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Vet Clin Exot Anim 7 (2004) 821831

Current research in avian chemotherapy


Lucio J. Filippich, BVSc, BSc, PhDa,*, Bruce G. Charles,
BPharm (Hons), GradDipBusAdmin, PhDb
a

School of Veterinary Science, The University of Queensland, St. Lucia,


Queensland, 4072 Australia
b
School of Pharmacy, The University of Queensland, St. Lucia, Queensland,
4072 Australia

The use of chemotherapy as a treatment modality in avian oncology has


increased over the past 2 decades. Several chemotherapeutic agents that have
been shown to be eective in the treatment of canine neoplasia, have been
used empirically in birds with varying outcomes [15]. Most of these agents
were administered to birds based on conventional mammalian dose rates
because pharmacokinetic data in birds were lacking. One reason for the
dearth of this data may be the restrictions in the number of samples and the
volume of blood per sample that can be obtained to facilitate an appropriate
pharmacokinetic analysis in small birds. Nevertheless, when extrapolating
drug-dosing regimes from one animal group to another, scaling formulae
have been advocated to correct for metabolic dierences between species [6].
These formulae assume that the dose needed to achieve therapeutic levels is
correlated to metabolic rate, and that the absorption, distribution, metabolism, and excretion of the drug are the same or achieve the same end result
for both animal groups. However, the dierences in the anatomy and
function of the alimentary tract of mammals and birds may alter oral drug
absorption [7]. Further, because most drugs are eliminated by hepatic or
renal excretion, with or without hepatic biotransformation, dierences
between mammals and birds in respect to renal anatomy and function [8
10], hepatic cytochrome P450 activity, and plasma protein levels can
potentially negate direct extrapolation of drug dosages between these two
animal groups [1113]. Also, within an avian group (psittacines), the
pharmacokinetic proles of certain drugs (eg, chloramphenicol, doxycycline)

Supported by grants from the Association of Avian Veterinarians, Australian Avicultural


Societies, and a bequest from Mrs. Elsie S. Annandale.
* Corresponding author.
E-mail address: L.Filippich@uq.edu.au (L.J. Filippich).
1094-9194/04/$ - see front matter 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.cvex.2004.04.007

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L.J. Filippich, B.G. Charles / Vet Clin Exot Anim 7 (2004) 821831

vary, and could lead to toxicity unless the dose is appropriately adjusted for
the species [14].
Recently, the pharmacokinetics of platinum analogs, cisplatin, and
carboplatin has been reported in Sulfur-crested cockatoos [1517]. These
platinum analogs are water-soluble, platinum (Pt)-containing compounds
that can inhibit DNA synthesis, and have some alkylating activity. They are
cell cycle-nonspecic and the lterable Pt (free or nonprotein-bound fraction)
is the active component responsible for the antineoplastic activity and the
toxicity [18]. Platinum analogs are among the most active chemical agents used
for the treatment of neoplasia and the parent compound, cisplatin (cisdichlorodiammineplatinum [II]), has been extensively used. In human
oncology, it is widely used alone or in combination with other anticancer
drugs against a variety of solid tumors especially those of gonadal origin, as
well as in the bladder, head, and neck [19,20]. The use of cisplatin in veterinary
medicine has been restricted mainly to the treatment of canine solid cancers
[2123]. Although its toxicity prole (nephrotoxicity, gastrointestinal toxicity,
and neurotoxicity) in mammals has limited its systemic use [18], in avian
oncology cisplatin has been used intratumorally as a radiosensitizer [24] to
treat brosarcoma in birds [25,26]. Intratumoral chemotherapy is a way of
maximizing cytotoxic drug concentrations in tumor tissue while minimizing
systemic exposure, and has a place for primary tumors conned to single
organs or regions of the body.

