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

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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.
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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
11-07-0267r.indd 2000 11/16/2012 1:00:53 PM
... In elephants, EEHV encodes both thymidine kinase (TK) (the usual target for famciclovir and acyclovir) and a serine/threonine protein kinase (PK) (the usual target for ganciclovir) similar to HSV and HCMV, but they have only 25% of both enzyme amino acids that identity with the orthologue target viruses for these drugs (Dastjerdi et al., 2016, Long et al., 2015, which might explain lower survival outcomes. In elephants, reports using famciclovir for EEHV clinical treatment found the active metabolite, penciclovir, in serum reached hypothetical levels for therapeutic effect in clinical ill cases based on human studies (Brock et al. 2012;Fuery et al. 2016a;2016b;Schmitt et al. 20010). However, the half-life of famciclovir in elephants is short at approximately 3 hours and likely may not adequately control viral replication in EEHV cases (Dastjerdi et al. 2016). ...
... However, the half-life of famciclovir in elephants is short at approximately 3 hours and likely may not adequately control viral replication in EEHV cases (Dastjerdi et al. 2016). To date, only two pharmacokinetic studies have been conducted in Asian elephant calves, one with famciclovir (Brock et al. 2012) and the other with acyclovir (Khammesri et al. in preparation), so more work is needed. From previous reports, successful recovery outcomes of EEHV cases have been associated with antiviral drugs in combination with supportive treatment (Bauer et al. 2018;Brock et al. 2012;Dastjerdi et al. 2016;Molenaar and Schaftenaar 2020;Schmitt et al. 2000;Sripiboon et al. 2017), specifically famciclovir at doses of 8-15 mg/kg BW (PO/PR) tid-qid (Brock et al. 2012) and acyclovir at doses of 12 mg/kg BW (IV) bid (Sripiboon et al. 2017) and 45 mg/kg BW (PO) tid (Khammesri et al. in preparation). ...
... To date, only two pharmacokinetic studies have been conducted in Asian elephant calves, one with famciclovir (Brock et al. 2012) and the other with acyclovir (Khammesri et al. in preparation), so more work is needed. From previous reports, successful recovery outcomes of EEHV cases have been associated with antiviral drugs in combination with supportive treatment (Bauer et al. 2018;Brock et al. 2012;Dastjerdi et al. 2016;Molenaar and Schaftenaar 2020;Schmitt et al. 2000;Sripiboon et al. 2017), specifically famciclovir at doses of 8-15 mg/kg BW (PO/PR) tid-qid (Brock et al. 2012) and acyclovir at doses of 12 mg/kg BW (IV) bid (Sripiboon et al. 2017) and 45 mg/kg BW (PO) tid (Khammesri et al. in preparation). We recommend early diagnosis by PCR testing and treatment with antiviral drugs plus supportive therapies like intravenous fluid therapy, plasma transfusion, antibiotics or vitamin C administration in clinical EEHV cases. ...
Article
Background: Elephant endotheliotropic herpesvirus causes a hemorrhagic disease (EEHV-HD) that is a major cause of death in juvenile Asian elephants with EEHV1 and EEHV4 being the most prevalent. Aim: To perform a retrospective clinical data analysis. Methods: Records of a total of 103 cases in Thailand confirmed by polymerase chain reaction (PCR) on blood and/or tissue samples. Results: The severity of clinical signs varied among EEHV subtypes. EEHV1A was the most prevalent with 58%, followed by EEHV4 with 34%, EEHV1B with 5.8% and EEHV1&4 co-infection with 1.9%. Overall case fatality rate was 66%. When compared among subtypes, 100% case fatality rate was associated with EEHV1&4 co-infection, 83% with EEHV1B, 75% with EEHV1A, and the lowest at 40% for EEHV4. Calves 2-4 years old were in the highest age risk group and exhibited more severe clinical signs with the highest mortality. Majority of cases were found in weaned or trained claves and higher number of cases were observed in rainy season. A gender predilection could not be demonstrated. Severely affected elephants presented with thrombocytopenia, depletion of monocytes, lymphocytes and heterophils, a monocyte:heterophil (M:H) ratio lower than 2.37, hypoproteinemia (both albumin and globulin), severe grade of heterophil toxicity, and low red blood cell (RBC) counts and pack cell volumes (PCV). Survival was not affected by antiviral drug treatment in the severely compromised animals. Conclusion: Early detection by laboratory testing and aggressive application of therapies comprising of supportive and anti-viral treatment can improve survival outcomes of this disease.
