A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Paraplatin Pharmacology, Pharmacokinetics, Studies, Metabolism - Carboplatin
Paraplatin Pharmacology, Pharmacokinetics, Studies, Metabolism - Carboplatin
CLINICAL PHARMACOLOGY
Carboplatin, like cisplatin, produces predominantly
interstrand DNA cross-links rather than DNA-protein cross-links. This
effect is apparently cell-cycle nonspecific. The aquation of carboplatin,
which is thought to produce the active species, occurs at a slower rate
than in the case of cisplatin. Despite this difference, it appears that
both carboplatin and cisplatin induce equal numbers of drug-DNA
cross-links, causing equivalent lesions and biological effects. The
differences in potencies for carboplatin and cisplatin appear to be
directly related to the difference in aquation rates.
In patients with creatinine clearances of about 60
mL/min or greater, plasma levels of intact carboplatin decay in a biphasic
manner after a 30-minute intravenous infusion of 300 to 500 mg/m2 of PARAPLATIN. The initial plasma half-life
(alpha) was found to be 1.1 to 2 hours (N = 6), and the postdistribution
plasma half-life (beta) was found to be 2.6 to 5.9 hours (N = 6). The
total body clearance, apparent volume of distribution and mean residence
time for carboplatin are 4.4 L/ hour, 16 L and 3.5 hours, respectively.
The Cmax values and areas under the plasma
concentration vs time curves from 0 to infinity (AUC 0-¥) increase linearly with dose, although
the increase was slightly more than dose proportional. Carboplatin,
therefore, exhibits linear pharmacokinetics over the dosing range studied
(300-500 mg/m2).
Carboplatin is not bound to plasma proteins. No
significant quantities of protein-free, ultrafilterable
platinum-containing species other than carboplatin are present in plasma.
However, platinum from carboplatin becomes irreversibly bound to plasma
proteins and is slowly eliminated with a minimum half-life of 5 days.
The major route of elimination of carboplatin is
renal excretion. Patients with creatinine clearances of approximately 60
mL/min or greater excrete 65% of the dose in the urine within 12 hours and
71% of the dose within 24 hours. All of the platinum in the 24-hour urine
is present as carboplatin. Only 3 to 5% of the administered platinum is
excreted in the urine between 24 and 96 hours. There are insufficient data
to determine whether biliary excretion occurs.
In patients with creatinine clearances below 60
mL/min the total body and renal clearances of carboplatin decrease as the
creatinine clearance decreases. PARAPLATIN dosages should therefore be
reduced in these patients (See DOSAGE AND ADMINISTRATION
section).
The primary determinant of PARAPLATIN clearance is
glomerular filtration rate (GFR) and this parameter of renal function is
often decreased in elderly patients. Dosing formulas incorporating
estimates of GFR (See DOSAGE AND
ADMINISTRATION section) to provide predictable PARAPLATIN plasma
AUCs should be used in elderly patients to minimize the risk of
toxicity.
CLINICAL STUDIES
Use with cyclophosphamide for
initial treatment of ovarian cancer: In two prospectively randomized,
controlled studies conducted by the National Cancer Institute of Canada,
Clinical Trials Group (NCIC) and the Southwest Oncology Group (SWOG), 789
chemotherapy naive patients with advanced ovarian cancer were treated with
PARAPLATIN or cisplatin, both in combination with cyclophosphamide, every
28 days for six courses before surgical reevaluation. The following
results were obtained from both studies:
Comparative Efficacy
Overview of Pivotal Trials
| |
NCIC |
SWOG |
|
Number of
patients randomized |
447
|
342
|
|
Median age
(years) |
60
|
62
|
|
Dose of
cisplatin |
75 mg/m2 |
100 mg/m2 |
|
Dose of
carboplatin |
300 mg/m2 |
300 mg/m2 |
|
Dose of
Cytoxan |
600 mg/m2 |
600 mg/m2 |
|
Residual
tumor < 2 cm
(number of
patients) |
39% (174/
447) |
14% (49/
342) |
Clinical Response in
Measurable Disease Patients
| |
NCIC |
SWOG |
|
Carboplatin
(number of patients) |
60% (48/
80) |
58% (48/
83) |
|
Cisplatin
(number of patients) |
58% (49/
85) |
43% (33/
76) |
|
95% C. I. of
difference
(Carboplatin
- Cisplatin) |
(- 13.9%,
18.6%) |
(- 2.3%,
31.1%) |
Pathologic Complete
Response*
| |
NCIC |
SWOG |
|
Carboplatin
(number of patients) |
11% (24/
224) |
10% (17/
171) |
|
Cisplatin
(number of patients) |
15% (33/
223) |
10% (17/
171) |
|
95% C. I. of
difference
(Carboplatin
- Cisplatin) |
(- 10.7%,
2.5%) |
(- 6.9%,
6.9%) |
Progression-Free Survival
(PFS)
| |
NCIC |
SWOG |
|
Median |
|
Carboplatin
|
59
weeks |
49
weeks |
|
Cisplatin |
61
weeks |
47
weeks |
|
2- year PFS* |
|
Carboplatin
|
31%
|
21%
|
|
Cisplatin |
31%
|
21%
|
|
95% C. I. of
difference
(Carboplatin
- Cisplatin) |
(-9.3,
8.7) |
(-9.0,
9.4) |
|
3- year PFS* |
|
Carboplatin
|
19%
|
8%
|
|
Cisplatin
|
23%
|
14%
|
|
95% C. I. of
difference
(Carboplatin
- Cisplatin) |
(-11.5,
4.5) |
(-14.1,
0.3) |
|
Hazard Ratio** |
1.10
|
1.02
|
|
95% C. I.
