Estimates of the pharmacokinetics of famciclovir and its active metabolite penciclovir in young Asian elephants (Elephas maximus)

Abstract

Objective:
To determine plasma pharmacokinetics of penciclovir following oral and rectal administration of famciclovir to young Asian elephants (Elephas maximus).

Animals:
6 healthy Asian elephants (5 females and 1 male), 4.5 to 9 years old and weighing 1,646 to 2,438 kg.

Procedures:
Famciclovir was administered orally or rectally in accordance with an incomplete crossover design. Three treatment groups, each comprising 4 elephants, received single doses of famciclovir (5 mg/kg, PO, or 5 or 15 mg/kg, rectally); there was a minimum 12-week washout period between subsequent famciclovir administrations. Serial blood samples were collected after each administration. Samples were analyzed for famciclovir and penciclovir with a validated liquid chromatography-mass spectroscopy assay.

Results:
Famciclovir was tolerated well for both routes of administration and underwent complete biotransformation to the active metabolite, penciclovir. Mean maximum plasma concentration of penciclovir was 1.3 μg/mL at 1.1 hours after oral administration of 5 mg/kg. Similar results were detected after rectal administration of 5 mg/kg. Mean maximum plasma concentration was 3.6 μg/mL at 0.66 hours after rectal administration of 15 mg/kg; this concentration was similar to results reported for humans receiving 7 mg/kg orally.

Conclusions and clinical relevance:
Juvenile Asian elephants are susceptible to elephant endotheliotropic herpesvirus. Although most infections are fatal, case reports indicate administration of famciclovir has been associated with survival of 3 elephants. In Asian elephants, a dose of 8 to 15 mg of famciclovir/kg given orally or rectally at least every 8 hours may result in penciclovir concentrations that are considered therapeutic in humans.

Full text

1996 AJVR, Vol 73, No. 12, December 2012
A
sian 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
Estimates of the pharmacokinetics of
famciclovir and its active metabolite penciclovir
in young Asian elephants (Elephas maximus)
A. Paige Brock, DVM; Ramiro Isaza, DVM, MS; Robert P. Hunter, PhD; Laura K. Richman, DVM, PhD;
Richard J. Montali, DVM; Dennis L. Schmitt, DVM, PhD; David E. Koch, PhD; William A. Lindsay, DVM
Objective—To determine plasma pharmacokinetics of penciclovir following oral and rectal
administration of famciclovir to young Asian elephants (Elephas maximus).
Animals—6 healthy Asian elephants (5 females and 1 male), 4.5 to 9 years old and weigh-
ing 1,646 to 2,438 kg.
Procedures—Famciclovir was administered orally or rectally in accordance with an incom-
plete crossover design. Three treatment groups, each comprising 4 elephants, received
single doses of famciclovir (5 mg/kg, PO, or 5 or 15 mg/kg, rectally); there was a minimum
12-week washout period between subsequent famciclovir administrations. Serial blood
samples were collected after each administration. Samples were analyzed for famciclovir
and penciclovir with a validated liquid chromatography–mass spectroscopy assay.
Results—Famciclovir was tolerated well for both routes of administration and underwent
complete biotransformation to the active metabolite, penciclovir. Mean maximum plasma
concentration of penciclovir was 1.3 µg/mL at 1.1 hours after oral administration of 5 mg/
kg. Similar results were detected after rectal administration of 5 mg/kg. Mean maximum
plasma concentration was 3.6 µg/mL at 0.66 hours after rectal administration of 15 mg/
kg; this concentration was similar to results reported for humans receiving 7 mg/kg orally.
Conclusions and Clinical Relevance—Juvenile Asian elephants are susceptible to ele-
phant endotheliotropic herpesvirus. Although most infections are fatal, case reports indi-
cate administration of famciclovir has been associated with survival of 3 elephants. In Asian
elephants, a dose of 8 to 15 mg of famciclovir/kg given orally or rectally at least every 8
hours may result in penciclovir concentrations that are considered therapeutic in humans.