... In elephants, EEHV encodes both thymidine kinase (TK) (the usual target for famciclovir and acyclovir) and a serine/threonine protein kinase (PK) (the usual target for ganciclovir) similar to HSV and HCMV, but they have only 25% of both enzyme amino acids that identity with the orthologue target viruses for these drugs (Dastjerdi et al., 2016, Long et al., 2015, which might explain lower survival outcomes. In elephants, reports using famciclovir for EEHV clinical treatment found the active metabolite, penciclovir, in serum reached hypothetical levels for therapeutic effect in clinical ill cases based on human studies (Brock et al. 2012;Fuery et al. 2016a;2016b;Schmitt et al. 20010). However, the half-life of famciclovir in elephants is short at approximately 3 hours and likely may not adequately control viral replication in EEHV cases (Dastjerdi et al. 2016). ...
... However, the half-life of famciclovir in elephants is short at approximately 3 hours and likely may not adequately control viral replication in EEHV cases (Dastjerdi et al. 2016). To date, only two pharmacokinetic studies have been conducted in Asian elephant calves, one with famciclovir (Brock et al. 2012) and the other with acyclovir (Khammesri et al. in preparation), so more work is needed. From previous reports, successful recovery outcomes of EEHV cases have been associated with antiviral drugs in combination with supportive treatment (Bauer et al. 2018;Brock et al. 2012;Dastjerdi et al. 2016;Molenaar and Schaftenaar 2020;Schmitt et al. 2000;Sripiboon et al. 2017), specifically famciclovir at doses of 8-15 mg/kg BW (PO/PR) tid-qid (Brock et al. 2012) and acyclovir at doses of 12 mg/kg BW (IV) bid (Sripiboon et al. 2017) and 45 mg/kg BW (PO) tid (Khammesri et al. in preparation). ...
... To date, only two pharmacokinetic studies have been conducted in Asian elephant calves, one with famciclovir (Brock et al. 2012) and the other with acyclovir (Khammesri et al. in preparation), so more work is needed. From previous reports, successful recovery outcomes of EEHV cases have been associated with antiviral drugs in combination with supportive treatment (Bauer et al. 2018;Brock et al. 2012;Dastjerdi et al. 2016;Molenaar and Schaftenaar 2020;Schmitt et al. 2000;Sripiboon et al. 2017), specifically famciclovir at doses of 8-15 mg/kg BW (PO/PR) tid-qid (Brock et al. 2012) and acyclovir at doses of 12 mg/kg BW (IV) bid (Sripiboon et al. 2017) and 45 mg/kg BW (PO) tid (Khammesri et al. in preparation). We recommend early diagnosis by PCR testing and treatment with antiviral drugs plus supportive therapies like intravenous fluid therapy, plasma transfusion, antibiotics or vitamin C administration in clinical EEHV cases. ...
Article
Full-text available
Background: Elephant endotheliotropic herpesvirus causes a hemorrhagic disease (EEHV-HD) that is a major cause of death in juvenile Asian elephants with EEHV1 and EEHV4 being the most prevalent. Aim: To perform a retrospective clinical data analysis. Methods: Records of a total of 103 cases in Thailand confirmed by polymerase chain reaction (PCR) on blood and/or tissue samples. Results: The severity of clinical signs varied among EEHV subtypes. EEHV1A was the most prevalent with 58%, followed by EEHV4 with 34%, EEHV1B with 5.8% and EEHV1&4 co-infection with 1.9%. Overall case fatality rate was 66%. When compared among subtypes, 100% case fatality rate was associated with EEHV1&4 co-infection, 83% with EEHV1B, 75% with EEHV1A, and the lowest at 40% for EEHV4. Calves 2-4 years old were in the highest age risk group and exhibited more severe clinical signs with the highest mortality. Majority of cases were found in weaned or trained claves and higher number of cases were observed in rainy season. A gender predilection could not be demonstrated. Severely affected elephants presented with thrombocytopenia, depletion of monocytes, lymphocytes and heterophils, a monocyte:heterophil (M:H) ratio lower than 2.37, hypoproteinemia (both albumin and globulin), severe grade of heterophil toxicity, and low red blood cell (RBC) counts and pack cell volumes (PCV). Survival was not affected by antiviral drug treatment in the severely compromised animals. Conclusion: Early detection by laboratory testing and aggressive application of therapies comprising of supportive and anti-viral treatment can improve survival outcomes of this disease.