(Carboplatin
- Cisplatin) |
(0.89,
1.35) |
(0.81,
1.29) |
- * Kaplan-Meier
Estimates Unrelated deaths occurring in the absence of progression
were counted as events (progression) in this analysis.
- ** Analysis
adjusted for factors found to be of prognostic significance were
consistent with unadjusted analysis.
Survival
| |
NCIC |
SWOG |
|
Median |
|
Carboplatin |
110
weeks |
86
weeks |
|
Cisplatin |
99
weeks |
79
weeks |
|
2- year Survival* |
|
Carboplatin |
51.9%
|
40.2%
|
|
Cisplatin
|
48.4%
|
39.0%
|
|
95% C. I. of
difference (Carboplatin - Cisplatin) |
(-6.2,
13.2) |
(-9.8,
12.2) |
|
3- year Survival* |
|
Carboplatin |
34.6%
|
18.3%
|
|
Cisplatin
|
33.1%
|
24.9%
|
|
95% C. I. of
difference
(Carboplatin
- Cisplatin) |
(-7.7,
10.7) |
(-15.9,
2.7) |
|
Hazard Ratio** |
0.98
|
1.01
|
|
95% C. I.
(Carboplatin
- Cisplatin) |
(0.78,
1.23) |
(0.78,
1.30) |
- *
Kaplan-Meier Estimates
- ** Analysis
adjusted for factors found to be of prognostic significance were
consistent with unadjusted
analysis.
Comparative Toxicity
The pattern of toxicity exerted by the PARAPLATIN
(carboplatin for injection)-containing regimen was significantly different
from that of the cisplatin-containing combinations. Differences between
the two studies may be explained by different cisplatin dosages and by
different supportive care.
The PARAPLATIN-containing regimen induced
significantly more thrombocytopenia and, in one study, significantly more
leukopenia and more need for transfusional support. The
cisplatin-containing regimen produced significantly more anemia in one
study. However, no significant differences occurred in incidences of
infections and hemorrhagic episodes.
Non-hematologic toxicities (emesis, neurotoxicity,
ototoxicity, renal toxicity, hypomagnesemia, and alopecia) were
significantly more frequent in the cisplatin-containing arms.
|
ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN
CANCER NCIC STUDY |
|
.
|
PARAPLATIN Arm Percent*
|
Cisplatin Arm Percent*
|
P- Values** |
|
Bone Marrow |
|
Thrombocytopenia, < 100,000/ mm3 |
70
|
29
|
<
0.001 |
|
<50,000/ mm3 |
41
|
6
|
<
0.001 |
|
Neutropenia, < 2,000 cells/ mm3 |
97
|
96
|
n.
s. |
|
< 1,000 cells/ mm3 |
81
|
79
|
n.
s. |
|
Leukopenia, < 4,000 cells/ mm3 |
98
|
97
|
n.
s. |
|
< 2,000 cells/ mm3 |
68
|
52
|
0.001 |
|
Anemia, < 11 g/ dL |
91
|
91
|
n.
s. |
|
< 8 g/ dL |
18
|
12
|
n.
s. |
|
Infections |
14
|
12
|
n.
s. |
|
Bleeding
|
10
|
4
|
n.
s. |
|
Transfusions |
42
|
31
|
0.018 |
|
Gastrointestinal |
|
Nausea and
vomiting |
93
|
98
|
0.010 |
|
Vomiting |
84
|
97
|
<
0.001 |
|
Other GI
side effects |
50
|
62
|
0.013 |
|
Neurologic |
|
Peripheral
neuropathies |
16
|
42
|
<
0.001 |
|
Ototoxicity |
13
|
33
|
<
0.001 |
|
Other
sensory side effects |
6
|
10
|
n.
