Asian elephants (Elephas maximus) are susceptible to a unique infection caused by EEHV.1,2 Since 1983, there have been at least 50 deaths in Asian elephants in North America, Europe, Asia, and Israel caused by this virus.3,4 Asian elephants that died of the virus ranged in age, although juvenile and young adult elephants were most frequently affected. Most elephants were < 7 years old. The EEHV has a tropism for capillary endothelial cells of the heart, liver, and tongue. Affected elephants usually have an acute onset of lethargy with a reluctance to move. Initial clinical signs also include intermittent anorexia, decreased amounts of feces, colic-like behavior, edema of the head, and cyanosis of the tip of the tongue.5 Postmortem findings include extensive myocardial hemorrhages, hydropericardium, and mesenteric and serosal petechiae throughout the peritoneal cavity.1
Although EEHV infections are typically fatal, there are confirmed cases in which elephants have survived infection. In 3 cases reported in the literature, survival was associated with administration of famciclovir.6,7 Dosages (5.5 to 8.0 mg/kg, PO, q 8 h) for the elephants that survived were selected without the benefit of elephant-specific pharmacokinetics and were often a direct allometric extrapolation from recommended dosages for humans (7 mg/kg, PO, q 8 h). One of the treated calves refused oral medication and was treated via rectal administration (10.6 mg/kg, q 12 h), in the absence of prior knowledge about rectal absorption of this drug in elephants.6,7
Following oral administration, famciclovir is rapidly deacetylated and oxidized to penciclovir during first-pass metabolism in the intestinal wall and liver.8 The mechanism of action of penciclovir is similar to that of acyclovir in that it interacts with viral DNA polymerase as a chain terminator.9
To our knowledge, no studies of pharmacokinetics of famciclovir in elephants have been reported. Plasma penciclovir concentrations in elephants peaked at 4.4 μg/mL at 1 hour after oral administration of famciclovir and decreased to undetectable concentrations at 8 hours after oral administration of 6.4 mg of famciclovir/kg.1 These results are analogous to therapeutic concentrations described for humans with genital herpes.10 Dosage regimens for famciclovir in elephants have been selected on the assumption that famciclovir administered to elephants would be absorbed, distributed, metabolized, and excreted in approximately the same manner as in humans. The early clinical success and preliminary plasma penciclovir concentrations were considered in the design of early treatment regimens.6 In humans, the mean ± SD volume of distribution of penciclovir is 1.08 ± 0.17 L/kg (estimated after IV injection of penciclovir), and mean t1/2 is approximately 2 hours (after oral administration of famciclovir).8,10,11 Following conversion of famciclovir to penciclovir in the liver and small intestines of humans, penciclovir is eliminated primarily by the kidneys.12 The purpose of the study reported here was to estimate pharmacokinetics of famciclovir in juvenile Asian elephants after oral and rectal administration of single doses of famciclovir.
Area under the plasma concentration–versus–time curve from 0 to the last quantifiable time point
Maximum plasma concentration
Elephant endotheliotropic herpesvirus
Apparent terminal half-life
Time of maximum plasma concentration
Famvir, SmithKline Beecham Pharmaceuticals, Philadelphia, Pa.
Moravek Biochemicals, Brea, Calif.
WinNonlin, version 5.3, Pharsight Corp, Cary, NC.
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