(Am J Vet Res 2012;73:1996–2000)
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 reluc-
tance to move. Initial clinical signs also include inter-
mittent 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 mes-
enteric and serosal petechiae throughout the peritoneal
cavity.
1
Received July 31, 2011.
Accepted March 21, 2012.
From the Department of Small Animal Clinical Sciences, College of
VeterinaryMedicine, University of Florida, Gainesville, FL 32608 (Brock, Isaza);
the Zoological Pharmacology Laboratory, Department of Anatomy and Physi-
ology, College of Veterinary Medicine, Kansas State University, Manhattan, KS
66506 (Hunter, Koch); National Zoological Park, Smithsonian, 3001 Connecti-
cut Ave NW, Washington, DC 20008 (Richman, Montali); Darr School of Agri-
culture, Missouri State University, Springfield, MO 65897 (Schmitt); and Ringling
Brothers Center for Elephant Conservation, 12850 Old Grade Rd, Polk City, FL
33868 (Schmitt, Lindsay). Dr. Hunter’s present address is Elanco Animal Health,
2500 Innovation Way, Greenfield, IN 46140. Dr. Montali’s present address is
Department of Molecular and Comparative Pathobiology, School of Medicine,
Johns Hopkins University, Baltimore, MD 21205. Dr. Koch’s present address is
Department of Natural and Applied Sciences, School of Liberal Arts, University
of Dubuque, Dubuque, IA 52001.
Supported in part by National Institutes of Health–National Center for Research
Resources Clinical and Translational Science Awards to the University of Florida
(KL2 RR029888 and UL1 RR029890), Feld Entertainment Inc, and the Kansas
State University College of Veterinary Medicine.
Presented in part as an oral presentation at the Conference of the American As-
sociation of Zoo Veterinarians, Minneapolis, October 2003.
The authors thank Gary Jacobson for assistance with drug administration and
sample collection.
Address correspondence to Dr. Brock (brockp@ufl.edu).
ABBREVIATIONS
AUC
0–Tlast
Area under the plasma concentration–
versus–time curve from 0 to the last
quantifiable time point
C
max
Maximum plasma concentration
EEHV Elephant endotheliotropic herpesvirus
t
1/2
Apparent terminal half-life
T
max
Time of maximum plasma concentration
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AJVR, Vol 73, No. 12, December 2012 1997
Although EEHV infections are typically fatal, there
are confirmed cases in which elephants have survived
infection. In 3 cases reported in the literature, sur-
vival was associated with administration of famciclo-
vir.
6,7
Dosages (5.5 to 8.0 mg/kg, PO, q 8 h) for the el-
ephants 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 rap-
idly 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. Plas-
ma penciclovir concentrations in elephants peaked at
4.4 µg/mL at 1 hour after oral administration of fam-
ciclovir and decreased to undetectable concentrations
at 8 hours after oral administration of 6.4 mg of fam-
ciclovir/kg.
1
These results are analogous to therapeu-
tic 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, distrib-
uted, 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 regi-
mens.
6
In humans, the mean ± SD volume
of distribution of penciclovir is 1.08 ± 0.17
L/kg (estimated after IV injection of pen-
ciclovir), and mean t
1/2
is approximately
2 hours (after oral administration of fam-
ciclovir).
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.
Materials and Methods
Animals—Six young (4.5- to 9-year-
old) Asian elephants (5 females and 1
male) that weighed 1,646 to 2,438 kg at
the Ringling Brothers Barnum and Bailey
Center for Elephant Conservation, Polk
City, Fla, were used in the study. Food was
not withheld prior to drug administration,
and the elephants had ad libitum access to
hay and water. Elephants were assessed as
healthy on the basis of results of multiple
physical examinations, CBCs, and serum
biochemical analyses prior to drug admin-
istration by the attending veterinarian.
Study procedures were approved by the Kansas State
University Animal Care and Use Committee.
Study design—Initially, a complete crossover de-
sign for 3 treatments was intended for all 6 elephants.
However, because these elephants were young, they
were occasionally uncooperative. Thus, a complete
crossover design was possible for only 3 elephants. The
other 3 elephants were each assigned to a treatment
group; thus, each treatment group was composed of 4
elephants. Elephants had not been administered fam-
ciclovir for a period of at least 12 weeks prior to the
study.
