Pharmacokinetics of Orally Administered Terbinafine in African Penguins (Spheniscus demersus) for Potential Treatment of Aspergillosis

PHARMACOKINETICS OF ORALLY ADMINISTERED

TERBINAFINE IN AFRICAN PENGUINS (SPHENISCUS

DEMERSUS) FOR POTENTIAL TREATMENT OF ASPERGILLOSIS

Ursula Bechert, D.V.M., Ph.D., J. Mark Christensen, Ph.D., Robert Poppenga, D.V.M., Ph.D.,

Hang Le, Ph.D., Jeff Wyatt, D.V.M., M.P.H., and Todd Schmitt, D.V.M.

Abstract: The objective of this study was to determine the pharmacokinetic parameters of orally administered

terbinafine hydrochloride based on 3, 7, and 15 mg/kg single- as well as multiple-dosage trials in order to calculate

dosing requirements for potential treatment of aspergillosis in African penguins (Spheniscus demersus). Ten adult

African penguins were used in each of these trials, with a 2-wk washout period between trials. Mean plasma

concentrations of terbinafine peaked in approximately 4 hrs at 0.11 6 0.017 mg/ml (mean 6 SD) following

administration of 3 mg/kg terbinafine, while 7 mg/kg and 15 mg/kg dosages resulted in peak plasma concentrations

of 0.37 6 0.105 and 0.33 6 0.054 mg/ml, respectively. The volume of distribution increased with increasing dosages,

being 37 6 28.5, 40 6 28.1, and 52 6 18.6 mg/L for 3, 7, and 15 mg/kg doses, respectively. The mean half-life was

biphasic with initial terminal half-life (tK) values of 9.9 6 4.5, 17.2 6 4.9 and 16.9 6 5.4 hrs, for 3, 7, and 15 mg/kg

doses, respectively. A rapid first elimination phase was followed by a slower second phase, and final elimination

was estimated to be 136 6 9.7 and 131 6 9.9 hrs, for 7 and 15 mg/kg doses, respectively. Linearity was

demonstrated for area under the curve but not for peak plasma concentrations for the three dosages used.

Calculations based on pharmacokinetic parameter values indicate that a 15 mg/kg terbinafine q24h dosage regimen

would result in steady-state trough plasma concentrations above the minimum inhibitory concentration (0.8–1.6 mg/

ml), and this dosage is recommended as a potential treatment option for aspergillosis in penguins. However,

additional research is required to determine both treatment efficacy and safety.

Key words: Terbinafine, pharmacokinetics, African penguins, aspergillosis.

INTRODUCTION

Aspergillosis is a common respiratory disease

of birds in both wild and captive environments

caused by a saprophytic mold found worldwide.

In wild penguin populations, aspergillosis has

been reported in association with stress or

challenging environmental conditions.10,35 In

New Zealand and Antarctica, 60% of 184

penguins were seropositive for aspergillosis by

indirect ELISA testing.31 African penguin (Sphe-

niscus demersus) populations in the wild are

endangered, and this species represents the

greatest percentage of captive penguins in North

America.18 In zoologic collections, aspergillosis is

a main health concern for waterfowl, raptors,

psittacines, and passerines and is considered to be

the most-important airborne disease of captive

indoor penguins.62 The most common aspergillo-

sis pathogen is Aspergillus fumigatus, followed by

infections with Aspergillus flavus and Aspergillus

niger.9,79,84 These fungi are prevalent in humid

environments and accumulate in the air-handling

systems and soil substrates of many institutional

exhibits.

Individual birds become susceptible to Asper-

gillus spp. when exposed to high concentrations

of fungal spores or when inherent immune

defenses are compromised due to stress, malnu-

trition, or pre-existing disease.18,41 The majority of

aspergillosis outbreaks in the northern hemi-

sphere occur during the summer (July–Septem-

ber).21 There is also evidence that the occurrence

of aspergillosis has been age-dependent in captive

penguin populations, occurring most commonly

in 2–3-mo-old chicks and only sporadically in

adults.21

The three stages of infection are an acute,

overwhelming dissemination of fungal spores to

critical organs that may be characterized by

anorexia, dyspnea, or occasionally, sudden death

without signs; subacute infection with respiratory

From the Oregon State University, College of

Science, 2082 Cordley Hall, Corvallis, Oregon 97331,

USA (Bechert); Oregon State University, College of

Pharmacy, 229 Pharmacy Building, Corvallis, Oregon

97331, USA (Christensen, Le); University of Pennsyl-

vania, New Bolton Center, 382 West Street Road,

Kennett Square, Pennsylvania 19348, USA (Poppenga);

Seneca Park Zoo, 2222 Saint Paul Street, Rochester,

New York 14621, USA (Wyatt); and SeaWorld, 500

Sea World Drive, San Diego, California 92109, USA

(Schmitt). Present address (Poppenga): University of

California–Davis, CAHFS Toxicology Laboratory,

Davis, California 95616, USA. Correspondence

should be directed to: Dr. Bechert (ursula.bechert@

oregonstate.edu).

