Paraplatin Mechanism of Action

Pharmacotherapeutic Group: Antineoplastic agent. ATC Code: L01XA02.
Pharmacology: Pharmacodynamics: Carboplatin has biochemical properties similar to the properties of cisplatin, thus producing predominantly interstrand DNA cross-links.
Pediatric Population: The safety and efficacy in children have not been established.
Pharmacokinetics: Following PARAPLATIN administration in humans, a linear relationship is observed between the dose and plasma concentrations of total and free ultrafilterable platinum. A similar linearity between dose and AUC/time curve for total platinum has been demonstrated. Repeated dosing during 4 consecutive days has not produced an accumulation of platinum in plasma. In humans, the administration of PARAPLATIN has led to terminal half-life values of free ultrafilterable platinum and carboplatin of approximately 6 and 1.5 hours, respectively.
During the initial phase, most of the free ultrafilterable platinum is present as carboplatin. No significant quantities of free, ultrafilterable, platinum-containing species other than carboplatin are present in plasma. Platinum from carboplatin becomes bound to plasma proteins and is slowly eliminated with a minimum half-life of 5 days. The terminal half-life of total platinum in plasma is 24 hours. In patients with creatinine clearance of 60 mL/min or greater receiving PARAPLATIN at doses ranging from 300 to 500 mg/m², the elimination curve exhibits a biphasic decrease with mean alpha and beta half-lives of 1.6 and 3.0 hours, respectively.
Therefore, at the dosages examined, carboplatin demonstrates linear, dose-independent pharmacokinetics in patients with creatinine clearance ≥60 mL/min. Approximately 87% of plasma platinum is protein bound within 24 hours following administration. PARAPLATIN is mainly excreted in the urine. Patients with creatinine clearance of approximately 60 mL/min or greater excrete 70% of the dose of carboplatin in the urine within 12 to 16 hours after administration. In patients with creatinine clearance below 60 mL/min, the total and renal clearances of carboplatin decrease as the creatinine clearance decreases. PARAPLATIN dosages should therefore be reduced in patients with creatinine clearance <60 mL/min (see Dosage & Administration).
Total body clearance and renal clearance of free ultrafilterable platinum are related to glomerular filtration rate and not to tubular secretion.
The variation in carboplatin clearance has been reported to be 3 to 4 times higher in pediatric patients. As for adult patients, data from literature suggest that renal function may contribute to changes in carboplatin clearance.
Toxicology: Preclinical Safety Data: Both in murine models and after xenograft transplantation of human tumors, the cytotoxic activity of carboplatin has shown to be comparable to the activity of cisplatin at a respective molar ratio of 4:1.
A comparative analysis of data from toxicity studies, following single and repeated multiple IV administration over several therapeutic courses, has revealed that at equal efficacy, carboplatin is less nephrotoxic (7.5 to 48 times), less ototoxic (8 times), less emetogenic (12 to 70 times), less lethal (8 to 12 times) and less neurotoxic than cisplatin. However, with reference to the latter toxicity, there is no valid animal model for predicting neurotoxicity in humans. LD₉₀ observed in CDF1 mice (males + females) and in Sprague-Dawley rats (males + females) is 545 mg/m² and 799 mg/m², respectively. The most significant toxicity of carboplatin following single and repeated doses to these animal species involves the hemopoietic system and is characterized by reversible anemia, neutropenia and thrombocytopenia.
Mutagenicity and Carcinogenicity: Carboplatin revealed to be a genotoxic/mutagenic substance in vivo and in vitro. In rats, which received carboplatin during organogenesis, embryotoxic and teratogenic effects were shown. The carcinogenic potential of carboplatin has not been investigated. Substances with similar mechanisms of action and similar mutagenicity have been described as carcinogenic.