Each of the 3 groups received a single dose of famci-
clovir (5 mg/kg, PO; 5 mg/kg, per rectum; or 15 mg/kg,
per rectum). Famciclovir tablets
a
were crushed and sus-
pended in an aqueous solution shortly (< 1 hour) before
administration, regardless of the route of administration.
Oral administration was achieved by injecting the solu-
tion in the pharyngeal region (caudal to the base of the
tongue) with a 400-mL nylon large animal dosing syringe
with a long, curved metal cannula tip. For rectal admin-
istration, fecal material was manually removed from the
distal aspect of the rectum. The person administering the
drug then reached into the rectum (arm-length depth [ap-
prox 0.8 m] to deposit the dose.
Blood samples were collected before (time 0) and
0.17, 0.33, 0.67, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours
after administration for both 5 mg/kg doses. Blood sam-
ples for the 15 mg/kg dose were collected before (time
0) and 0.25, 0.5, 0.67, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and
24 hours after administration. Blood samples (10 mL)
were collected from auricular veins with an angel wing
extension set and placed into evacuated tubes contain-
Figure 1—Mean ± SD plasma penciclovir concentrations in young (4.5- to 9-year-
old) Asian elephants (Elephas maximus) at various times after oral administration
(5 mg/kg [black circles]) and rectal administration (5 mg/kg [black inverted triangles]
and 15 mg/kg [white circles]) of famciclovir. Six elephants were included in the
study; values reported represent results for 4 elephants/treatment. *Represents
results for 3 elephants for the 5 mg/kg oral treatment and 5 mg/kg rectal treatment.
†Represents results for 2 elephants for the 5 mg/kg oral treatment and 1 elephant
for the 5 mg/kg rectal treatment. ‡Represents results for 1 elephant for the 5 mg/
kg oral treatment and 1 elephant for the 5 mg/kg rectal treatment. §Represents
results for 1 elephant for the 15 mg/kg rectal treatment.
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1998 AJVR, Vol 73, No. 12, December 2012
ing potassium oxalate and sodium fluoride. Tubes sub-
sequently were centrifuged to obtain plasma.
Drug assay—Famciclovir and penciclovir concen-
trations were determined in elephant plasma via a vali-
dated liquid chromatography–mass spectrometry assay
at the Department of Anatomy and Physiology, College
of Veterinary Medicine, Kansas State University. Chro-
matographic and extraction conditions were slightly
modified from those described in another study.
13
Ana-
lytic standards of famciclovir
b
and penciclovir
b
were
purchased. All other chemicals used were of high-per-
formance liquid chromatography grade.
Samples were quantitated with a standard curve
prepared in famciclovir- and penciclovir-naïve el-
ephant plasma via peak-area ratio and linear-correla-
tion weighted 1/x. Concentrations used to create the
standard curve ranged from 0.5 to 15 µg/mL. Quality-
control samples were prepared with famciclovir- and
penciclovir-naïve elephant plasma in bulk at concen-
trations of 2.5, 6.0, and 12.5 µg/mL; aliquots (500 µL)
were frozen at –70°C until used in assays (extracted
in duplicate with each assay). Accuracy and precision
were ± 15% of actual values, and recovery was > 80%
across the range of concentrations of the assay.
Data analysis—Pharmacokinetic variables were
determined for each elephant via noncompartmental
analysis.
14,15,c
Parameters calculated for plasma were
AUC
0–Tlast
, C
max
, and T
max
, which were obtained directly
from the data. The AUC
0–Tlast
was calculated from time
0 to the last quantifiable concentration via the linear
trapezoidal rule. All values were reported as median,
range, and mean ± SD, with the exception of t
1/2
, which
was reported as the harmonic mean.
