Gamithromycin in swine: Pharmacokinetics and clinical evaluation against swine respiratory disease

Abstract

The pharmacokinetics of gamithromycin were evaluated in 26 male castrated and female crossbred swine administered gamithromycin 15% w/v (Zactran®, Boehringer Ingelheim) intravenously at 6 mg/kg bodyweight or intramuscularly at 3, 6 or 12 mg/kg bodyweight. Blood samples were collected up to Day 10 to establish the plasma profile of gamithromycin, bioavailability and dose proportionality. When administered by intramuscular injection at 6 mg/kg BWT, pharmacokinetic parameters were as follows: area under the curve until last quantifiable plasma concentration, 5.13 ± 0.957 µg*hours/ml; maximum plasma concentration, 960 ± 153 ng/ml at 5 to 15 min; terminal half‐life of 94.1 ± 20.4 hr. Absolute bioavailability was 92.2%. Increase in systemic exposure was proportional to the gamithromycin dose level over the range 3–12 mg/kg BWT. No gender‐related statistically significant difference in exposure was observed. For clinical evaluation of Zactran® against swine respiratory disease, 305 pigs from six commercial farms in three countries in Europe with signs associated with Actinobacillus pleuropneumoniae and/or Haemophilus parasuis and/or Pasteurella multocida and/or Bordetella bronchiseptica were used. At each site, animals were treated once in a 1:1 ratio with a single intramuscular dose of Zactran® (6 mg gamithromycin/kg bodyweight) or Zuprevo® (4% w/v tildipirosin at 4 mg/kg bodyweight; MSD Animal Health) at the recommended dose respectively. Animals were observed and scored daily for 10 consecutive days for signs of swine respiratory disease (depression, respiration and rectal temperature), and animals presenting signs of clinical swine respiratory disease (Depression Score 3 and/or Respiratory Score 3 associated with Rectal Temperature > 40.0°C) were removed from the study and considered as treatment failure. Animals which remained in the study were individually assessed for ʽtreatment successʼ or ʽtreatment failureʼ (Depression Score ≥ 1 and Rectal Temperature > 40.0°C or Respiratory Score ≥ 1 and Rectal Temperature > 40.0°C). Using a non‐inferiority hypothesis test (non‐inferiority margin = 0.10), the proportion of treatment successes in the Zactran® group (97%) was equivalent to or better than that in the Zuprevo® group (93%).

Non-radiolabeled Study to Evaluate the Metabolism and Residue Kinetics of Veterinary Drugs in Food-producing Animals and Anti-doping Analysis in Equine Sports: Application of High-Resolution Mass Spectrometry

“…This data was used to establish a reliable in vivo and in vitro correlation. In addition, similar PK profiles in sheep, cattle, and swine further support the fact that GAM has similar absorption, distribution, metabolism, and elimination properties across the species [65][66][67]. Considering the available data for this minor species (sheep), a non-radiolabeled marker residue study for determination of the M/T ratios in edible tissues and a combination of cold semi-quantitative LC-HRMS and quantitative triple quadrupole LC-MS/MS approach was carried out [61] and accepted by the European Medicines Agency (EMA) [64] to have adequately defined the human food safety profile of Zactran in sheep.…”

Efficacy of gamithromycin injection against cattle respiratory disease

“…gamithromycin injection (Zactran®), developed by the French company Merial, was approved by the European Union to treat BRD caused by M. haemolytica, P. multocida, and H. somni. Gamithromycin has the advantages of a broad antibacterial spectrum, rapid absorption, lasting e cacy, safety, and low toxicity and has overall application prospects in livestock and poultry breeding production [11,12] .…”

Pharmacodynamic Target Assessment and PK/PD Cutoff Determination for Gamithromycin Against Streptococcus suis in Piglets

“…Gamithromycin is a semisynthetic azalide that is approved for the treatment of SRD due to A. pleuropneumoniae and Pasteurella multocida ( 6 , 7 ). Intramuscular and subcutaneous administrations have been developed with promising pharmacokinetic and efficacy results in pigs ( 8 , 9 ).…”

“…Intramuscular and subcutaneous administrations have been developed with promising pharmacokinetic and efficacy results in pigs (8,9). Our previous pharmacokinetic/pharmacodynamic (PK/PD) studies in piglets have demonstrated the potency and efficacy of gamithromycin for Haemophilus parasuis (6). Given that gamithromycin has activity against a wider range of respiratory pathogens and other macrolides/azalides are used for the treatment of respiratory tract infections (6,(10)(11)(12), a logical consideration is to what extent gamithromycin could be valuable for S. suis infections.…”

“…Our previous pharmacokinetic/pharmacodynamic (PK/PD) studies in piglets have demonstrated the potency and efficacy of gamithromycin for Haemophilus parasuis (6). Given that gamithromycin has activity against a wider range of respiratory pathogens and other macrolides/azalides are used for the treatment of respiratory tract infections (6,(10)(11)(12), a logical consideration is to what extent gamithromycin could be valuable for S. suis infections. While it is recognized that the area under the concentration-time curve/MIC (AUC/MIC) is the predictive PK/PD index that well-describes the efficacy of azalide antibiotics (9,(13)(14)(15), data regarding the PK/PD profiles of gamithromycin are not currently available for S. suis.…”