Cisplatin
Cisplatin in normal saline solution (1 mg/25 mL, Cytomix, Victorian
Hospital Association Trading Company) has been infused intravenously over
1 hour at 1 mg/kg in Sulfur-crested cockatoos (Cacatua galerita) [15]. The
allometrically scaled mammalian dose (70 mg/m2) for cisplatin in birds is 6.4
mg/kg and it was found to be nephrotoxic in cockatoos [12,13], supporting
earlier ndings that the meter-squared calculation for cisplatin can overdose
small dogs less than 10 kg [27]. Intravenous uid therapy (lactated Ringers
solution) for 1 hour (50 mL/kg/h) before and for 2 hours (25 mL/kg/h) after
completion of the cisplatin infusion was used to hydrate the birds because
intensive saline diuresis before and for several hours after cisplatin infusion
has been found to minimize cisplatin nephrotoxicity [23,28]. All birds
tolerated the infusion and at 24 hours after dosing; all birds were bright,
alert, and eating, although some showed transient vomiting and changes in the
consistency of their droppings for up to 72 hours postinfusion.
Following cisplatin administration, total plasma Pt decayed bi-exponentially over 96 hours, similar to what has been reported in humans [29,30], dogs
[31], and rodents [32]. Total plasma Pt concentrations rapidly decline in the
rst 3 hours postinfusion with a mean half-life (T1/2,a) of 0.398  0.0332 hours,
followed by a prolonged log-linear decay phase with a T1/2,b of 79  10.0 hours

L.J. Filippich, B.G. Charles / Vet Clin Exot Anim 7 (2004) 821831

823

(Table 1 and Fig. 1). Filterable plasma Pt declined monoexponentially with


a mean T1/2 of 0.413  0.122 hours from cessation of the infusion to 2 hours
postinfusion, at which time the concentrations declined below the minimum
quantiable Pt concentration (Table 2 and Fig. 2). The protein binding of Pt
at the end of the cisplatin infusion was 16.3  12.9%, and it increased to
84.8  6.02% bound by 2 hours after the infusion. Thus, relatively little Pt was
bound soon after termination of the cisplatin infusion, but the binding increased vefold by 2 hours after the end of the cisplatin administration. Such
a temporal shift in the binding prole most likely reects rapidly diminishing
concentrations of lterable Pt due to its higher systemic clearance (Cl),
compared with the Cl of total plasma Pt, together with increasing amounts of
lterable Pt being tightly bound to plasma macromolecules such as albumin.
The lengthy T1/2,b of more than 3 days in the cockatoo was similar to study
results in mice [33], and human patients [29,30], and is due to a low Cl and
a high volume of distribution (V), both of which aect half-life independently.
The mean V for lterable Pt (0.356 L/kg) was less than total body water
(0.7 L/kg, ie, about 70% of body weight), indicating that lterable Pt was
most likely distributed in plasma water and other extracellular uids and not
tissue bound. However, a much larger V was calculated for total Pt (4.19 L/kg)
indicating that protein-bound Pt may be distributed to the tissues such as
kidney (4.54  0.74 lg/g) and liver (2.83  0.194 lg/g), which had the highest
concentration of Pt per unit dry tissue mass at 96 hours after cisplatin
administration (Table 3). The organ distribution of Pt was compared with the
data of Litterst et al [31], who gave a bolus dose of cisplatin to dogs at the same
dose (1 mg/kg), and who employed the same tissue sampling time (96 hours)
used in this cockatoo study. The Pt distribution to the dog kidney (corrected
for an assumed water content of 80%) was 3.75 lg/g (compared with 4.54 lg/g
in cockatoos), and 1.75 lg/g in the liver (compared with 2.83 lg/g in
cockatoos). There is the possibility that partitioning into red cells also might

Table 1
Pharmacokinetic values of total plasma platinum following cisplatin infusion (1 mg/kg,
intravenously over 1 hour) to 6 cockatoos
CMAX TMAX
(mg/L) (h)
Mean 1.48
SD
0.22

1.0
0.0

AUC01
(mg/L.h)

AUCEXTR
(%)

MRT Cl
Vss
T1/2,a
(h)
(ml/h/kg) (L/kg) (h)

26.9
2.23

42.3
5.70

111
15.7

373
3.2

4.19
0.014

T1/2,b
(h)

0.398 79.0
0.0332 10.0

Abbreviations: CMAX, maximum plasma concentration; TMAX, time to reach maximum


concentration; AUC01, area-under-plasma concentration versus time curve; AUCEXTR., percent
of AUC01 extrapolated to innite time; MRT, mean residence time; Cl, systemic clearance; Vss,
apparent volume of distribution (steady state); T1/2,a, half-life in the a phase; T1/2,b, half-life in the
b phase.
(From Filippich LJ, Bucher AM, Charles BG. Platinum pharmacokinetics in sulphur-crested
cockatoos (Cacatua galerita) following single-dose cisplatin infusion. Aust Vet J
2000;78(6):406411, with permission.)

