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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
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
824
L.J. Filippich, B.G. Charles / Vet Clin Exot Anim 7 (2004) 821831
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.)
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
825
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
826
L.J. Filippich, B.G. Charles / Vet Clin Exot Anim 7 (2004) 821831
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.
L.J. Filippich, B.G. Charles / Vet Clin Exot Anim 7 (2004) 821831
827
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.)
828
L.J. Filippich, B.G. Charles / Vet Clin Exot Anim 7 (2004) 821831
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.
L.J. Filippich, B.G. Charles / Vet Clin Exot Anim 7 (2004) 821831
829
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