Pharmacokinetics of Amikacin in Scimitar-Horned Oryx (Oryx dammah) from a Single Intravenous Dose Author(s): Kathryn C. Gamble, James M. Jensen, Dawn M. Boothe, J. Jill Heatley and Kelly E. Helmick Source: Journal of Zoo and Wildlife Medicine, Vol. 26, No. 3 (Sep., 1995), pp. 359-366 Published by: American Association of Zoo Veterinarians Stable URL: http://www.jstor.org/stable/20095491 . Accessed: 28/06/2013 16:59 Your use of the JSTOR archive indicates your acceptance of the Terms & Conditions of Use, available at . http://www.jstor.org/page/info/about/policies/terms.jsp
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Journal of Zoo and Wildlife Medicine 26(3): 359-366, 1995 Copyright 1995 by American Association of Zoo Veterinarians
PHARMACOKINETICS OF AMIKACIN IN SCIMITAR-HORNED ORYX {ORYX DAMM AH) FROM A SINGLE INTRAVENOUS DOSE C. Gamble,
Kathryn
J. Jill Heatley,
James
D.V.M.,
M.
Jensen,
B.S., and Kelly E. Helmick,
Dawn
D.V.M.,
M.
Boothe,
D.V.M.,
Ph.D.,
D.V.M.
Abstract: Single-dose pharmacokinetics of amikacin in seven adult scimitar-horned oryx (Oryx dammah) was determined. The intravenous dose of 5.8 mg/kg (mean) was based on metabolic energy scaling. Blood samples were collected through an indwelling jugular catheter at 0, 5, 15, 30, 45, 60, 75, 90, 120, 240, 300, 360, 480, 600, 720, and 1,440 min after amikacin administration. curves
Drug-concentration-versus-time
were
best
fit
to
a
open
two-compartment
model
with
a
serum concentration after distribution of 30.5 ? 4.7 jug/ml and amean elimination half maximum life of 97.0 ?31.8 min. Model-independent parameters were: area under the curve, 5,478 ? 2,828 jug/min/ml; volume of distribution (steady state), 0.152 ? 0.02 L/kg; clearance, 1.2 ? 0.4 ml/min/ kg; and mean residence time, 136.5 ? 49.0 min. Mean serum amikacin concentrations reached the recommended peak concentration (25 ii%/m\) then fell below the recommended trough concentration (2 Mg/ml) by 8 hr after administration. The serum amikacin concentrations were above the minimum inhibitory concentration (MIC) levels of selected bacteria for up to 6 hr. Based on this study, amikacin administered parenterally to scimitar-horned oryx at 5.8 mg/kg at 12-hr intervals should produce therapeutic serum concentrations for susceptible bacteria. scimitar-horned oryx, Oryx dammah, pharmacokinetics. Key words: Amikacin,
INTRODUCTION a semisynthetic Amikacin, aminoglyco side antimicrobial, is frequently adminis tered for treatment of bacterial in infections is not well many animal species. Amikacin so absorbed oral administration, following standard parenteral routes of administra serum tion are used to attain therapeutic or concentrations. intramuscular Following serum con subcutaneous administration, are to those centrations comparable achieved same
with
From
administration
of
the
dose.4'5714
a bactericidal drug at thera amikacin irreversi
Considered peutic
i.v.
concentrations,
the Department
Pharmacology
of Veterinary
(Gamble,
Boothe,
Physiology
Heatley,
Helmick)
and and
theDepartment of LargeAnimal Medicine and Surgery (Jensen),College of Veterinary Medicine, Texas A&M University, College ent addresses: Mystic Boulevard, Mystic, and Dallas
mick); Texas
quests Dallas,
Station, Texas 77843, Marinelife Aquarium, Connecticut Zoo,
621
06355, East
USA.