... In other species, like cats, dogs and humans, the acyclovir T 1/2el is approximately 3 h Jankowski et al., 1998;Krasny et al., 1981;Laskin, 1983;Owens et al., 1996), which is shorter than what we observed. Drug metabolism and elimination in the elephant calves and horse are presumed to be similar as both are hind-gut fermenters (Hunter & Isaza, 2008), and the body weight of elephant calves is similar to that of adult horses, so allometric scaling could be helpful in estimating appropriate dose regimens (Brock et al., 2012;. The pharmacokinetic parameter, T 1/2el of acyclovir per IV and PO routes (5.87 ± 0.74 h and 8.74 ± 2.47 h) was longer than that of T 1/2el in humans Jankowski et al., 1998;Laskin, 1983), but similar to that found in the horse (Bentz et al., 2006;Garre et al., 2007;Wilkins et al., 2005). ...
Article
Full-text available
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 (T1/2) 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.
... 33 Other successful transrectal drug administrations used oral formulations. 32,34,35 Therefore, the decision was made to try administration of oral enrofloxacin per rectum. Apart from a measurable recovery of the elephant, the efficacy of enrofloxacin administered per rectum can still be disputed. ...
Article
An adult female Asian elephant (Elephas maximus) presented with clinical signs of colic unresponsive to analgesia, which progressed to hypothermia and collapse within 48 hours. Repeated sedations using butorphanol and detomidine were performed for initial diagnostic sampling, first aid and subsequent treatment. Initial haematology showed evidence of septicaemia and disseminated intravascular coagulation; urine analysis was consistent with metabolic acidosis. The initial treatment focused on rectal administration of enrofloxacin, metronidazole and fluids. By Day 7, the immune system was recovering as demonstrated by blood parameters but ileus had developed. Sedation interventions were discontinued and treatment consisted of oral ranitidine, fibre provision and rehydration. Salmonella saintpaul was cultured from the faeces and a disease risk analysis identified a possible infection route through food contamination. Serial haematology provided direction in clinical decision making throughout this challenging case.
... Une néphrotoxicité modérée ainsi que des maux de tête, de la nausée et des diarrhées sont rapportés chez l'homme, survenant surtout lorsque le dosage est mal ajusté(Plumb, 2011). Ainsi chez l'éléphant il est conseillé de vérifier la bonne hydratation de l'animal avant l'administration afin de limiter la possible néphrotoxicité.La posologie tirée de l'étude pharmacocinétique est de 8 à 15 mg/kg toutes les 8 h afin de rester dans l'intervalle de dose thérapeutique(Brock et al., 2012). L'absence d'effets secondaires observés conduit à préférer la dose de 15 mg/kg afin de maximiser les chances d'efficacité, ce que recommande le comité de conseil.□ ...
... A pharmacokinetic study using famciclovir, an antiviral drug, in six Asian elephants was published by Brock et al. (2012). Anthelmintic agents have also been investigated, but most of these trials have been therapeutic in nature, and pharmacokinetic studies are still needed to define safe and therapeutic dosing regimens. ...
