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Antimicrobial Agents and Chemotherapy, December 2007, p. 4308-4314, Vol. 51, No. 12
0066-4804/07/$08.00+0 doi:10.1128/AAC.00116-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
Pharmacokinetics of Acyclovir after Intravenous Infusion of Acyclovir and after Oral Administration of Acyclovir and Its Prodrug Valacyclovir in Healthy Adult Horses
B. Garré,1,2
K. Shebany,1
A. Gryspeerdt,2
K. Baert,1
K. van der Meulen,2
H. Nauwynck,2
P. Deprez,3
P. De Backer,1 and
S. Croubels1*
Department of Pharmacology, Toxicology, Biochemistry, and Organ Physiology,1 Laboratory of Virology,2 Department of Internal Medicine and Clinical Biology of Large Animals, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium3
Received 26 January 2007/ Returned for modification 2 July 2007/ Accepted 2 September 2007
The purpose of this study was twofold. The first aim was to evaluate the oral bioavailability and pharmacokinetics (PKs) of acyclovir in horses after intravenous (i.v.) administration and after oral administration of acyclovir and its prodrug, valacyclovir. Second, we aimed to combine these PK data with pharmacodynamic (PD) information, i.e., 50% effective concentrations (EC50 values) from in vitro studies, to design an optimal dosage schedule. Three treatments were administered to healthy adult horses: 10 mg of acyclovir/kg of body weight delivered as an i.v. infusion over 1 h, 20 mg of acyclovir/kg administered as tablets by nasogastric intubation, and 20 mg of valacyclovir/kg administered as tablets by nasogastric intubation. Total plasma concentrations were measured by a high-performance liquid chromatography method combined with fluorescence detection, while unbound plasma concentrations were determined by liquid chromatography-tandem mass spectrometry. The peak concentration of i.v. acyclovir was approximately 10 µg/ml for both the total and the unbound plasma concentrations. The mean half-life of elimination was between 5.05 h (total concentration) and 11.9 h (unbound concentration). Oral administration of acyclovir resulted in low maximum concentration in plasma (Cmax) and poor bioavailability. A 10-times-higher Cmax and an 8-times-higher bioavailability were achieved with oral administration of valacyclovir. The i.v. administration of 10 mg/kg acyclovir and the oral administration of 20 mg/kg valacyclovir achieved concentrations within the sensitivity range of equine herpesvirus type 1 (EHV-1). The higher bioavailability of valacyclovir makes it an attractive candidate for the prophylactic and/or therapeutic treatment of horses infected with EHV-1. The results from the PK/PD modeling showed that a dosage of 40 mg/kg valacyclovir, administered three times daily, would be sufficient to reach plasma concentrations above the EC50 values.
* Corresponding author. Mailing address: Department of Pharmacology, Toxicology, Biochemistry, and Organ Physiology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium. Phone: 32 9 264 73 46. Fax: 32 9 264 74 97. E-mail: siska.croubels{at}ugent.be
Published ahead of print on 10 September 2007.
Antimicrobial Agents and Chemotherapy, December 2007, p. 4308-4314, Vol. 51, No. 12
0066-4804/07/$08.00+0 doi:10.1128/AAC.00116-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
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