Journal of Zoo and Wildlife Medicine 41(2): 263–274, 2010

Copyright 2010 by American Association of Zoo Veterinarians

263

tract granulomas over several weeks duration;

and chronic, granulomatous infection continuing

for several months.61,62,87 Mycotic granulomas are

frequently found near the tracheal bifurcation,

but can also develop in other areas of the

respiratory tract, liver, kidneys, eyes, and brain.54

Chronic aspergillosis is the more-common form,

and affected birds exhibit voice change, anorexia,

biliverdinuria, lethargy or depression, dyspnea,

emaciation, and, occasionally, ataxia or paralysis

if the central nervous system is involved.88

Because of the ubiquitous nature of Aspergillus

spp., establishing a definitive diagnosis of asper-

gillosis is difficult. Identification of cases is

usually based on initial observations, but clinical

signs are not diagnostic and, if chronic, resemble

other debilitating diseases. Antemortem diagno-

ses are typically made using a combination of

radiographs, complete blood counts (CBC),

serum biochemistry panels, serum electrophoresis

to detect b and c globulin elevations, and

determination of Aspergillus antigen and anti-

body levels.47,87 Blood, cerebrospinal fluid, and

bone marrow specimens rarely yield Aspergillus

spp., and radiographic findings alone are not

diagnostic because other conditions can produce

similar images. Quantification of antibody titers

against Aspergillus to diagnose aspergillosis has

produced conflicting results, and serial assays are

recommended over isolated tests.81 Definitive

diagnosis requires both histologic evidence of

Aspergillus hyphae and cultures from specimens

obtained by biopsy or aspiration from involved

organs.79 Bronchoalveolar lavage, with assay of

the fluid by smear, culture, or antigen (or both),

detection has excellent specificity for invasive

aspergillosis.42,44

Currently, there are four classes of antifungal

agents with activity against Aspergillus; the

polyenes, such as amphotericin B; the triazoles,

including itraconazole, fluconazole, and vorico-

nazole; the echinocandins, such as caspofungin

and micofungin; and the allylamines, including

terbinafine. Although amphotericin B is the

human standard for treatment of aspergillosis,79

it must be administered by injection and there are

concerns about its nephrotoxic side effects.23 The

triazoles are currently a more-popular choice for

treatment of birds due to their broad spectrum of

activity, relative ease of administration, and low

toxicity.19,22,25,63 However, treatment failures re-

main a concern,76 and differences in absorption

between generic, bulk-compounded itraconazole

powder and Sporanox ready-made doses (Torpac

Inc., Fairfield, New Jersey 07004, USA) have

been demonstrated.8 Some drug therapies can

cause adverse side effects (e.g., flucytosine has the

potential to cause bone marrow toxicity13), and

most drugs are fungistatic in nature. In most

instances, dosing schedules for these drugs,

derived from pharmacokinetic data to maintain

blood levels above the minimum inhibitory

concentration (MIC), have not been established

for birds. Therefore, it is not known whether lack

of treatment success is due to the inherent

inability of fungistatic drugs to effectively inhibit

Aspergillus spp. in vivo, to inadequate dosing, or

to both.

Terbinafine hydrochloride (LamisilH, Novartis,

East Hanover, New Jersey 07936, USA) was

released in 1996 for treatment of human mycotic

nail infections (onychomyscosis).33,46 The allyl-

amines are a relatively new class of antifungal

agents which have a different mechanism of

action as compared to the azoles.2,60 Terbinafine

(Fig. 1) is thought to have fungicidal activity59 by

inhibiting squalene epoxidases, thereby causing

cytotoxic accumulation of intracellular squa-

lene.68 Secondarily, enzyme inhibition results in

a depletion of ergosterol, which is the fungal

counterpart of cholesterol in mammalian cells.

This interferes with membrane function and cell

growth, resulting in a fungistatic action.67 The

different mechanisms of action provide terbina-

fine with a comparative advantage over other

drugs that are either fungistatic or fungicidal in

nature, and because the metabolism of terbina-

fine utilizes less than 5% of the cytochrome P450

capacity of the liver,82 there is less interference

with other drugs that could potentially result in

negative side effects.1,20 In humans, it is estimated

that approximately 10% of terbinafine metabo-

lites initially eliminated in bile undergo entero-

hepatic recycling.4

Terbinafine can be given orally or topically,

has excellent absorption rates between 70% and

80%,16 a bioavailability of approximately 40% in

humans, and approximately 70% of the metab-

olites are eliminated in the urine.2,40 Potential use

of terbinafine as a treatment for aspergillosis in

penguins is of interest because high concentra-

tions of terbinafine accumulate in connective

tissues, and air sacs have a relatively poor blood

supply, making delivery of most therapeutic

agents to this region difficult.