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Fig. 1. Mean (SD) total plasma platinum (Pt) concentration after an intravenous infusion of 1
mg/kg cisplatin over 1 hour to six cockatoos. (From Filippich LJ, Bucher AM, Charles BG.
Platinum pharmacokinetics in sulfur-crested cockatoos [Cacatua galerita] following single-dose
cisplatin infusion. Aust Vet J 2000;78[6]:406411, with permission.)

contribute to the relatively high V of total Pt in the cockatoo, because it was


reported that protein-bound cisplatin is rapidly taken up by erythrocytes [34].
However, this issue remains equivocal in view of the result of an earlier study in
dogs, which concluded that very little cisplatin is retained by red cells [31].
A semilogarithmic plot of Pt urinary excretion rate versus midpoint 30minute urine collection periods was linear over the rst 90 minutes postinfusion (Fig. 3) with a T1/2 of 0.384  0.0493 hours, which agreed closely with
that obtained from the analysis of the lterable plasma Pt data (0.413  0.122
hours). This indicates that the monoexponential decline in plasma concenTable 2
Pharmacokinetic values (mean  SD) of lterable plasma platinum following cisplatina or
carboplatinb infusion to 6 cockatoos
Platinum
Cisplatin
Carboplatin
a

CMAX
(mg/L)

TMAX
(h)

AUC01
(mg/L.h)

MRT
(h)

Cl
(ml/h/kg)

Vss
(L/kg)

T1/2
(h)

1.31
0.168
27.3
4.06

1.0
0.0
0.05
0.0

1.44
0.15
15.0
2.17

0.51
0.08
1.15
0.12

699
72.3
330
63.6

0.356
0.055
0.378
0.073

0.413
0.122
1.00
0.17

Cisplatin (1 mg/kg, intravenous over 1 hour).


Carboplatin (5 mg/kg, intravenous [four birds] or intraosseous [two birds] over 3 minutes).
See Table 1 for key.
(From Filippich LJ, Bucher AM, Charles BG. Platinum pharmacokinetics in sulphur-crested
cockatoos (Cacatua galerita) following single-dose cisplatin infusion. Aust Vet J 2000;78(6):
406411; and Filippich LJ, Charles BG, Sutton RH, Bucher AM. Carboplatin pharmacokinetics following a single-dose infusion in sulphur-crested cockatoos (Cacatua galerita). Aust Vet
J 2004;82(6):2731, with permission.)
b

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L.J. Filippich, B.G. Charles / Vet Clin Exot Anim 7 (2004) 821831

Fig. 2. Mean (SD) total (lled circles) and lterable (open circles) plasma platinum (Pt)
concentrations up to 2 hours after cessation of an intravenous infusion of 1 mg/kg cisplatin to
six cockatoos. Duration of infusion shown by thatched area. (From Filippich LJ, Bucher AM,
Charles BG. Platinum pharmacokinetics in sulfur-crested cockatoos [Cacatua galerita]
following single-dose cisplatin infusion. Aust Vet J 2000;78[6]:406411, with permission.)

tration was due mainly to renal clearance (ClR) and not extensive distribution
to tissues. However, there was a slight departure from linearity during the nal
collection period (90 to120 minutes), indicating possible multicompartment
kinetics for lterable Pt or, alternatively, there may be some tubular
reabsorption as is suspected to occur in human patients. In humans, the ClR
was reported to be almost twice that of the estimated creatinine clearance,
Table 3
Tissue distribution of platinum (mean  SD) at 96 hours following cisplatina or carboplatinb
infusion to four cockatoos
Platinum content (lg/g DM)
Tissue/organ

Cisplatin

Kidney
Liver
Proventriculus
Lung
Pancreas
Heart
Muscle

4.54
2.83
1.64
1.50
0.91
0.84
0.38









0.74
0.19
0.29
0.40
0.31
0.14
0.06

Carboplatin
7.04
3.08
1.56
1.46
0.29
0.72
0.34









3.01
1.79
0.95c
0.77
0.16
0.42
0.13

Cisplatin (1 mg/kg, intravenous over 1 hour).