Pres
55 Coogan USA (Hel
Clarendon, Dallas, re all reprint Address 75203, USA (Gamble). to Dr. Kathryn C. Gamble, 621 East Clarendon, Texas 75203, USA.
subunits of bacteria, bly binds to ribosomal thus interfering with their protein synthe sis.59 Its solitary spectrum is extensive and includes gram-negative bacteria (even prob lematic species such as Pseudomonas and and Nocardia, Klebsiella), Staphylococcus, several Mycobacteria Ami species.3'92021'24 kacin can also be combined with other an to eliminate timicrobials organ susceptible isms. Of the aminoglycosides, can amikacin often be used in aminoglycoside-resistant infections since it has limited accessibility to degradation by bacterial enzymes.4'91014 Characteristic of this antimicrobial group, amikacin is associated with ototoxicity, neuromuscular and nephrotox blockade, Of is the most these, nephrotoxicity icity.4'514 are because problematic aminoglycosides re concentrated selectively by the proximal nal tubules and exclusively from eliminated the body by glomerular filtration.45'914 Tox icity is correlated with failure to eliminate to serum concentrations amikacin below the recommended in trough during a dosing terval.1'49 In contrast, bactericidal activity is primarily to maximum serum correlated concentrations.1319
Clinically,
359
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regimens
can
360
be guided centrations
JOURNALOF ZOOAND WILDLIFEMEDICINE
serum drug con by monitoring to assure that treatment during
peak and trough concentrations appropriate are achieved. However, for the most effec use in veteri of antimicrobials tive initial
the actual sampling process, animals were allowed access to adjacent paddocks. Diets and free-choice of concentrate supplement were in amounts suf pasture hay provided ficient health.
to maintain and good body condition were to returned the feeding Oryx
baseline nary patients, pharmacokinetics for appropriate should be employed dosing. for exotic species often have Regimens from clinical been formulated experience. has been re this approach More recently, doses of established fined by modification in other species by metabolic energy scal species is ing.2526 Ideally, the comparative
Appropriate were followed
similar to the target species. Pharmacoki routes netic studies of a variety of parenteral in hu for amikacin have been documented
mobilization and to minimize
mans, bits,
cats, dogs, horses, and several avian
cies.5"71115-18'23'27
However,
rab
calves, sheep, and reptilian no
spe
aminogly
has been reported coside pharmacokinetics The in the literature for exotic hoofstock. the of this study was to establish purpose in desert an of amikacin pharmacokinetics scimitar-horned oryx (Oryx using as a model. These data were then dammah) used as a basis for amikacin dosing guide lines for this hoofstock group. telope,
MATERIALS AND METHODS
intravenous
and
ruminant fasting procedures for prior to immobilization im Narcotic catheterization. was used to allow reversibility
anesthetic interference with or dis the antimicrobial assay physiologic tribution of amikacin. Due to limited sup two anesthetic protocols plies of narcotics, were used. Intramuscular administration of Lemmon 650 Company, etorphine (M99, Cathill
Road,
Sellersville,
Pennsylvania
19443, USA; 25-35 Mg/kg) or carfentanil P.O. Laboratories, Colorado 80524, used for the anes was achieved thetic induction. Reversal by routes with di standard split administrative Company, prenorphine (M5050, Lemmon
citrate (Wildnil, Wildlife Box 8938, Fort Collins, 25-45 Mg/kg) was USA;
Road, Sellersville, Pennsylvania 30-40 USA; Mg/kg) or naltrexone P.O. Box Laboratories, (Trexonil, Wildlife Fort Colorado 80524, USA; Collins, 8938, for the two in 2.5-4.5 mg/kg), respectively, 19443,
and two female apparently scimitar-horned oryx (Oryx healthy 114 and 146 between dammah), weighing fa were two The studied. participating kg, and Exotic Animal cilities were the Wildlife Center
Drug administration sample collection
650 Cathill
Animals Five
schedule typical for the facility within 12 hr of immobilization.
