Pharmacokinetics and analytical determination of acyclovir in Asian elephant calves (Elephas maximus)

Siripat Khammesri; Chadarat Ampasavate; Darunee Hongwiset; Raktham Mektrirat; Siriluk Sangsrijan; Janine L Brown; Chatchote Thitaram

doi:10.1016/j.vas.2021.100227

Pharmacokinetics and analytical determination of acyclovir in Asian elephant calves (Elephas maximus)

Vet Anim Sci. 2021 Dec 24:15:100227. doi: 10.1016/j.vas.2021.100227. eCollection 2022 Mar.

Authors

Siripat Khammesri^{1

2}, Chadarat Ampasavate³, Darunee Hongwiset^{3

4}, Raktham Mektrirat⁵, Siriluk Sangsrijan⁴, Janine L Brown^{1

6}, Chatchote Thitaram^{1

7}

Affiliations

¹ Center of Elephant and Wildlife Health and Research, Faculty of Veterinary Medicine, Chiang Mai University, Thailand.
² Graduate Program in Veterinary Science, Faculty of Veterinary Medicine, Chiang Mai University, Thailand.
³ Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University Thailand.
⁴ Pharmacy Service Center, Faculty of Pharmacy, Chiang Mai University, Thailand.
⁵ Department of Veterinary Biosciences and Public Health, Faculty of Veterinary Medicine, Chiang Mai University, Thailand.
⁶ Center for Species Survival, Smithsonian Conservation Biology Institute, Front Royal, VA, USA.
⁷ Department of Companion Animal and Wildlife Clinic, Faculty of Veterinary Medicine, Chiang Mai University, Thailand.

Abstract

A therapeutic regimen that includes antiviral drugs is critical for the survival of Asian elephant (Elephas maximus) calves infected with elephant endotheliotropic herpesvirus hemorrhagic disease (EEHV-HD), with acyclovir showing considerable promise. The purpose of this study was to determine the pharmacokinetics and bioavailability of acyclovir following intravenous (IV) and oral (PO) administration in Asian elephants. A single dose of acyclovir (15 mg/kg, IV or 45 mg/kg, PO) was administered to four healthy elephant calves, with a minimum 2-week washout period between treatments. Serial plasma samples were collected after each injection for acyclovir analysis using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique. Maximum plasma acyclovir concentrations were 27.02 ± 6.79 µg/mL at 0.94 ± 0.31 h after IV administration, and 1.45 ± 0.20 µg/mL at 3.00 ± 0.70 h after PO administration. The half-life of the elimination phase (T_1/2) was 5.84 ± 0.74 and 8.74 ± 2.47 h after IV and PO administration, respectively. After IV administration, acyclovir concentrations were higher than the half-maximal inhibitory concentration (IC₅₀) of those found for herpes simplex virus (HSV) 1 and 2 in humans, and equid alpha herpesvirus-1 (EHV-1) for at least 12 h. By contrast, the bioavailability of oral administration was low, only 6.03 ± 0.87%, so higher doses by that route likely are needed to be effective. Due to the high concentration of plasma acyclovir after IV administration, the dose may need to be adjusted to prevent any negative side effects.

Keywords: %CV, Mean precision; AUC0-inf, Total area under the plasma concentration-time curve from time zero to infinity; AUC0-t, Total area under the plasma concentration-time curve from time 0–48h; Acyclovir; Asian elephant; Bioavailability; Cl, Total clearance; Cmax, Peak plasma concentration; EEHV, Elephantendotheliotropic herpesviruses; EEHV-HD, Elephant endotheliotropic herpesvirus hemorrhagic disease; EHV, Equid alphaherpesvirus; Elephant endotheliotropic herpesvirus (EEHV); F, Bioavailability; HSV, Herpes simplex virus; IV, Intravenous administration; Kel, Elimination rate constant; LC-MS/MS, Liquid chromatography-tandem mass spectrometry; LLOQ, Lower limit of quantitation; MAT, Mean absorption time; MRM, Multiple reaction monitoring; MRT, Mean residence time; PO, Oral administration; Pharmacokinetics; QC, Quality control; S/N, Signal to noise ratio; T1/2, Elimination half-life; Tmax, Time to reach peak plasma; Vd(ss), Steady-state volume of distribution; m/z, Mass-to-charge ratio; r2, Coefficients of determination.