Nonlinear Mixed-Effect Pharmacokinetic Modeling and Distribution of Doxycycline in Healthy Female Donkeys after Multiple Intragastric Dosing-Preliminary Investigation.

Abstract

Simple SummaryRational use of antibiotic is of most importance for human and animal health. Donkeys have differences in metabolism compared to horses, and drug dosage should not be extrapolated from horses’ data. Doxycycline, a common antibiotic used in equine medicine, has never been investigated in donkeys. The aim of this preliminary study was to describe the concentrations of doxycycline obtain in serum and other body tissue and fluid following its oral administration in donkeys at the recommended horse dosage. Doxycycline was administered to eight healthy, adult jennies. Serum, urine, synovial fluid and uterine tissue were collected. Doxycycline concentrations were measured with a commercial ELISA. A pharmacological model was used to analyze the serum concentration and calculate some pharmacological parameters. Results suggest that doxycycline is well absorbed following oral administration and calculated serum parameters suggest high tissue distribution. However, the concentration of doxycycline reached in all fluids and tissues analyzed would unlikely result in therapeutic concentration against common equine pathogens. Further investigations are warranted. This data can be used for designing future studies of doxycycline in donkeys. In the meantime, oral doxycycline at the horse dosage should not be consider a suitable treatment in donkeys until proven efficacious. Doxycycline (DXC) is a broad-spectrum antibacterial antimicrobial administered to horses for the treatment of bacterial infections which may also affect donkeys. Donkeys have a different metabolism than horses, leading to differences in the pharmacokinetics of drugs compared to horses. This study aimed to describe the population pharmacokinetics of DXC in donkeys. Five doses of DXC hyclate (10 mg/kg) were administered via a nasogastric tube, q12 h, to eight non-fasted, healthy, adult jennies. Serum, urine, synovial fluid and endometrium were collected for 72 h following the first administration. Doxycycline concentration was measured by competitive enzyme immunoassay. Serum concentrations versus time data were fitted simultaneously using the stochastic approximation expectation-maximization algorithm for nonlinear mixed effects. A one-compartment model with linear elimination and first-order absorption after intragastric administration, best described the available pharmacokinetic data. Final parameter estimates indicate that DXC has a high volume of distribution (108 L/kg) as well as high absorption (10.3 h−1) in donkeys. However, results suggest that oral DXC at 10 mg/kg q12 h in donkeys would not result in a therapeutic concentration in serum, urine, synovial fluid or endometrium by comparison to the minimum inhibitory concentration of common equine pathogens. Further studies are recommended to identify appropriate dosage and dosing intervals of oral DXC in donkeys.