Pharmacokinetics of gamithromycin in swine plasma and bronchoalveolar cells

Gamithromycin, the active pharmaceutical ingredient in Zactran® 15% w/v gamithromycin injection from Merial, is a novel azalide antimicrobial developed for the treatment of swine respiratory disease. Gamithromycin is a 15-membered semi-synthetic macrolide with a uniquely positioned alkylated nitrogen at the 7a-position of the lactone ring.

The PK properties and dose proportionality of gamithromycin in swine plasma were determined after a single intravenous (IV) dose of 6 mg/kg or intramuscular (IM) injection at 3, 6, 12 mg/kg body weight (BW). Additionally, gamithromycin concentration in bronchoalveolar (BAL) cells was determined in another study following single IM administration of gamithromycin at 6 mg/kg BW for better understanding of the PK/PD relationships.

A total of 28 healthy pigs were randomly assigned to 5 groups to study plasma PK and dose proportionality. Group 1 had 2 pigs as Control, Group 2 had 8 pigs dosed IV at 6 mg/kg BW, and Groups 3-5 consisted 6 pigs dosed once IM at 3, 6, 12 mg/kg BW, respectively.

To determine gamithromycin concentrations in BAL cells, 36 healthy pigs were allocated to 11 groups. Six pigs served as untreated controls. Pigs in 10 groups (n=3 each) were administered a single IM dose of 6 mg/kg BW on Day 0. BAL cells were sampled at various time points after dosing. The collected plasma and BAL samples were analyzed using validated methods with tandem mass spectrometry.

Gamithromycin was rapidly absorbed into the systemic circulation and distributed to tissues quickly. Maximum gamithromycin plasma concentration was 960 ng/mL at 0.083-0.25 hours (h) with a terminal half-life of 94.1 h in pigs dosed IM at 6 mg/kg BW. Volume distribution and clearance were 39.2 L/kg and 1030 mL/kg/h, respectively. The absolute bioavailability was 92.2%. Dose proportionality was observed with AUCs.

Maximum gamithromycin concentration of 20.5 μg/mL was achieved in BAL cells at 24 h after dose. Terminal half-life was 87.1 h in BAL cells. The maximum ratio of gamithromycin concentration in BAL cells over in plasma was 1870 at 5 days post dose.

Gamithromycin was well absorbed after IM administration to pigs. Dose proportionality was established over the range of 0.5x to 2.0x the recommended dosage of 6 mg/kg BW. Based on minimum inhibitory concentrations of gamithromycin for target pathogens, potential therapeutic concentrations was achieved in 30 min after dose and persisted for > 6-10 days.

Zactran® is a registered trademark of Merial, Inc.

Disclosure of Interest: R. Huang Conflict with: MERIAL Inc., D. Hamel Conflict with: MERIAL GmbH, R. Tessman Conflict with: MERIAL Inc., A. Mullins Conflict with: MERIAL Inc., T. Malinski Conflict with: MERIAL Inc., S. Rehbein Conflict with: MERIAL GmbH, L. Letendre Conflict with: MERIAL Inc.