Results
All elephants remained clinically normal during
the duration of the study. No apparent adverse effects
were detected in any of the 6 elephants. Famciclovir
was tolerated well for both routes of administration and
underwent rapid biotransformation to the active com-
pound penciclovir (ie, no plasma samples had quantifi-
able concentrations of famciclovir). After oral admin-
istration of famciclovir, we did not detect quantifiable
concentrations of penciclovir or famciclovir before 0.67
hours. However, after rectal administration of both dos-
es, penciclovir was quantifiable at the first time point
(0.17 and 0.25 hours for 5 and 15 mg/kg, respectively)
in all elephants (Figure 1).
Plasma penciclovir concentration versus time
curves were plotted for the 3 treatments (Figure 1).
Pharmacokinetic variables were summarized (Table 1).
Only the AUC
0–Tlast
, which was reported as the percent-
age of area under the curve extrapolated to infinity, was
> 20% in some elephants. After oral administration of
a single dose of 5 mg/kg, C
max
was 1.3 µg/mL, with a
T
max
of 1.1 hours. The same dose administered rectal-
ly resulted in a C
max
of 1.2 µg/mL, with a T
max
of 0.34
hours. Rectal administration of a single dose of 15 mg/
kg yielded a t
1/2
of 2.6 hours, with a C
max
of 3.6 µg/mL
and T
max
of 0.66 hours.
Discussion
The study reported here provided estimated sys-
temic penciclovir concentrations following administra-
tion of a single dose of famciclovir (5 mg/kg orally or
5 and 15 mg/kg rectally) to Asian elephants. Although
the oral and rectal routes of administration had simi-
lar extents of exposure, the oral route was associated
with slightly slower detection of quantifiable systemic
concentrations and more variation in plasma concen-
trations of penciclovir. In part, the latter 2 findings may
have been attributable to the fact that oral administra-
tion was provided to elephants in the fed state, although
low numbers of animals may also have contributed to
these findings.
The median AUC
0–Tlast
of penciclovir was similar
after both oral and rectal administration of famciclovir
at a dose of 5 mg/kg. The lack of detectible famciclo-
vir concentrations was attributable to the fact that the
drug was absorbed well and then rapidly metabolized
to penciclovir or that famciclovir was metabolized prior
to absorption. The rectal route had faster absorption,
with a T
max
ranging from 0.34 to 0.66 hours after rectal
administration, compared with 1.1 hours after oral ad-
ministration. The harmonic mean t
1/2
was 1.6 hours and
C
max
was 1.3 µg/mL after oral administration of famci-
clovir to elephants. These results are similar to those re-
Dose and route Variable Mean ± SD Median Range
5 mg/kg, PO AUC
0–Tlast
(h•µg/mL) 2.20 ± 0.68 2.30 1.3–2.90
C
max
(µg/mL) 1.30 ± 0.77 1.20 0.58–2.30
T
max
(h) 1.10 ± 0.63 0.84 0.68–2.00
t
1/2
(h) 1.60* 3.80 0.55–7.10
5 mg/kg, per rectum AUC
0–Tlast
(h•µg/mL) 2.40 ± 1.10 2.10 1.30–3.90
C
max
(µg/mL) 1.20 ± 0.12 1.20 1.00–1.30
T
max
(h) 0.34 ± 0.02 0.34 0.32–0.35
t
1/2
(h) 2.20* 2.50 1.50–3.30
15 mg/kg, per rectum AUC
0–Tlast
(h•µg/mL) 8.50 ± 3.50 8.80 4.30–12.00
C
max
(µg/mL) 3.60 ± 1.40 4.10 1.60–4.70
T
max
(h) 0.66 ± 0.24 0.61 0.43–0.98
t
1/2
(h) 2.60* 2.40 2.10–3.60
Values reported represent results for 4 elephants/treatment.
*Value reported is the harmonic mean.
Table 1—Pharmacokinetic values for penciclovir after oral and rectal administration of a single dose of
famciclovir to young (4.5- to 9-year-old) Asian elephants (Elephas maximus).
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AJVR, Vol 73, No. 12, December 2012 1999
ported in humans, in which oral administration of 500
mg (approx 7 mg/kg) of famciclovir yields an apparent
t
1/2
of approximately 2 hours with a C
max
of 3.3 µg/mL.