Article
African elephants Loxodonta africana and Asian elephants Elephas maximus are not thriving in many captive settings and are threatened throughout their native ranges. Many zoos support in situ conservation projects and provide opportunities to conduct ex situ research in controlled settings with comparably approachable animals. Zoo elephant projects may facilitate fieldwork with free‐ranging elephants (e.g. development of non‐invasive sampling and analytical tools), which may then also improve the husbandry of elephants in human care. Free‐ranging elephants also benefit from drug therapies and veterinary care when they are orphaned, kept as working elephants or brought in as rehabilitation cases – especially as human–elephant conflicts become more common as a result of ever‐expanding human populations. Much has been learned about the basic biology and husbandry needs of elephants but, often, the more we learn, the more questions arise. There are physiological differences between African and Asian elephants, and this should affect the management of these animals. This paper will provide brief overviews of the current state of knowledge regarding the pharmacology, nutrition, reproduction, sensory biology and diseases (primarily elephant endotheliotropic herpesvirus infections) relevant to elephants with recommendations for future research. African elephants Loxodonta africana and Asian elephants Elephas maximus are not thriving in many captive settings and are threatened throughout their native ranges. Many zoos support in situ conservation projects and provide opportunities to conduct ex situ research with approachable animals. Human–elephant interactions and ecosystems vary regionally, necessitating different elephant population‐management approaches, and, for this reason, research goals may at times appear diametrically opposed. Much has been learned about the basic biology and husbandry needs of elephants but the more we learn, the more questions arise. There are physiological differences between African and Asian elephants, and this should affect the management of these animals. This paper will provide brief overviews of the current state of knowledge regarding the pharmacology, nutrition, reproduction, sensory biology and diseases (primarily elephant endotheliotropic herpesvirus infections) relevant to elephants with recommendations for future work. (Photo: ‘Anna’, an African elephant, at The Maryland Zoo in Baltimore, USA, participating in a pharmacokinetic study. Ursula Bechert, University of Pennsylvania)
Article
Elephant endotheliotropic herpesvirus (EEHV) is a major cause of death in Asian elephant (Elephas maximus) calves. A 2-year, 11-month-old female, captive Asian elephant presented with facial edema and a mild fever. Blood samples were collected and showed EEHV1A positivity with a high viral load by real time PCR. Heterophil toxicity also was reported for the first time in this case. The calf was treated orally with acyclovir, 45 mg/kg tid for 28 days, which reduced the EEHV1A viral load to undetectable levels within 9 days and the calf survived. A successful outcome with oral acyclovir administration provides another and affordable option to treat EEHV hemorrhagic disease in Asian elephants, and one that is easier to administer in untrained calves.
Chapter
This chapter offers essential drug information for a wide range of elephants, including African elephants and Asian elephants in an easy‐to‐consult format. It provides dosing amounts for all important drugs, including antimicrobials, antifungals, antiviral, analgesia, anesthetic, antiparasitics, emergency drugs and other. The drug doses are sorted by type and arranged alphabetically. Each dose is referenced with a journal or textbook source, including the number of animals in the study where available, making it easy to find trusted information. The chapter takes a tabular approach to find a referenced dose for these animals, eliminating time spent searching through other sources easily. It is an essential reference for all veterinarians seeing zoo and wild animal patients, including zoo and wildlife veterinarians, veterinary specialists, and veterinary students.
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Famciclovir (Famvir®) is the oral prodrug of penciclovir, an agent that has demonstrated antiviral activity against herpes simplex viruses, type 1 (HSV-1) and 2 (HSV-2) [which cause orolabial and/or genital herpes simplex], and against varicella zoster virus (VZV) [a reactivation of which leads to herpes zoster]. Famciclovir has efficacy similar to that of aciclovir (in immunocompetent or immunocompromised patients) or valaciclovir (in immunocompetent patients) in the treatment of herpes zoster, and efficacy similar to aciclovir in the treatment of first or recurrent episodes of genital herpes (in immunocompetent or immunocompromised patients). Famciclovir also has efficacy in the suppression of recurrent episodes of genital herpes, and in the treatment of orolabial herpes, in immunocompetent patients. As such, famciclovir is a well tolerated first-line option for the treatment of herpes zoster and the treatment and suppression of genital herpes, and is approved for the treatment of recurrent orolabial herpes. Convenient patient-initiated single-day (for recurrent genital herpes) and single-dose (for orolabial herpes) dosage regimens may contribute to treatment compliance, patient acceptability and subsequent treatment outcomes. Pharmacodynamic Properties The proposed mechanism of antiviral action of penciclovir, which is the active form of orally administered famciclovir, involves the competitive inhibition by the phosphorylated agent, penciclovir triphosphate, of viral DNA polymerase, thereby inhibiting DNA synthesis and replication in virus-infected cells. Famciclovir/penciclovir had antiviral activity generally similar to that of aciclovir in in vivo and in vitro studies. The higher intracellular concentrations of penciclovir triphosphate and its greater stability in infected cells may outweigh the greater affinity of aciclovir for viral DNA polymerase than that of penciclovir triphosphate for the same substrate, and account for the prolonged in vivo antiviral activity of penciclovir relative to that of aciclovir. Famciclovir is extensively and consistently absorbed after oral administration (bioavailability 77%), and is rapidly converted to penciclovir. The pharmacokinetics of penciclovir are linear and dose proportional, with no accumulation of the drug after multiple doses. The volume of distribution indicates extensive distribution into the tissues. Penciclovir is poorly (<20%) bound to plasma proteins and is excreted in the urine. Therapeutic Efficacy In large, well designed trials, famciclovir has shown efficacy in the treatment of herpes zoster, the treatment and suppression of genital herpes, and the treatment of orolabial herpes. Seven-day regimens of famciclovir demonstrated efficacy that was no different (in terms of time to lesion healing and/or resolution of pain or other symptoms) to those of aciclovir, valaciclovir or brivudine in the treatment of herpes zoster in immunocompetent patients, and demonstrated a significantly shorter time to resolution of post-herpetic neuralgia than placebo. The efficacies of famciclovir and aciclovir did not differ significantly in the treatment of immunocompromised patients. In the treatment of first or recurrent episodes of genital herpes in immunocompetent patients, 5-day regimens of famciclovir and aciclovir had similar efficacy. A single-day famciclovir regimen has shown clinical benefit compared with placebo in immunocompetent patients with recurrent episodes. In immunocompromised patients with recurrent genital or orolabial herpes, similar proportions of famciclovir and aciclovir recipients developed new lesions during the 7-day treatment period, and the median time to complete lesion healing was similar for both treatment groups. Suppressive treatment with famciclovir was significantly more effective than placebo in immunocompetent patients with recurrent genital herpes in terms of time to recurrence, number of recurrences and proportion of patients recurrence-free for a specified period, and in HIV-infected patients with anogenital or orolabial herpes with regard to number of days with symptoms and number of days that HSV virus was isolated from the affected area. In one study of immunocompetent patients with recurrent genital herpes, approximately two-thirds of famciclovir and valaciclovir recipients were recurrence free during the 16-week treatment period. In immunocompetent patients with recurrent orolabial herpes, early treatment with a patient-initiated, single-dose famciclovir regimen significantly reduced lesion healing time compared with placebo. Tolerability Individual trial reports and a pooled analysis of several clinical trials indicate that famciclovir is well tolerated, and the nature, severity and incidence of adverse events reported with famciclovir are generally similar to those with placebo or aciclovir. The most frequently reported treatment-emergent adverse events were headaches and gastrointestinal symptoms. In the pooled analysis, the incidences in famciclovir versus placebo recipients of adverse events considered to be at least possibly treatment-related were 9.3% versus 7.9% for headache, 4.5% versus 4.2% for nausea and 2.4% versus 2.3% for diarrhoea; the incidences in famciclovir versus aciclovir recipients were 6.0% versus 4.6% for headache, 3.7% versus 2.7% for nausea, 1.7% versus 2.3% for abdominal pain and 1.3% versus 1.9% for diarrhoea. Treatment withdrawal rates due to adverse events were similar with famciclovir (2.4%) and placebo (1.6%), and serious adverse events related to famciclovir therapy were rare.
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Within the past 4 years, tuberculosis (TB) has emerged as a disease of concern in elephants. The population of elephants in North America is declining [Wiese, 1997], and transmissible diseases such as TB may exacerbate this trend. Guidelines for the Control of Tuberculosis in Elephants, which require the screening of all elephants for TB, were instituted in 1997 [USDA, 1997; 2000]. Between August 1996 and May 2000, Mycobacterium tuberculosis was isolated from 18 of 539 elephants in North America, indicating an estimated prevalence of 3.3%. Isolation of the TB organism by culture is the currently recommended test to establish a diagnosis of TB; however, culture requires 8 weeks. Further research is essential to validate other diagnostic tests and treatment protocols. Zoo Biol 19:393–403, 2000. © 2000 Wiley-Liss, Inc.