male adult
at Texas
A&M
College University, and the Bamberger Station, Texas, USA, in Johnson City, Texas, USA. This Ranch was under the guidelines performed project Animal Use of the University Laboratory the at Texas A&M University, Committee of the College Review Committee Hospital and client consent of Veterinary Medicine, Ranch. from the Bamberger were Animals free-ranging normally within pasture enclosures but were managed in restraint
facilities for the duration for chute confinement
study. Except
of the during
duction protocols. were weighed Animals a polyurethane of placement
before
aseptic
indwelling jug 16 gauge, 8 inches, ular catheter (L-Cath, Luther Medical Inc., Santa Ana, Products,
California 92705, USA). Attached a J-loop and catheter, connected sequentially
to the
line were and closed with an
extension
tubing placement injection port. Extension was important to allow access to the port during standing squeeze chute restraint. The line was taken caudally along the neck to terminate dorsally at the withers. The cath eter and line were secured to the skin with
simple interrupted sutures of 0 PDS (PDS
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ET AL.-PHARMACOKINETICS
GAMBLE
Inc., sulfate, Ethicon, II, polydioxanone New Jersey 08876, USA). Somerville, After reversal agents were administered, oryx were monitored closely until they were could enter the trial standing. An animal once it was observed to return to its pre No sedation awareness and temperament. animal was started earlier than 30 min fol lowing The
reversal. amikacin
metabolic
dose
energy
was
calculated by from the canine
scaling
dose (11 mg/kg every 12 hr) by ZooDose 1.0 (Wildlife and Exotic Animal Tele J. Jensen and J. Johnson, Tex Consultants, as A&M University, Veterinary Teaching Texas 77843, Hospital, Station, College USA).26 Metabolic used by ZooDose
energy scaling equations 1.0 are applied as follows
(weight in kg):Minimum energy cost (MEC) is calculated for both the model animal, MECmodel (e.g., the dog), and the target an for imal, MEQarget (e.g., the oryx). These are derived mulae from allometric scaling rate versus body size. The pro of metabolic constant, K, is the y-intercept portionality for the line of this plot; it is constant across of animals, energy groupings comparable such as placental mammals, where K = 70. =
MEC^,
=
MECmodel
^(weight0
75),
^(weight0
75).
The minimum energy cost dose (MECdose) from the dose derived is the generalized can model animal's dose (dosemodel), which be applied to any target species. dosemodei
= total daily
drug dose
(mg),
= MECdose
OF AMIKACIN
IN ORYX DAMMAH
361
Iowa 50501, Inc., Fort Dodge, oratories, administra antimicrobial USA). Following tion, the catheter assembly was thoroughly rinsed with 0.9% saline of at least threefold line volume. After discarding the catheter the initial 5-10 ml of fluid withdrawn from the catheter line, 5-10-ml samples of blood were withdrawn at 5, 15, 30, 45, 60, 90, 300, 360,480,600, 120,240, 720, and 1,440 min. Catheter patency was maintained with 0.1% (v/v) heparinized saline between blood collections that were 360 min or less apart and 0.2% (v/v) heparinized saline when the period between blood collections was longer than 360 min. Whole blood was placed in 4 hr of clot tubes and centrifuged within to recover the serum. The serum collection was placed into 4-ml plastic storage tubes and stored frozen at 10?C until analysis. Serum
amikacin
analysis
were detected Amikacin concentrations im in serum by fluorescence polarization Di munoassay (TDX, Abbott Laboratories Abbott Illinois Division, Park, agnostic to the manufac 60064, USA), according turer's guidelines. This assay has been val idated and the manufacturer's control sera were processed experimental alongside limit for this samples. The lower detection assay was 0.8 Mg/ml (TDX Operation Man Divi Laboratories ual, Abbott Diagnostic sion, Abbott Park, Illinois 60064, USA). A serum sample was processed baseline for to determine each animal for background that animal's below twice assay. Samples to have unde this value were considered serum concentrations. tectable amikacin
dosemodel/MECmodel. Serum-drug-concentrations-versus-time
resolves this nonspecific The final equation to the specific exotic dose to one applicable species
(doseexotic).
doseexotic (mg/day) After
complete
= MEQ^ anesthetic
x
MECdose.
