12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism by which ZINECARD exerts its cytoprotective activity is not fully understood. Dexrazoxane is a cyclic derivative of EDTA that penetrates cell membranes. Results of laboratory studies suggest that dexrazoxane is converted intracellularly to a ring-opened chelating agent that interferes with iron-mediated free radical generation thought to be responsible, in part, for anthracycline-induced cardiomyopathy.
The pharmacokinetics of dexrazoxane have been studied in advanced cancer patients with normal renal and hepatic function. The pharmacokinetics of dexrazoxane can be adequately described by a two-compartment open model with first-order elimination. Dexrazoxane has been administered as a 15 minute infusion over a dose range of 60 to 900 mg/m2 with 60 mg/m2 of doxorubicin, and at a fixed dose of 500 mg/m2 with 50 mg/m2 doxorubicin. The disposition kinetics of dexrazoxane are dose-independent, as shown by linear relationship between the area under plasma concentration-time curves and administered doses ranging from 60 to 900 mg/m2. The mean peak plasma concentration of dexrazoxane was 36.5 µg/mL at 15- minute after intravenous administration of 500 mg/m2 dose of ZINECARD over 15 to 30 minutes prior to the 50 mg/m2 doxorubicin dose.
The important pharmacokinetic parameters of dexrazoxane are summarized in Table 2:
|Dose Doxorubicin (mg/m2)||Dose ZINECARD (mg/m2)||Number of Subjects||Elimination Half-Life (h)||Plasma Clearance (L/h/m2)||Renal Clearance (L/h/m2)||†Volume of Distribution (L/m2)|
|50||500||10||2.5 (16)||7.88 (18)||3.35 (36)||22.4 (22)|
|60||600||5||2.1 (29)||6.25 (31)||—||22.0 (55)|
Following a rapid distributive phase (0.2 to 0.3 hours), dexrazoxane reaches post-distributive equilibrium within two to four hours. The estimated mean steady-state volume of distribution of dexrazoxane is 22.4 L/m2 after 500 mg/m2 of ZINECARD dose followed by 50 mg/m2 of doxorubicin, suggesting distribution throughout total body water (25 L/m2).
In vitro studies have shown that dexrazoxane is not bound to plasma proteins.
Qualitative metabolism studies with dexrazoxane have confirmed the presence of unchanged drug, a diacid-diamide cleavage product, and two monoacid-monoamide ring products in the urine of animals and man. The metabolite levels were not measured in the pharmacokinetic studies.
Urinary excretion plays an important role in the elimination of dexrazoxane. Forty-two percent of a 500 mg/m2 dose of ZINECARD was excreted in the urine. Renal clearance averages 3.35 L/h/m2 after the 500 mg/m2 ZINECARD dose followed by 50 mg/m2 of doxorubicin.
Pharmacokinetics following ZINECARD administration have not been evaluated in pediatric patients.
Effect of Renal Impairment
The pharmacokinetics of dexrazoxane were assessed following a single 15-minute IV infusion of 150 mg/m2 of ZINECARD. Dexrazoxane clearance was reduced in subjects with renal dysfunction. Compared with controls, the mean AUC0–inf value was two-fold greater in subjects with moderate (CLCR 30–50 mL/min) to severe (CLCR <30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC-inf) could be achieved if dosing were reduced by 50% in subjects with creatinine clearance values <40 mL/min compared with control subjects (CLCR >80 mL/min) [see Use in Specific Populations (8.7) and Dosage and Administration (2.2)].
Effect of Hepatic Impairment
Pharmacokinetics following ZINECARD administration have not been evaluated in patients with hepatic impairment. The ZINECARD dose is dependent upon the dose of doxorubicin [see Dosage and Administration (2.2)].