The published MIC range of terbinafine

against A. fumigatus in humans is broad, ranging

from 0.02–5 mg/ml for dosages ranging from

62.5–250 mg/day.12,28,29,36,74,75 Potential adverse

reactions, reported in up to 5.6% of 465 humans

264 JOURNAL OF ZOO AND WILDLIFE MEDICINE

studied, included gastrointestinal and dermato-

logic symptoms and liver enzyme abnormalities.40

Pharmacokinetic studies have not been previous-

ly conducted to determine appropriate terbina-

fine dosing regimens for penguins. The objective

of this study was to determine dosage require-

ments that would result in an effective MIC of

terbinafine in plasma, in the range of 1–4 mg/ml,

by conducting single and multiple oral-dose trials

using African penguins as an avian model.

MATERIALS AND METHODS

Animals

Eighteen adult, healthy African penguins

(twelve males and six females) housed at the

Seneca Park Zoo in Rochester, New York (USA)

were used for pharmacokinetic trials. Penguins

ranged in weight from 2.7–3.3 kg (3 6 0.3 kg;

mean 6 SD) and were approximately 1–11 years

of age (6.7 6 3.47 yrs). All birds were given

preliminary physical examinations, including

routine CBC and serum biochemistry profiles,

to confirm health status. Individuals were main-

tained in an indoor, climate-controlled 27-m2

holding area with access to an outdoor 36-m2

exhibit with a 56,781-L recirculating, fresh-water

pool. Maintenance food consisted of free-choice

fish comprised of capelin, squid, trout, mackerel,

herring, and smelt, offered twice a day (2–25 fish

daily) and supplemented with one-half of a bird

formulation Sea TabTM (Pacific Research Labo-

ratories, Inc., Vashon, Washington 98070, USA).

This research was conducted under a protocol

approved by the Institutional Animal Care and

Use Committees at Oregon State University and

the Seneca Park Zoo, which is accredited by the

Association of Zoos and Aquariums.

Study design

Three trials were conducted using 3, 7, and

15 mg/kg single dosages of orally administered

terbinafine hydrochloride, with a 2-wk washout

period between trials (n 5 10 each). Not all of the

birds were used in each trial because penguins

that were molting or breeding were precluded

from the study (Table 1). Multiple-dose trials, to

determine optimal dosing frequency, were con-

Figure 1. Chemical structure of terbinafine and mechanism of action (Courtesy of www.doctorfungus.org

E 2010).

BECHERT ET AL.—TERBINAFINE DOSAGE REQUIREMENTS FOR PENGUINS 265

ducted with ten penguins using 15 mg/kg dosages

administered once daily for 4 days. Terbinafine

tablets were compounded into slurry, at a

concentration of 45 mg/ml, by Animal Pharmacy

(Canandaigua, New York 14424, USA). Drug

dosages were based on body weights determined

prior to the initiation of each trial. Each penguin

was manually restrained, as terbinafine was

administered orally using a syringe placed in the

throat past the epiglottis.

Penguins were manually restrained while blood

samples were taken from the right or left jugular

vein, using 22-gauge needles and collected in 5-ml

heparinized VacutainerTM tubes (BD Diagnostics,

Franklin Lakes, New Jersey 07417, USA). One-

milliliter blood samples for initial, single-dose

trials were collected at 25, 15, 30, 45 min, 1, 2, 4,

10, 12, and 24 hr postadministration (10 ml total

over 24 hr). Blood samples for multiple-dose

trials were collected in heparin hourly for 4 hr

after each administration, and then every 6 hr,

plus 1 hr prior to the next administration, in

order to detect peak and trough concentrations.

Samples were placed into glass tubes and

centrifuged for 10 min at 1,300 g (International

Equipment Company, Needham, Maryland

02494, USA). Plasma was decanted into plastic,

screw-cap vials (VWR International, West Ches-

ter, Pennsylvania 19380, USA), frozen, and sent

to the New Bolton Center, University of Penn-

sylvania in Kennett Square, where they were

maintained at 24uC until time of analysis.

