Kemocarb Mechanism of Action

Pharmacology: Mechanism of action: 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 aquations rates.
Pharmacodynamics: 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: See Tables 1, 2, 3, 4 and 5.

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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 six clinical complete responses in 47 patients. The duration of these responses ranged from 45 to 71 + weeks.
Pharmacokinetics: 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 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 C_max 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 - 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. Carboplatin dosages should therefore be reduced in these patients. The primary determinant of 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 to provide predictable carboplatin plasma AUCs should be used in elderly patients to minimize the risk of toxicity.