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Paraplatin

"A set of proteins involved in the body's natural defenses produces a large number of mutations in human DNA, according to a study led by researchers at the National Institutes of Health. The findings suggest that these naturally produced mutat"...

Paraplatin

Paraplatin

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 mg/m2 to 500 mg/m2 of carboplatin. 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 versus time curves from 0 to infinity (AUC inf) increase linearly with dose, although the increase was slightly more than dose proportional. Carboplatin, therefore, exhibits linear pharmacokinetics over the dosing range studied (300 mg/m2 to 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 (carboplatin) dosages should therefore be reduced in these patients (see DOSAGE AND ADMINISTRATION).

The primary determinant of PARAPLATIN (carboplatin) 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) to provide predictable PARAPLATIN (carboplatin) 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 carboplatin or cisplatin, both in combination with cyclophosphamide every 28 days for 6 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 cyclophosphamide 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% CI 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% CI of difference (Carboplatin-Cisplatin) (-10.7%, 2.5%) (-6.9%, 6.9%)
* 114 Carboplatin and 109 Cisplatin patients did not undergo second look surgery in NCIC study. 90 Carboplatin and 106 Cisplatin patients did not undergo second look surgery in SWOG study.

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% CI of difference (Carboplatin-Cisplatin) (-9.3, 8.7) (-9.0, 9.4)
3-year PFS*
  Carboplatin 19% 8%
  Cisplatin 23% 14%
  95% CI of difference (Carboplatin-Cisplatin) (-11.5, 4.5) (-14.1, 0.3)
Hazard Ratio** 1.10 1.02
  95% CI (Carboplatin-Cisplatin) (0.89, 1.35) (0.81, 1.29)
* Kaplan-Meier EstimatesUnrelated deaths occurring in the absence of progression were counted as events (progression) in thisanalysis.
** Analysis adjusted for factors found to be of prognostic significance were consistent with unadjustedanalysis.

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% CI 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% CI of difference (Carboplatin-Cisplatin) (-7.7, 10.7) (-15.9, 2.7)
Hazard Ratio** 0.98 1.01
  95% CI (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 carboplatin-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 carboplatin-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

    Carboplatin 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 < 2000 cells/mm3 97 96 ns
< 1000 cells/mm3 81 79 ns
  Leukopenia < 4000 cells/mm3 98 97 ns
< 2000 cells/mm3 68 52 0.001
  Anemia < 11 g/dL 91 91 ns
< 8 g/dL 18 12 ns
  Infections   14 12 ns
  Bleeding   10 4 ns
  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 ns
  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 ns
  SGOT elevations   17 13 ns
  Alkaline phosphatase elevations   - - -
Electrolytes loss
  Sodium   10 20 0.005
  Potassium   16 22 ns
  Calcium   16 19 ns
  Magnesium   63 88 < 0.001
Other side effects
  Pain   36 37 ns
  Asthenia   40 33 ns
  Cardiovascular   15 19 ns
  Respiratory   8 9 ns
  Allergic   12 9 ns
  Genitourinary   10 10 ns
  Alopecia +   50 62 0.017
  Mucositis   10 9 ns
* Values are in percent of evaluable patients.
** ns=not significant, p > 0.05.
+ May have been affected by cyclophosphamide dosage delivered.

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER SWOG STUDY

    Carboplatin Arm Percent* Cisplatin Arm Percent* P-Values**
Bone Marrow
  Thrombocytopenia < 100,000/mm3 59 35 < 0.001
< 50,000/mm3 22 11 0.006
  Neutropenia < 2000 cells/mm3 95 97 ns
< 1000 cells/mm3 84 78 ns
  Leukopenia < 4000 cells/mm3 97 97 ns
< 2000 cells/mm3 76 67 ns
  Anemia < 11 g/dL 88 87 ns
< 8 g/dL 8 24 < 0.001
  Infections   18 21 ns
  Bleeding   6 4 ns
  Transfusions   25 33 ns
Gastrointestinal
  Nausea and vomiting   94 96 ns
  Vomiting   82 91 0.007
  Other GI side effects   40 48 ns
Neurologic
  Peripheral neuropathies   13 28 0.001
  Ototoxicity   12 30 < 0.001
  Other sensory side effects   4 6 ns
  Central neurotoxicity   23 29 ns
Renal
  Serum creatinine elevations   7 38 < 0.001
  Blood urea elevations   - - -
Hepatic
  Bilirubin elevations   5 3 ns
  SGOT elevations   23 16 ns
  Alkaline phosphatase elevations   29 20 ns
Electrolytes loss
  Sodium   - - -
  Potassium   - - -
  Calcium   - - -
  Magnesium   58 77 < 0.001
Other side effects
  Pain   54 52 ns
  Asthenia   43 46 ns
  Cardiovascular   23 30 ns
  Respiratory   12 11 ns
  Allergic   10 11 ns
  Genitourinary   11 13 ns
  Alopecia +   43 57 0.009
  Mucositis   6 11 ns
* Values are in percent of evaluable patients.
** ns=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, carboplatin achieved 6 clinical complete responses in 47 patients. The duration of these responses ranged from 45 to 71+ weeks.

Last reviewed on RxList: 6/30/2009
This monograph has been modified to include the generic and brand name in many instances.

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