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J Pharm Sci. 2015 Jan;104(1):233-43. doi: 10.1002/jps.24244. Epub 2014 Nov 18.

Development and application of a multiroute physiologically based pharmacokinetic model for oxytetracycline in dogs and humans.

Author information

1
Institute of Computational Comparative Medicine (ICCM) and The Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, 66506.

Abstract

Oxytetracycline (OTC) is a commonly used tetracycline antibiotic in veterinary and human medicine. To establish a quantitative model for predicting OTC plasma and tissue exposure, a permeability-limited multiroute physiologically based pharmacokinetic model was developed in dogs. The model was calibrated with plasma pharmacokinetic data in beagle dogs following single intravenous (5 mg/kg), oral (100 mg/kg), and intramuscular (20 mg/kg) administrations. The model predicted other available dog data well, including drug concentrations in the liver, kidney, and muscle after repeated exposure, and data in the mixed-breed dog. The model was extrapolated to humans and the human model adequately simulated measured plasma OTC concentrations after intravenous (7.14 mg/kg) and oral exposures (6.67 mg/kg). The dog model was applied to predict 24-h OTC area-under-the-curve after three therapeutic treatments. Results were 27.75, 51.76, and 64.17 μg/mL*h in the plasma, and 120.93, 225.64, and 279.67 μg/mL*h in the kidney for oral (100 mg/kg), intravenous (10 mg/kg), and intramuscular (20 mg/kg) administrations, respectively. This model can be used to predict plasma and tissue concentrations to aid in designing optimal therapeutic regimens with OTC in veterinary, and potentially, human medicine; and as a foundation for scaling to other tetracycline antibiotics and to other animal species.

KEYWORDS:

Food Animal Residue Avoidance Databank (FARAD); computational ADME; disposition; dogs; in silico modeling; mathematical model; oxytetracycline; pharmacokinetics; physiologically based pharmacokinetic (PBPK) modeling; tetracycline antibiotics

PMID:
25407474
DOI:
10.1002/jps.24244
[Indexed for MEDLINE]

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