Paraplatin

Clinical Pharmacology

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CLINICAL PHARMACOLOGY

Paraplatin

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/mm²of carboplatin. The initial plasma half-life (alpha) was found to be 1.1 to 2 hours (n = 6), and the post-distribution 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 inf) increase linearly with dose, although the increase was slightly more than dose proportional. Carboplatin, therefore, exhibits linear pharmacokinetics over the dosing range studied (300-500 mg/mm²).

Carboplatin is not bound to plasma proteins. No significant quantities of protein-free, ultrafilterable platinum-containing species other than carbo-platin 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).

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) 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 carboplatin 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 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% 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%)
*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% 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.