Terbinafine analysis

Plasma drug concentrations were quantified

within 30 days of receipt by high-performance

liquid chromatography (HPLC) after sample

preparation.17,86 Ten microliters internal standard

(50 ng/ml; Sandoz #85-190, Batch #79901) was

added to 0.5 ml plasma in a glass tube. To this

plasma mixture, 1 ml 0.2 M borate buffer (pH 9)

and 8 ml n-hexane were added. Each tube was

horizontally shaken for 25 min at 200 oscillations/

min, followed by centrifugation for 10 min at 750 g

at room temperature. Seven milliliters superna-

tant (n-hexane) was transferred to a 16 3 125 mm

glass tube, and 1 ml 1.0 N sulfuric acid 2-propanol

solution (85:15 v/v) was added. Each tube was

shaken horizontally for 15 min at 200 oscillations/

min and then centrifuged for 5 min at 750 g. The

upper organic phase was discarded, and 800 ml of

the aqueous phase was transferred to an amber

glass mini-injection vial. The sample was injected

into a Spectra System HPLC with a P4000

gradient pump and a UV3000 UV-VIS detector

set at a wavelength of 225 (Thermo Separation

Products, Piscataway, New Jersey 08854, USA)

and a Keystone Betasil C18 column (250 3

4.6 mm, particle diameter 5 mm; Thermo Fischer

Scientific, Waltham, Maryland 02451, USA). The

flow rate was 0.9 ml/min, the injection volume was

20 ml, and the column temperature was 30uC. The

mobile phase was an aqueous solution of 0.012 M

triethylamine/0.020 M orthophosphoric acid with

acetonitrile (57:43 v/v).

Table 1. African penguins (Spheniscus demersus) used in pharmacokinetic trials (n 5 10 each).

Penguin ID Hatch date 3 mg/kg 7 mg/kg 15 mg/kg Multiple-dose trial

105297 May 1993 X X X

105079 Feb 2002 X X

105114 Apr 2002 X X

104708 Nov 1994 X X X X

104720 Dec 1995 X X Xa X

104721 Dec 1995 X X X

104903 Oct 1999 X X

104986 Dec 2000 X Xa X

105040 July 2001 X Xa X

104757 Apr 1993 X

104993 Feb 2004 X

104763 Mar 1995 X X

105041 July 2001 X X X

104759 May 1993 X

104709 Sept 1993 X X

104762 Feb 1995 X

104931 May 2000 X

104761 Aug 1994 X X

a Samples not analyzed.


A standard curve for terbinafine was generated

using 0.01, 0.1, 0.5, 1.0, and 5 ppm standards in

plasma, and plasma concentrations of terbinafine

were quantified using this standard curve. A

linear fit, forced through zero, was achieved by

evaluating the signal area of the samples com-

pared to the matrix-matched, identically handled,

spiked plasma samples. A correlation coefficient

for calibration curves was calculated (r2 5 0.975;

range 0.926–0.999). The limit of detection (LOD)

and limit of quantitation (LOQ)s were deter-

mined to be 0.01 ppm and 0.1 ppm based upon

the matrix-matched spikes. Spike recoveries were

80% or greater. The interassay coefficient of

variation was 10.7%. The internal standard, at

1 ppm, was added to all blanks, standards, spikes,

and samples. Separate 0.5- and 1.0-ppm spikes

were run to check run precision (80% recovery or

greater required), and a duplicate plasma sample

was run every ten samples (80% or greater

precision required).

Pharmacokinetic and statistical analyses

Pharmacokinetic data were modeled and fitted

for individual birds using compartmental and

noncompartmental approaches with Win Nonlin

(2002 Version 3.2, Pharsight Corporation, Moun-

tain View, California 94040, USA). Parameters

determined for each penguin (mean 6 SD)

included the maximal concentration (Cmax), time

of maximal concentration (Tmax), volume of

distribution (Vd/F), area under the curve

(AUC), mean residence time (MRT), clearance

rate (Cl/F), terminal half-life (tK), and the

elimination rate constant (Kel). The AUC was

calculated using the linear trapezoidal rule

method, or from integration of the fitted

equation to the concentration time curve. The

elimination half-life for terbinafine (tKel) was

determined by dividing the natural logarithm of

2 (0.693) by Kel. For the 7 and 15 mg/kg single-

dose trials, the 3-wk washout period was

insufficient to completely eliminate terbinafine

from the system of all penguins. Plasma terbin-

afine concentrations were corrected for any

residual carryover remaining in effected penguins

from the washout period of the previous dose in

the manner detailed by Girolamo et al.27

Terbinafine was administered as a single, daily

dose basis for the 3, 7, and 15 mg/kg doses, allowing

terbinafine accumulation after multiple dosing to

be calculated according to the following equation:77

Accumulation factor~1

1{e{lT,

where l is the terminal elimination rate constant,

and T is the dosing interval.