recovery,
50 ml
of blood was collected for baseline (time 0) serum analysis and the calculated amikacin was administered i.v. subsequently Fort 50 Lab Dodge mg/ml, (AmiglydeV?,
dose
curves were
from data collected generated for each animal. Each curve was analyzed by linear regression (R-stripII, Micromath Salt Lake City, Utah Scientific Software, two At least models were de 84199, USA). from each animal's data and the veloped most appropriate model was selected based on residual analysis using model selection criterion (MSC). The simpler model was se lected when MSC values differed by less than
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362
JOURNAL
OF ZOO AND WILDLIFE
MEDICINE
[foerapeutic range
i-1-1-1-r
0.00
100.00 200.00 300.00 400.00 500.00 600.00
Time (min) Figure
1. Time-concentration
elimination
curve
for intravenous
amikacin
5.8-mg/kg
dose
(mean)
in scimitar
horned oryx (n = 7 except for 300 min [n = 6], 360 min [n = 6], 480 min [n= 5], and 600 min [n = 3]). Peak to-trough
therapeutic
range
for amikacin
on graph
is 2-25
25%. For those MSC values that differed by more elimination than 25%, the terminal to determine constant (kel) was evaluated the model effects on area under the curve The simpler model was (AUC) calculations. was not affected by more selected when AUC than 10%. The equation by which param eters were established is that which predicts drug concentration (Cp) at time (t) after a single i.v. bolus dose:
= Cp(t) ?
Ge-*',
= terminal elim where C? = y-intercept, k? of each curve, and n ination rate constant = number of first-order nec rate processes ver serum to concentration essary predict sus time. The model was used to determine serum concentra of maximum parameters and elimination constant, tion, terminal For each elimination half-life animal, (?0.s). the area under the curve (AUC) was cal to infinity by the trapezoidal rule culated curve (AUMC) and area under the moment was calculated to infinity from elimination were then used to determine lines and both at the parameters of volume of distribution
/?g/ml.
steady state (VdJ, clearance (Cls), and mean in each time (MRT) for amikacin residence animal.12
The mean rameter was
of each pharmacokinetic pa established 3.1, An (Statistix P.O. Box 12185, Talla alytical Software, except for half hassee, Florida 32317, USA), mean was cal a harmonic life, for which serum concentra amikacin culated. Mean tion at each time point was also calculated to produce an overall study plot. These pa serum ami rameters and the therapeutic were used to cal kacin concentration range culate a recommended scimitar-horned oryx.
dosing
regimen
in
RESULTS amikacin concentration-time plots a two-compartment elimination in each scimitar-horned model oryx. The curve is mean-concentration-versus-time Serum fit
best
in Figure represented The recommended
1.
serum maximum was of amikacin concentration (25 i?g/ml) amikacin in all animals. Serum reached fell below the recommended concentrations minimum therapeutic (2 ixg/ml) by 8 hr after
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GAMBLE
Table dose.
1.
Amikacin
ET AL. - PHARMACOKINETICS
pharmacokinetic
parameters
IN OR YX DAMMAH
OF AMIKACIN
for scimitar-horned
oryx
AUC Oryx?
Voy
Clsd
MRTC
B??05f
TAMU1 11,611
0.120
0.5
235.52
35.5 231.0
1.0 1.1 1.4 1.5 1.2 1.8
117.80 138.04 104.56 122.32 153.29 83.92
37.9 86.6 115.5 28.5 28.9 86.6 30.8 77.0 24.4 115.5 27.4 69.3
0.152
1.2
136.50
0.02
0.4
TAMU2 5,543 TAMU3 5,210 BRI 4,240 BR2 3,975 BR3 4,728 BR4 3,044
0.125 0.148 0.148 0.185 0.185 0.154
Mean 5,478
2,828SD
serum concen Amikacin for 6 hr above maintained concentration minimum (MIC) inhibitory selected from cited literature, for bacteria such as E. coli, Klebsiella, Pseudomonas, and M. avium, Salmonella, Mycobacteria administration. trations were
from the paratuberculosis.3'*'9*20'22 Amikacin to non be eliminated should dose given 12 hr after ad concentrations detectable by in healthy oryx. Pharmacoki animals for the individual are listed in Table 1. One
netic parameters with their means
oryx (TAMU1 ) has outlying values in AUC, and t0m5.This animal had cath Cls, MRT, eterization and, at least par complications administered had amikacin perivas tially, drug administra cularly. This extravenous of affect the volume tion could ultimately serum concen and maximum distribution tration
for this individual.