On the basis of results of the present study and previous
reports,
1,6,7
a dose of 8 to 15 mg/kg administered orally
or rectally every 8 hours to Asian elephants should re-
sult in drug concentrations similar to those considered
therapeutic in humans. Unfortunately, to the authors’
knowledge, there is currently no information regarding
therapeutic plasma concentrations for the treatment of
EEHV. Once this information is available, it is likely
that dosing recommendations for famciclovir will re-
quire adjustment.
The recovery of a young elephant from EEHV in-
fection following rectal administration of famciclovir
provided preliminary clinical evidence that there was
an alternative to oral administration.
6
The present
study provided direct evidence that rectally adminis-
tered famciclovir was efficiently absorbed in elephants.
These findings are similar to those of other studies
16,17
that confirmed aqueous suspensions of metronidazole
and isoniazid are well absorbed when administered
rectally to elephants. Analysis of the data in the study
reported here indicated that oral administration may re-
sult in more pharmacokinetic variation than does rectal
administration; however, because of the low numbers
of elephants for each treatment, this finding should not
be overinterpreted. Additional research is needed to
determine whether rectal administration is preferable
to oral administration. Having the option to administer
famciclovir rectally may be clinically valuable because
herpesvirus infections typically affect young elephants,
and medicating a poorly trained, sick, and generally
uncooperative elephant is a challenge.
18
Many healthy
elephants are reluctant to voluntarily take medication
orally, even when it is mixed in food. Elephants can
be trained to accept a gag and to allow administration
of medication into the caudal aspect of the orophar-
ynx.
18,19
However, even well-trained animals may refuse
oral administration of medication when they are sick
or anorectic. Thus, rectal administration may offer an
important alternative for elephants that are reluctant to
accept oral administration of medications or unable to
consume the medication because of edema of the face
and tongue. Many trained elephants are accustomed to
rectal palpation for reproductive evaluations, and even
untrained elephants can be safely restrained inside a
chute during the procedure.
Allometric scaling is a mathematical conversion
based on body mass that uses a dose established for one
species to estimate a dose for another species. Allome-
tric scaling of pharmacokinetic variables is of interest
to zoological veterinarians because elephants and other
large animals are at the high end of the body weight
scale, and this method can provide an estimate for de-
signing therapeutic regimens when species-specific
pharmacokinetic information is not available. Adhering
to the principles of metabolic scaling, extrapolation of
a dose for humans would be expected to yield a lower
dose for a much heavier elephant. Allometric scaling
for conversion of famciclovir administration was used
in the treatment of 1 elephant.
6
Thus, the human dose
of 7 mg/kg was used to estimate a dose of 4.06 mg/kg
for that elephant.
6
However, not all drugs are scalable.
14
Specifically, drugs that are extensively metabolized by
the liver are considered poor candidates for allometric
scaling because of considerable interspecific hetero-
geneity in phase I and phase II drug metabolic reac-
tions.
14,20,21
On the basis of results of the present study,
it appears that famciclovir doses obtained via allometric
scaling are not supported by the current data and that
famciclovir doses should not be determined via allome-
tric scaling, as was presumed in the case reports.
For the study reported here, we did not detect
clinically relevant differences in plasma penciclovir
concentrations, compared with the plasma penciclovir
concentrations reported for humans after famciclovir
administration. The results of the present study support
oral or rectal administration of a dose of 8 to 15 mg of
famciclovir/kg every 8 hours for the treatment of EEHV
in Asian elephants.
a. Famvir, SmithKline Beecham Pharmaceuticals, Philadelphia, Pa.
b. Moravek Biochemicals, Brea, Calif.
c. WinNonlin, version 5.3, Pharsight Corp, Cary, NC.
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In the report “Expression of interleukin-1β, interleukin-8, and interferon-γ in blood samples obtained from healthy
and sick neonatal foals” (Am J Vet Res 2012;73:1418–1427), the units for plasma lactate concentration in panel F and y-axis
unit increments in panels D, E, and F of Figure 3 were incorrectly labeled. The correct units for plasma lactate concentra-
tion and y-axis scales should appear as follows:
Correction: Expression of interleukin-1β, interleukin-8, and interferon-γ in blood samples obtained from healthy
and sick neonatal foals
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