Pharmacokinetics and Comprehensive Analysis of the Tissue Distribution of Eravacycline in Rabbits

Abstract

Eravacycline (7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline or TP-434) is a novel, fully synthetic broad-spectrum fluorocycline with potent activity against Gram-positive bacteria, anaerobes, and multidrug-resistant Enterobacteriaceae We characterized the plasma pharmacokinetics of eravacycline and conducted a comprehensive analysis of the eravacycline tissue distribution in rabbits after multiple-day dosing. For single-dose pharmacokinetic analysis, eravacycline was administered to New Zealand White (NZW) rabbits at 1, 2, 4, 8, and 10 mg/kg of body weight intravenously (i.v.) once a day (QD) (n = 20). For multidose pharmacokinetic analysis, eravacycline was administered at 0.5, 1, 2, and 4 mg/kg i.v. QD (n = 20) for 6 days. Eravacycline concentrations in plasma and tissues were analyzed by a liquid chromatography-tandem mass spectrometry assay. Mean areas under the concentration-time curves (AUCs) following a single eravacycline dose ranged from 5.39 μg · h/ml to 183.53 μg · h/ml. Within the multidose study, mean AUCs ranged from 2.53 μg · h/ml to 29.89 μg · h/ml. AUCs correlated linearly within the dosage range (r = 0.97; P = 0.0001). In the cardiopulmonary system, the concentrations were the highest in the lung, followed by the heart > pulmonary alveolar macrophages > bronchoalveolar lavage fluid; for the intra-abdominal system, the concentrations were the highest in bile, followed by the liver > gallbladder > spleen > pancreas; for the renal system, the concentrations were the highest in urine, followed by those in the renal cortex > renal medulla; for the musculoskeletal tissues, the concentrations were the highest in muscle psoas, followed by those in the bone marrow > adipose tissue; for the central nervous system, the concentrations were the highest in cerebrum, followed by those in the aqueous humor > cerebrospinal fluid > choroid > vitreous. The prostate and seminal vesicles demonstrated relatively high mean concentrations. The plasma pharmacokinetic profile of 0.5 to 4 mg/kg in NZW rabbits yields an exposure comparable to that in humans (1 or 2 mg/kg every 12 h) and demonstrates target tissue concentrations in most sites.

Keywords: eravacycline; pharmacokinetics; rabbits; tissue distribution.

FIG 1

Plasma pharmacokinetics of eravacycline after intravenous administration of a single dose to healthy New Zealand White rabbits.

FIG 2

Eravacycline plasma AUC-versus-dose correlation. Correlations were determined by the use of Spearman's rank correlation after administration of a single dose (A) and multiple doses (B). Dotted lines represent 95% confidence intervals.

FIG 3

Plasma pharmacokinetics of eravacycline after intravenous administration of multiple doses to healthy New Zealand White rabbits.

FIG 4

Distribution of eravacycline after intravenous multiple dosing to healthy New Zealand White rabbits in cardiopulmonary tissue/fluid. For the assessment of tissue concentrations of eravacycline, samples were collected on day 7, 1 h after last infusion. All values are expressed as mean ± SEM.

FIG 5

Distribution of eravacycline after intravenous multiple dosing to healthy New Zealand White rabbits in intraabdominal tissue/fluid. For the assessment of tissue concentrations of eravacycline, samples were collected on day 7, 1 h after last infusion. All values are expressed as mean ± SEM.

FIG 6

Distribution of eravacycline after intravenous multiple dosing to healthy New Zealand White rabbits in renal tissue/fluid. For the assessment of tissue concentrations of eravacycline, samples were collected on day 7, 1 h after last infusion. All values are expressed as mean ± SEM.

FIG 7

Distribution of eravacycline after intravenous multiple dosing to healthy New Zealand White rabbits in musculoskeletal tissue. For the assessment of tissue concentrations of eravacycline, samples were collected on day 7, 1 h after last infusion. All values are expressed as mean ± SEM.

FIG 8

Distribution of eravacycline after intravenous multiple dosing to healthy New Zealand White rabbits in CNS tissue/fluid. For the assessment of tissue concentrations of eravacycline, samples were collected on day 7, 1 h after last infusion. All values are expressed as mean ± SEM.

FIG 9

Distribution of eravacycline after intravenous multiple dosing to healthy New Zealand White rabbits in male reproductive tissues. All values are expressed as mean ± SEM.