Carboplatin (5 mg/kg, intravenous [four birds] or intraosseous [two birds] over 3 minutes).
c
Data from three birds only.
(From Filippich LJ, Bucher AM, Charles BG. Platinum pharmacokinetics in sulphur-crested
cockatoos (Cacatua galerita) following single-dose cisplatin infusion. Aust Vet J 2000;78(6):406
411; Filippich LJ, Charles BG, Sutton RH, Bucher AM. Carboplatin pharmacokinetics following
a single-dose infusion in sulphur-crested cockatoos (Cacatua galerita). Aust Vet J 2004;82(6):
2731, with permission.)
b

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Fig. 3. Mean (SD) urinary excretion rate of platinum (Pt) versus postinfusion, midpoint
collection time after an intravenous infusion of 1 mg/kg cisplatin to 6 cockatoos. (From
Filippich LJ, Bucher AM, Charles BG. Platinum pharmacokinetics in sulfur-crested cockatoos
[Cacatua galerita] following single-dose cisplatin infusion. Aust Vet J 2000;78[6]:406411, with
permission.)

indicating that tubular secretion may account for about half the Cl [35]. The
role of renal tubular secretion in the cockatoo was not determined in this study
because glomerular ltration rate was not measured. Nevertheless, the mean
ClR of lterable Pt during the 2-hour postinfusion period was 167  60.2 mL/
h/kg, which accounts for an average 23.8% of the total Cl of lterable Pt.
These ndings agree with human data [35], which reported that the ClR in
ovarian cancer patients averaged only 22% of the Cl, while in rats the ClR was
less than half the Cl [32].

Carboplatin
Carboplatin (cis-diammine [1,1-cyclobutanedicarboxylato] platinum [II]),
an analog of cisplatin, has been shown to have a similar mechanism of action
and ecacy but with reduced toxicity [18,36,37]. Carboplatin in 5% dextrose
solution (0.4 mg/mL, Cytomix, Victorian Hospital Association Trading
Company) has been infused over 3 minutes at 5 mg/kg intravenously or
intraosseously (ulna) in Sulfur-crested cockatoos [16,17]. Unlike cisplatin,
carboplatin can be given slowly as a bolus dose, and hydration is not required.
The carboplatin dose of 5 mg/kg was determined from published Pt
pharmacokinetic data in Sulfur-crested cockatoos [15] and by adjusting the
carboplatin dose commonly used in chemotherapy in dogs (300 mg/m2)
[36,38], using a published allometric scaling algorithm [6]. No adverse eects
were observed, except for mild transient alimentary tract signs, such as
inappetence and vomiting, which did not warrant the use of antiemetics.

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827

The pharmacokinetic data for carboplatin given intraosseously was not


very dierent from that given intravenously, indicating that the availability of
Pt was not reduced by the intraosseously route, which is a useful alternative
route of administering drugs to birds. The mean maximum lterable plasma Pt
concentration (Cmax) was 27.3  4.06 mg/L and occurred at the end of the
3-minute infusion, thenceforth declining exponentially over the next 6 hours
(6 half-lives) to an average concentration of 0.128  0.065 mg/L (0.45% of
Cmax) (Table 2). The lterable plasma Pt displayed a biphasic decay prole
with an initial log-linear phase of about 15 minutes followed by a second
(terminal) phase (Fig. 4). In humans, Go and Adjei [18] reported that Pt had
a triphasic disposition with a very short initial phase (5 to 15 minutes), an
intermediate phase half-life of 30 to 60 minutes, then a prolonged terminal
phase (>5 days). However, in the cockatoo study, Pt was not measured
beyond 6 hours (6 half-lives) due to limitations in assay sensitivity associated
with very small sample sizes from birds weighing about 800 g, although in two
birds there was some indication that the 6-hour sample may have been the rst
data point in a deeper third compartment.
The area under the plasma Pt concentrationtime curve extrapolated to
innite time (AUC01) was 15  2.17 mg/L.h; the area extrapolated past the
last (6 hour) data point to innite time averaged only 1.25% (range 0.37
2.1%) of the AUC01 (Table 2), thereby demonstrating the adequacy of the
blood sampling design and the sensitivity of the Pt assay in bird plasma. The
AUC of lterable Pt is an expression of the total systemic carboplatin
exposure, and is considered a major determinant of clinical toxicity and