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A rapid, sensitive and reliable reversed-phase high-performance liquid chromatographic (HPLC) method with UV detection has been developed for the assay of a novel anti-herpes agent, 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (BRL-39123), in human plasma and urine. The drug and the internal standard, the structural analogue BRL-42377, were extracted from the biological matrix by adsorption on a cation-exchange column and were subsequently eluted under alkaline conditions prior to HPLC. The method is reproducible, with coefficients of variation of ca. 5%, and linear from 0.1 to at least 30 micrograms ml-1 in plasma and from 50 to at least 2000 micrograms ml-1 in urine. The method has been used extensively to measure BRL-39123 in plasma and urine samples generated during clinical studies and is adequate for defining pharmacokinetics at projected therapeutic doses.
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To characterize the pharmacokinetics of a single 500 mg oral dose of famciclovir in subjects with varying degrees of renal impairment. Twenty-seven subjects were enrolled in an open-label parallel-group study. Eighteen patients had renal impairment (average age [ +/- SD], 49 +/- 12 years), and nine subjects were healthy volunteers (average age, 28 +/- 7 years). Patients with renal impairment were stratified into groups based on estimated creatinine clearance (CLCR): mild impairment (CLCR, 60 to 80 ml/min/1.73 m2), moderate impairment (CLCR, 30 to 59 ml/min/1.73 m2) and severe impairment (CLCR, 5 to 29 ml/min/1.73 m2). Plasma and urine specimens were analyzed for concentrations of penciclovir, the antivirally active metabolite of famciclovir, by reverse-phase HPLC. Plasma data were analyzed with use of model-independent methods. In subjects with normal renal function (CLCR > 80), the mean maximum plasma concentrations of penciclovir was 2.83 micrograms/ml (range, 1.30 to 3.82 micrograms/ml) and the mean time to reach maximum concentration was 0.89 hours (range, 1/2 to 1 1/2 hours). The mean apparent terminal elimination half-life was 2.15 hours (range, 1.56 to 2.87 hours). A linear relationship was observed between the plasma elimination rate constant and CLCR and between renal clearance and CLCR. Mean area under the plasma concentration-time curve from zero to infinity was approximately tenfold higher and the plasma elimination rate constant was approximately fourfold lower in patients with severe renal impairment than in subjects with normal renal function. Consideration should be given to modification of the dosing schedule of famciclovir from the usual 8-hour interval to a 12-hour interval for patients with moderate renal impairment (CLCR 30 to 59 ml/min/1.73 m2) or a 24-hour interval for patients with severe renal impairment (CLCR < 30 ml/min/1.73 m2).
Article
Famciclovir is an oral prodrug of the antiherpesvirus nucleoside analogue, penciclovir. Following oral administration famciclovir undergoes extensive first pass metabolism to penciclovir and essentially no parent compound is recovered from plasma or urine. Penciclovir plasma concentrations reach a maximum less than 1 hour after famciclovir administration in fasting individuals, but are delayed if famciclovir is taken within 2 hours of a meal. The bioavailability of penciclovir, measured by urinary recovery, is approximately 60% and is not affected by food. Over the likely therapeutic dose range of famciclovir 125mg to 750mg, the pharmacokinetics of penciclovir are linear. The volume of distribution of penciclovir after intravenous administration is more than 1 L/kg, indicating extensive distribution into the tissue. Penciclovir is predominantly eliminated unchanged by the kidney, partly by active tubular excretion and has a terminal phase elimination half-life (t½β) of between 2 and 2.5 hours and a renal clearance (CLR) of between 25 and 30 L/h in individuals with normal renal function. In those with severe renal impairment the CLR falls markedly and the t½β increases to over 18 hours. Haemodialysis appears to be effective in clearing penciclovir from plasma. Elderly individuals tolerate famciclovir well, despite slower elimination secondary to age-related lower renal clearance. Uncomplicated herpes zoster does not affect the pharmacokinetic profile of penciclovir. In the limited studies undertaken so far, no significant drug interactions have been demonstrated.