Pharmacokinetics of Amikacin in Scimitar-Horned ...

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


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


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


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


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


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,