Estimates predicting appropriate doses, and

dosing intervals, for terbinafine were based on

the published range for MIC against A. fumiga-

tus. Because the MIC range of terbinafine against

A. fumigatus in humans is 0.02–5 mg/ml, initial

target peak therapeutic serum concentrations

were 1–4 mg/ml.

Dose proportionality of terbinafine was deter-

mined using AUC0–t, AUC0R‘, and Cmax, with

respect to the AUC0–t value, AUC0R‘ value, and

Cmax value of the lowest dose (3 mg/kg), according

to the following equations:

R~AUC0?t, 3, 7, or 15 mg=kg

AUC0?t, 3 mg=kg

and

R~C max3, 7, or 15 mg=kg

C max3 mg=kg

,

where R is the dose-proportionality ratio. Line-

arity was tested using a lack-of-fit F-test. In

addition, a power function relationship was used

to describe the relationship between AUC0–t,

AUC0R‘, Cmax, and Dose:

AUC~a(Dose)band C max~a(Dose)b,

where a represents the coefficient, and b repre-

sents the exponent of the power function

determined by regression (Excel, Microsoft, Red-

mond, Washington 98052, USA). If the AUC0–t

and AUC0R‘ dose relationship is linear, then the

exponent b should be in unity. Linearity was

indicated if the 95% confidence interval for the

exponent b included the value of 1.0.77

Following the oral administration of terbinafine

at three different doses, statistical comparisons of

mean plasma concentrations, at each sampling

time, and estimates of the pharmacokinetic pa-

rameters among the three doses, were made using

an analysis of variance. Statistical software was

used for analysis (SAS, Version 8.0, InnaPhase

Corporation, Cary, North Carolina 27513, USA).

RESULTS

Results for initial penguin CBC and biochem-

istry analyses were within the normal range

described for this species (Table 2), with the

exception of slightly elevated creatine phospho-

kinase levels, and all birds were healthy through-

out the duration of the study.

Plasma concentrations of terbinafine versus

time, after administration of single doses of 3, 7,

and 15 mg/kg, are presented in Figure 2. For the


15 mg/kg trial, samples from three of the

penguins were misplaced, so only seven sets of

samples were analyzed and included in the

results.

A double peak in the plasma concentration

time curve was observed in the absorption phase.

Pharmacokinetic parameters from both compart-

mental and noncompartmental analysis are sum-

marized in Table 3. Values for the 3 mg/kg dose

for V/F, AUC, Cl/F, and MRT are quite similar

using either method of analysis. Pharmacokinetic

parameters for MRT, based on compartmental

analysis, decreased slightly for the 7 mg/kg dose

from 24.7 6 4.41 hr to 20.0 6 4.04 hr,

respectively. An increasing apparent volume of

distribution (Vd/F) was observed with increasing

dosages using noncompartmental analysis; a Vd/F

of 37 6 28.5 L/kg for the 3 mg/kg dose increased

to 40 6 28.1 L/kg for the 7 mg/kg dose and,

finally, to 52 6 18.6 L/kg for the 15 mg/kg dose.

Mean pharmacokinetic parameters obtained

for multiple dosing trials using 15 mg/kg are

summarized in Table 4. Absorption of terbina-

fine following each of three oral administrations

was rapid with a 1K–2 hr absorption half-life.

On average, the absorption rate constant was

1.81 6 0.048 hr21, the initial elimination half-life

was 15.8 6 9.95 hr, and the slower, second half-

life was 129 6 6.0 hr.

An approximate linear relationship was ob-

served between AUC0–t and dose (Fig. 3), which

Table 2. Hematologic and serum biochemical values for African penguins (Spheniscus demersus).