Fig. 4. Mean (SD) lterable plasma platinum (Pt) concentrations after an intravenous (I.V.,
four birds) or intraosseous (I.O., two birds) 3-minute infusion of 5 mg/kg carboplatin to
cockatoos. (From Filippich LJ, Charles BG, Sutton RH, Bucher AM. Carboplatin
pharmacokinetics following a single-dose infusion in sulfur-crested cockatoos [Cacatua
galerita]. Aust Vet J 2004;82(6):2731, with permission.)

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response [39,40]. In human beings, a relationship between AUC and response


to ovarian cancer appears to exist, with a maximum response occurring when
AUC is greater than 83.3 mg/L.h [18,40]. The signicance of such a relationship, if any, to certain tumor types in birds has yet to be determined.
Compared with cisplatin [15], lterable plasma Pt concentrations for
carboplatin persisted somewhat longer than for cisplatin. The mean T1/2 for
lterable Pt from carboplatin (1.0  0.17 hours), while still short, was longer
than the very brief T1/2 of cisplatin (0.413  0.122 hours). This dierence is due
mostly to the dierence in Cl between these two drugs (330  63.6 mL/h/kg
carboplatin versus 699  72.3 mL/h/kg cisplatin) as the apparent carboplatin
V of 0.378  0.073 L/kg was close to that of cisplatin (0.356  0.055 L/kg) in
Sulfur-crested cockatoos [15]. The V of carboplatin was higher than the
estimated plasma volume of parrots (0.1 L/kg, which is 10% of body weight)
and less than total body water (0.7 L/kg, which is 70% of body weight),
indicating that lterable Pt from carboplatin most likely is distributed mainly
in plasma water and other extracellular uids. The distribution of Pt at 96
hours after carboplatin administration was similar to that reported for
cisplatin in cockatoos (Table 3) [15]. As for cisplatin, the kidneys received
the greatest accumulation of Pt from carboplatin (7.04  3.01 lg/g), followed
by the liver (3.08  1.79 lg/g). Because carboplatin is more stable in aqueous
solution than cisplatin, it is quite likely that the tissue and plasma Pt
concentrations measured were from carboplatin itself, compared with the
mixture of parent and hydrolysis products generated by the more rapid
breakdown of cisplatin [41].
In conclusion, despite anatomic, physiologic, and biochemical dierences
among animal species, the pharmacokinetic disposition of Pt in Sulfur-crested
cockatoos is similar in some respects to the kinetics reported previously in
dogs [42] and humans [18]. Thus, it is likely that specic dosing requirements
will be largely determined by the sensitivity of the tumor type to Pt and by its
toxicity in birds, rather than any large-scale dosage alterations driven by
signicant pharmacokinetic dierences. The current recommendation in dogs
is to administer carboplatin on several occasions at three weekly intervals [43].
Recently, several birds with carcinoma have responded favorably when cyclic
carboplatin therapy (3 to 4 weeks) was administered systemically at 5 mg/kg or
less [4446]. Preliminary studies by one of the author (L.J.F.) suggests that
carboplatin at three times the 5 mg/kg dose, intraosseously can be given to
parrots on two occasions at three weekly intervals without causing myelosuppression, which is the dose-limiting toxicity in mammals [18,36].

Acknowledgments
We thank Mr. A.J. Shorter and Dr. M. Ridings (CSIRO Tropical
Agriculture, Cunningham Laboratory, St. Lucia, Queensland, Australia) for
performing the Pt analyses.

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829

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