s. |
|
Central
neurotoxicity |
28
|
40
|
0.009 |
|
Renal |
|
Serum
creatinine elevations |
5
|
13
|
0.006 |
|
Blood urea
elevations |
17
|
31
|
<
0.001 |
|
Hepatic |
|
Bilirubin
elevations |
5
|
3
|
n.
s. |
|
SGOT
elevations |
17
|
13
|
n.
s. |
|
Alkaline
phosphatase elevations |
–
|
–
|
–
|
|
Electrolytes loss |
|
Sodium
|
10
|
20
|
0.005 |
|
Potassium |
16
|
22
|
n.
s. |
|
Calcium |
16
|
19
|
n.
s. |
|
Magnesium
|
63
|
88
|
<
0.001 |
|
Other side effects |
|
Pain
|
36
|
37
|
n.
s. |
|
Asthenia
|
40
|
33
|
n.
s. |
|
Cardiovascular |
15
|
19
|
n.
s. |
|
Respiratory |
8
|
9
|
n.
s. |
|
Allergic
|
12
|
9
|
n.
s. |
|
Genitourinary |
10
|
10
|
n.
s. |
|
Alopecia+
|
50
|
62
|
0.017 |
|
Mucositis
|
10
|
9
|
n.
s. |
- * Values are
in percent of evaluable patients
- ** n. s. =
not significant, p > 0.05
- + May have
been affected by cyclophosphamide dosage delivered
|
ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN
CANCER SWOG STUDY |
| . |
PARAPLATIN Arm Percent*
|
Cisplatin Arm Percent*
|
P- Values** |
|
Bone Marrow |
|
Thrombocytopenia, < 100,000/ mm3 |
59
|
39
|
<
0.001 |
|
<
50,000/ mm3 |
22
|
11
|
0.006 |
|
Neutropenia,
<
2,000 cells/ mm3 |
95
|
97
|
n.
s. |
|
<
1,000 cells/ mm3 |
84
|
78
|
n.
s. |
|
Leukopenia,
<
4,000 cells/ mm3 |
97
|
97
|
n.
s. |
|
<
2,000 cells/ mm3 |
76
|
67
|
n.
s. |
|
Anemia,
< 11 g/ dL |
88 |
87
|
n.
s. |
|
<
8 g/ dL |
8
|
24
|
<
0.001 |
|
Infections
|
18
|
21
|
n.
s. |
|
Bleeding
|
6
|
4
|
n.
s. |
|
Transfusions |
25
|
33
|
n.
s. |
|
Gastrointestinal |
|
Nausea and
vomiting |
94
|
96
|
n.
s. |
|
Vomiting |
82
|
91
|
0.007 |
|
Other GI
side effects |
40
|
48
|
n.
s. |
|
Neurologic |
|
Peripheral
neuropathies |
13
|
28
|
0.001 |
|
Ototoxicity |
12
|
30
|
<
0.001 |
|
Other
sensory side effects |
4
|
6
|
n.
s. |
|
Central
neurotoxicity |
23
|
29
|
n.
s. |
|
Renal |
|
Serum
creatinine elevations |
7
|
38
|
<
0.001 |
|
Blood urea
elevations |
-
|
-
|
-
|
|
Hepatic |
|
Bilirubin
elevations |
5
|
3
|
n.
s. |
|
SGOT
elevations |
23
|
16
|
n.
s. |
|
Alkaline
phosphatase elevations |
29
|
20
|
n.
s. |
|
Electrolytes loss |
|
Sodium
|
-
|
-
|
-
|
|
Potassium |
-
|
-
|
-
|
|
Calcium |
-
|
-
|
-
|
|
Magnesium
|
58
|
77
|
<
0.001 |
|
Other side effects |
|
Pain
|
54
|
52
|
n.
s. |
|
Asthenia
|
43
|
46
|
n.
s. |
|
Cardiovascular |
23
|
30
|
n.
s. |
|
Respiratory |
12
|
11
|
n.
s. |
|
Allergic
|
10
|
11
|
n.
s. |
|
Genitourinary |
11
|
13
|
n.
s. |
|
Alopecia+
|
43
|
57
|
0.009 |
|
Mucositis
|
6
|
11
|
n.
s. |
- * Values are
in percent of evaluable patients
- ** n. s. =
not significant, p >0.05
- + May have
been affected by cyclophosphamide dosage delivered
Use as a single agent for
secondary treatment of advanced ovarian cancer: In two prospective,
randomized controlled studies in patients with advanced ovarian cancer
previously treated with chemotherapy, PARAPLATIN (carboplatin for
injection) achieved six clinical complete responses in 47 patients. The
duration of these responses ranged from 45 to 71+ weeks.
top