Determination Units1 week pre–study (n 5

18; mean 6 SD)ISISa reference values as

mean 6 SD (range) Reference sample size

Hematologic

Hematocrit (PCV) % 48 6 6.7 46 6 7.4 (25–62) 345

White blood cell 103/ml 13 6 3.6 16 6 8.0 (3–43) 232

Heterophils 103/ml 7 6 2.7 9 6 4.9 (1–26) 229

Lymphocytes 103/ml 5 6 1.6 6 6 4.7 (0–33) 230

Monocytes 103/ml 1 6 1.5 1 6 0.9 (0–6) 150

Basophils 103/ml 0 6 0.2 0 6 0.4 (0–3) 108

Eosinophils 103/ml 0 0 6 0.4 (0–2) 103

Hemoparasites Negative Negative

Biochemical

Glucose mg/dl 230 6 23.4 223 6 40 (40–98) 192

Cholesterol mg/dl 285 6 43.9 307 6 97 (158–960) 123

Total protein g/dl 5 6 0.5 5 6 0.9 (3–9) 210

Uric acid mg/dl 8 6 3.7 11 6 8.2 (1–37) 185

Albumin g/dl 2 6 0.1 2 6 0.6 (1–4) 144

Globulin g/dl 3 6 0.5 3 6 0.6 (2–6) 146

ASTb IU/L 219 6 92.9 183 6 103 (40–955) 189

CPKc U/L 1299 6 759.6 455 6 593 (25–4702) 132

Calcium mg/dL 11 6 0.5 11 6 2.3 (5–22) 187

Phosphorus mg/dL 3 6 1.0 4 6 2.1 (1–12) 141

Sodium mEqu/L 151 6 5.2 150 6 5 (136–162) 114

Chloride mEqu/L 115 6 23.1 111 6 4 (99–122) 107

Potassium mEqu/L 4 6 1.0 5 6 1.4 (3–9) 111

a ISIS 5 International Species Information System.b AST 5 aspartate aminotransferase.c CPK 5 creatine phosphokinase.

Figure 2. Plasma concentrations of terbinafine ver-

sus time after administration of single doses of 3, 7, and

15 mg/kg to African penguins (Spheniscus demersus).


is supported by a lack of statistically significant

deviation from linearity in the dose normalized

AUC0R‘ (P-value . 0.1). Using the power model,

the exponent of dose for AUC [0.164*Dose1.17]

was not significantly different from unity with

95% confidence interval of this exponent (0.95–

1.39). However, the relationship between Cmax

and dose is nonlinear, based on the power model

with exponent of dose for Cmax [0.0092*Dose1.3],

and the 95% confidence interval does not include

one (1.03–1.57). The Cmax may be increasing

disproportionately due to slower absorption at

the higher dose (15 mg/kg), where Cmax is lower

than expected.

Two elimination phases were observed. The

first elimination phase was relatively rapid, with a

tK of 10–17 hr, and the second elimination phase

was comparatively slow with a tK of 129 hr

following administration (Fig. 4). Accumulation

of terbinafine was calculated, based on 7 and

15 mg/kg daily doses in penguins, using the

terminal elimination rate constant and a 24-hr

dosing interval. The calculation gave a steady

trough terbinafine plasma concentration of 0.61

and 1.3 mg/ml, for 7 and 15 mg/kg daily doses,

respectively.

DISCUSSION

A double peak in the plasma concentration

time curve was observed during the absorption

phase. The initial rapid absorption seen is most

Table 3. Pharmacokinetic parameters of orally administered terbinafine (mean 6 SD) in African penguins(Spheniscus demersus) analyzed by compartmental (upper) and noncompartmental (lower) methods.

Parameter (units) 3 mg/kg (n 5 10) 7 mg/kg (n 5 10) 15 mg/kg (n 5 7)

Cmax (mg/ml) 0.1 6 0.02 0.2 6 0.10 0.2 6 0.06

0.1 6 0.02 0.4 6 0.11 0.3 6 0.05

Tmax (hr) 2.7 6 0.96 1.6 6 0.90 2.4 6 1.33

4.0 6 0.94 4.0 6 0.87 4.0 6 1.23

AUC0–t (mg hr/L) 1.2 6 0.12 3.7 6 1.12 5.4 6 1.13

1.2 6 0.17 4.3 6 1.86 6.0 6 1.16

Cl/F (L/hr) 2.6 6 0.40 1.9 6 0.61 2.8 6 0.29

2.6 6 0.38 1.6 6 0.69 2.1 6 0.35

tK (hr) 10.0 6 4.9 13.0 6 4.9 17.0 6 4.50

10.0 6 4.5 17.0 6 4.9 17.0 6 5.40

Kel (hr21) 0.1 6 0.02 0.1 6 0.04 0.0 6 0.04

0.1 6 0.02 0.1 6 0.04 0.0 6 0.05

Vd/F(mg/L) 37.0 6 22.90 37.0 6 23.80 68.0 6 21.60

37.0 6 28.50 40.0 6 28.10 52.0 6 18.60

MRT (hr) 14.3 6 2.78 20.0 6 4.04 24.3 6 6.67

14.3 6 2.85 24.7 6 4.41 24.3 6 7.25

Ka (hr21) MAT (hrs) 0.8 6 0.44 2.5 6 1.37 1.6 6 0.87

1.0 6 0.20 0.4 6 0.40 0.7 6 0.63

Terminal tK (hrs) 123.0 6 6.00 13.0 6 9.90 130.0 6 11.10

121.0 6 10.00 136.0 6 9.70 131.0 6 9.90

Table 4. Pharmacokinetic parameters of terbina-fine after oral, multiple dosing of 15 mg/kg every 24 hrto African penguins (Spheniscus demersus).

