Pharmacokinetics of Acyclovir after Intravenous Infusion of Acyclovir and after Oral Administration of Acyclovir and Its Prodrug Valacyclovir in Healthy Adult Horses

Abstract

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 (EC 50 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 g/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 (C max ) and poor bioavailability. A 10-times-higher C max 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 EC 50 values.

Quantification ofEquid herpesvirus 5DNA in clinical and necropsy specimens collected from a horse with equine multinodular pulmonary fibrosis

“…However, the severe and progressive clinical course suggests a poor efficacy of acyclovir administered orally in the horse, as previously reported. 5,6,16 On the other hand, steroid therapy could have induced an immunosuppression, facilitating viral replication.…”

To Be Drug or Prodrug: Structure-Property Exploratory Approach Regarding Oral Bioavailability

“…The percentage of human intestinal absorption (% HIA) for selected prodrugs and precursors was obtained from pharmacokinetic data previously reported (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) and well-known databanks (29-31). The classification based on % HIA, previously reported by Zhao et al (24), was used to score the absorption profile of prodrugs and precursors as high, moderate and low (see Table 1).…”

Pharmacokinetics of Penciclovir after Oral Administration of its Prodrug Famciclovir to Horses

“…The antiherpesvirus drug acyclovir has been used for the treatment of EHV-1-associated neurological disorders [13,20,36]. Oral administration is preferable to intravenous infusion during outbreaks, but pharmacokinetic studies have revealed that acyclovir given orally to horses is poorly bioavailable and reaches low plasma concentrations [4,15,35] that do not exceed the 50% effective concentration (EC 50 ) against EHV-1 strains, as determined by in vitro plaque reduction assay [16]. In contrast, oral administration of valacyclovir, the prodrug of acyclovir, achieves concentrations within the sensitivity range of EHV-1 [15,23].…”

“…Oral administration is preferable to intravenous infusion during outbreaks, but pharmacokinetic studies have revealed that acyclovir given orally to horses is poorly bioavailable and reaches low plasma concentrations [4,15,35] that do not exceed the 50% effective concentration (EC 50 ) against EHV-1 strains, as determined by in vitro plaque reduction assay [16]. In contrast, oral administration of valacyclovir, the prodrug of acyclovir, achieves concentrations within the sensitivity range of EHV-1 [15,23]. Therefore, valacyclovir is now considered to be an attractive candidate for treatment of EHV-1-associated neurological disorders, even though its therapeutic efficacy has not been proven in a controlled study.…”

“…Following oral administration of valacyclovir to horses at 20 mg/kg, the total plasma concentration of acyclovir, the active metabolite of valacyclovir, rapidly increased, with a C max of 4.16  1.42 g/ml at 0.90  0.18 hr [15]. The mean elimination half-life was 2.03 hr and the mean AUC 0-inf was 10.0  3.68 ghr/ml.…”