Paraplatin (Carboplatin) - Clinical Pharmacology

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 C_max 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/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).

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 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*

*114 PARAPLATIN and 109 Cisplatin patients did not undergo second look surgery in NCIC study
90 PARAPLATIN and 106 Cisplatin patients did not undergo second look surgery in SWOG study
	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)

* 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.
	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)

Survival

* Kaplan-Meier Estimates
** Analysis adjusted for factors found to be of prognostic significance were consistent with unadjusted analysis.
Median	NCIC	SWOG
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)

Comparative Toxicity

The pattern of toxicity exerted by the PARAPLATIN-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

* Values are in percent of evaluable patients.
**ns= not significant, p>0.05.
+ May have been affected by cyclophosphamide dosage delivered.
		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	<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

ADVERSE EXPERIENCES IN PATIENTS WITH OVARIAN CANCER SWOG STUDY

* Values are in percent of evaluable patients.
**ns = not significant, p >0.05.
+ May have been affected by cyclophosphamide dosage delivered.
		PARAPLATIN 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

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 lyophilized powder) for INJECTION achieved six clinical complete responses in 47 patients. The duration of these responses ranged from 45 to 71 + weeks.