluid (ISF) and epithelial lining fluid (ELF) 27–29 . Therefore, it is necessary to determine the active concentration of free antimicrobial drugs at the target site using PK-PD modeling to achieve a rational dosage regimen.…”

Pharmacokinetics of tildipirosin in beagle dogs

“…Tildipirosin has been approved for parenteral treatment of respiratory disease in cattle and swine (EMA, 2010). This macrolide antibiotic is rapidly absorbed and extensively distributed to tissues where they achieve multifold higher concentrations relative to those observed in pigs and cattle plasma samples (Anadon & Reeve-johnson, 1999;Norcia et al, 2004).Due to the extensive use of TD, several studies on the pharmacokinetics, pharmacodynamics, particularly, distribution, and metabolism have been conducted in various species, including pigs (Rose et al, 2013;Torres et al, 2016) and cattle (Menge et al, 2012). In pigs, it is postulated that the metabolism of tildipirosin proceeds by reduction and sulfate conjugation with subsequent hydration (or ring opening), by demethylation, by dihydroxylation, and by S-cysteine and S-glutathione conjugation (EMA, 2015).…”