Parameter 15 mg/kg (n 5 10)

Cmin (mg/ml)a 0.4 6 0.14

Cmax (mg/ml)a 2.1 6 0.94

Caverage (mg/ml)a 0.6 6 0.48

Tmax (hr) 0.8 6 0.84

Cl/F (ml/hr/kg) 0.5 6 0.71

Ka (hr21) 1.8 6 0.05

MRT (hr) estimated at steady

state 34.0 6 15.40

tK (hr) 16.0 6 9.90

Terminal tK (hrs) 129.0 6 6.00

a Last observed dose.

Figure 3. Approximate linear relationship between

AUC0–t and dose for 3, 7, and 15 mg/kg single, oral

administrations of terbinafine.


likely associated with rapid dissolution of terbin-

afine and gastric emptying of fine drug particles,

followed by the remaining larger particles requir-

ing dissolution prior to absorption, and resulting

in the second absorption peak.45 Absorption

characteristics of terbinafine are not altered when

taken with food;26 however, other physiologic

processes may have played a role in the

absorption characteristics seen in this study.

Penguins have an ability to regulate digestion,

increasing gastric activity during shallow diving

and reducing activity during deep dives in the

wild.58 King penguins (Aptenodytes patagonicus)

are able to adjust gastric pH and motility during

their incubation period.80 Breeding African pen-

guins exhibit a delay in gastric emptying when on

shore to feed their brood,83 and slowing of

digestive processes has also been seen in Magel-

lanic penguins (Spheniscus magellanicus) by

varying gastric pH56 and by adjusting gastric

motility to modify stomach temperatures.57,58 Diet

composition may also affect mean gastrointesti-

nal retention time, as demonstrated in Gentoo

penguins (Pygosellis papua), where a high lipid

content increased retention time.65

Plasma concentration time profiles of terbina-

fine in penguins were characterized by a rapid

initial-elimination phase and then a slower

second-elimination phase (5–6 days), as seen in

red-tailed hawks (Buteo jamaicensis).5 Human

serum terbinafine concentration time profiles,

based on single oral doses of 250 mg in humans,

are similar but of shorter duration, with an initial

elimination tK of 22 hr and a final elimination tK

of just under 4 days.39 In multiple dose studies

conducted in humans, terbinafine distribution

and elimination are similar to that seen after

single dose administration, with the tK variously

reported as 165 6 49 hr,51 293 6 165 hr,64 16 6

2.8 days,30 and up to 3 wk.50,85 The clearance rate

of terbinafine in plasma can also be affected by

other drugs. In humans, terbinafine Cl/F is

reduced by one-third in the presence of cimeti-

dine, and clearance doubles in the presence of

rifampicin.78

The half-life of terbinafine is significantly

influenced by its lipophilic and keratophilic

nature, the large volume of distribution, accu-

mulation in peripheral tissues, and slow redistri-

bution into blood.37 An increase in the Vd/F was

observed following sequential oral doses of

terbinafine in penguins. The Vd in humans has

been reported to range from 11 L/kg51 to 28 L/

kg.39 This compares to a range of 40–52 L/kg, for

7 and 15 mg/kg doses, respectively, in this study.

The Vd/F continuously increased in penguins with

higher dosage levels, suggesting terbinafine accu-

mulation in peripheral tissues.

Approximate linearity of pharmacokinetics to

terbinafine dosage was demonstrated for AUC0R‘,

while nonlinearity for Cmax was demonstrated

using the power model. Slower absorption at the

higher dose (15 mg/kg) could indicate possible

saturation of terbinafine dissolution in the gastro-

intestinal tract. Drug absorption of highly lipo-

philic drugs, like terbinafine, reach a maximum

rate that is equivalent to the saturated drug

dissolution process in the gastrointestinal tract.24

One study reported an MIC range of 0.01–2 mg/

ml for terbinafine against Aspergillus isolates with

a primary fungicidal action of 0.02–4 mg/ml.69

Another in vitro study of terbinafine against three

Aspergillus spp. showed that the MIC90 of

terbinafine never exceeded 1.6 mg/ml, with a

range of 0.8–1.6 mg/ml.74 Recent studies have

shown good activity (MIC , 1 mg/ml) of

terbinafine against A. fumigatus in vitro,41 while

others have not (MIC 5 2 to .16 mg/ml).48

Varying results are likely due, in part, to different

methodologies used, varying definitions of end-

point (e.g., trace growth, no growth), as well as to

inoculum size. Even within individual studies,

reproducibility has reportedly been poor.48 Al-

though the published MIC range of terbinafine

against A. fumigatus is broad, most studies report

values ,2 mg/ml. Therefore, plasma concentra-

tions between 1 and 2 mg/ml are likely to be

efficacious in the treatment of aspergillosis in

penguins, although clinical trials are certainly

needed to demonstrate efficacy in vivo.