DISCUSSION The
initial 24 hr of amikacin in most studied species to a two-compartment
cokinetics fit best ei
5,7,n,i5,i6,i9,23,27
pharmacokinetics
in the scimitar-horned ilar to that of other species amikacin pharmacokinetics
kacin
pharma has been mod of
ami
oryx was sim i.v. for which is available.
From
equine
(mean)
i.v.
30.5 97.0h
4.7
49.03 31.8
? are female.), BR = Bamberger TAMU = Texas A&M University (TAMU1 and TAMU2 bArea under the time-concentration curve (/?g/min/ml). c Volume of distribution (steady state) (L/kg). dClearance (ml/min/kg). e Mean residence time (min). fElimination half-life (min). 8Maximum serum concentration after distribution (jug/ml). h Harmonic mean given for i0.swith pseudo-SD.
ministration
a 5.8-mg/kg
following
363
Ranch.
and ovine
studies,
respective
ly, the Vd (0.174 and 0.2 L/kg), Cls (1.28 and t0m5 (94.2 and 115.5 i.v. doses of 6.6 mg/kg in and 7.5 mg/kg.723 Amikacin disposition the scimitar-horned oryx of this study (Vdss, and t0m5995.6 0.152 L/kg; Cls, 1.2 ml/min/kg; that in the more paralleled closely min) horse. The ?0.5 reported from this study is
and 0.7 ml/min/kg), min) resulted from
somewhat to, though higher comparable as such in other that species, reported than, the canine (61.8 min), feline (78.8 min), and and lower than (60 min) models, psittacine that reported for humans (168 min).5141518 has been administered Amikacin paren as as for 5 low in doses cats, mg/kg terally for equines of 6.6-7.5 mg/kg at a midrange for and as high as 10mg/kg and ruminants, the range of amikacin dogs.5'7182327 With and an ami animals in domestic dosages kacin dose for desert antelope unavailable, metabolic energy scaling (MES) was used for dose. This of an appropriate determination of an es for conversion allows technique tablished drug dose in a model species to a species. Typically, target dose for a novel animal and is sim is a domestic the model or in anatomic ilar to the exotic species The model species pref aspects. physiologic
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JOURNALOF ZOOAND WILDLIFEMEDICINE
364
established erably should have a clinically dose for the drug in question. In this study, the dose for scimitar-horned oryx was mod eled after the canine dose available in the ZooDose database and a 5.8-mg/kg dose was established.
in carnivore
Differences
and
herbivore
could affect the cal physiology MES has been dem dose; however, to predict consistent doses despite onstrated these differences.2'2526 For example, report culated
ed ovine (7.5 mg/kg) and calf (7.5 mg/kg) doses, applied to the studied oryx group as = to more similar physiologic models (K dose ranges comparable to 70), predicted those predicted the canine dose, specif by and 5.6-6.0 mg/kg. ically, 5.2-5.6 mg/kg to achieve a spe The i.v. dose necessary cific target concentration termined by the volume
is primarily de of distribution. in host immu species differences Though nity and bacterial MIC may be clinically for significant, desired serum concentration each species is generally presumed to be the same. Ruminants have a larger water vol ume in the gastrointestinal tract than the can in canine monogastric which model, crease distribution and thus increase the dose In contrast, water conservation is required. more efficient in desert antelope than in the temperate domestic ruminants, potentially and decreasing dose affecting distribution The reduced surface area of requirements. the larger antelope in comparison to the standard canine model will similarly affect volume. Predictions distribution from MES are affected by these factors and are a source of
di scaling between widely the need to species. This reinforces scaled doses with pharmacokinetic in target exotic species to assure ac
incomplete
vergent evaluate
studies curate application. The MES scimitar-horned duced a maximum (mean)
oryx dose pro serum concen
of 30.9 ? 4.5 following distribution current thera The recommended ??g/ml. is 25 for amikacin maximum ??g/ml.5 peutic are considered Bacteria suscepti clinically tration
ble if theirMIC is 16 Mg/ml or less. Selected bacteria
tended
to remain
in the following
ranges of serum MIC: E. coli,