Administration of terbinafine should be done

at a frequency that minimizes fluctuations in drug

concentrations through time. Based on the

Figure 4. Multiple-dose trials—plasma concentra-

tions of terbinafine versus time in African penguins

(Spheniscus demersus).


pharmacokinetic parameters of terbinafine calcu-

lated in this study, steady-state trough levels in

African penguins are predicted to occur in 2 wk

at 1.2 mg/ml, using 15 mg/kg dosages s.i.d., which

falls within the reported in vitro MIC90 range of

0.8–1.6 mg/ml for terbinafine against A. fumiga-

tus.74 This is less than the recommended dose of

30 mg terbinafine/kg given orally every 24 hr for

cats (Felis catus) and dogs (Canis lupus famil-

iaris),26 but is the same dosage recommended for

red-tailed hawks,5 and approximates the oral

dosage of 10–15 mg/kg given every 12–24 hr

generically recommended for avian species.15

Steady-state plasma levels of terbinafine in

humans are also reached within 10–14 days of

treatment.34

In vitro tests have demonstrated an additive or

synergistic effect when terbinafine was used in

combination with itraconazole or fluconazole49,69

and amphotericin B.69 However, negative results

of terbinafine and amphotericin B in vitro have

also been reported,14,49 and one study demon-

strated a difference of effect based on time of

administration.3 Data are sparse on the efficacy

of combination therapy, and several combina-

tions that demonstrated synergy in vitro failed to

do so in animal models.3 Clearly, again, in vivo

trials are needed to determine actual efficacy of

potential additive or synergistic effects, or both,

of drug combinations.73

Human clinical trials have yielded some

promising results for treatment of lower respira-

tory tract Aspergillus infections using terbinafine.

In one study, fourteen patients given between 5

and 15 mg terbinafine/kg/day for 84–264 days

were all considered microbiologically cured, and

eight were clinically cured.71 Other clinical case

reports have also demonstrated the efficacy of

terbinafine for treatment of refractory pulmonary

aspergillosis,55,70,72 as well as for treatment and

prevention of Aspergillus infection in lung-trans-

plant patients.34 However, controlled trials and

prospective observational studies are still needed

to establish the correlation of in vitro susceptibil-

ity with the clinical outcome.11 Similarly, recom-

mended dosages of terbinafine for treatment of

aspergillosis in penguins need to be used, in

controlled trials, to demonstrate actual clinical

efficacy.

Future alternative therapeutic treatments for

A. fumigatus infections may include vaccinations

that boost cell-mediated immunity.6,7,38,43 Mater-

nal or parental antibody passage in birds can be

achieved through egg yolk or crop milk.66

Prenatal transfer of Aspergillus spp. antibodies

has been demonstrated in African black-footed

penguins, and evidence supported a potential

protective role of maternal antibodies against

aspergillosis for S. demersus chicks during the

first 4 wk posthatch.32 Additionally, because of

the significant correlation of Aspergillus antibody

levels between female penguins and their eggs, it

was suggested that penguin eggs could be used to

predict the prevalence of Aspergillus in wild

penguin populations.32 Alternative drug therapies

are also likely to emerge in the future. Recent

sequencing of the A. fumigatus genome,52 coupled

with the genetic tools now available for research

on antifungal drug resistance mechanisms, may

eventually lead to a shift from random screens for

antifungal agents to screens against specific

molecular targets.53

CONCLUSIONS

Based on these results, it is recommended that

a 15 mg/kg per day oral dose of terbinafine be

used for the treatment of aspergillosis in penguins

to provide steady-state trough plasma concentra-

tions above the MIC of 1 mg/ml. Patients with

either liver or renal impairment should receive

lower dosages. Terbinafine has few side effects

and has no reported interactions with other

agents, although cimetidine and rifampin may

alter the clearance rate of terbinafine. However,

because the drug is eliminated so slowly over time

and accumulates in tissues, long-term multiple

dosing, as well as clinical efficacy trials for

treatment of aspergillosis, should be conducted

with penguins before safe and therapeutic dosing

regimens can be confirmed.

Acknowledgments: The authors thank the staff

at the Seneca Park Zoo, especially Garrett

Caulkins, B.S., L.V.T., Seneca Park Zoo Animal

Health Center Supervisor, for conducting the

dosing trials in African penguins. They also

acknowledge the work of Carol Buckley, who

analyzed plasma samples at the University of

Pennsylvania, New Bolton Center. This study

was funded by the Morris Animal Foundation.

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Received for publication 16 October 2009


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Pharmacokinetics of Orally Administered Terbinafine in African Penguins (Spheniscus demersus) for Potential Treatment of Aspergillosis