(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)
*
Coefficient of variation
†
Steady-state volume of distribution
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)
Coefficient of variation
†
Steady-state volume of distribution
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 steady-state volume of distribution of dexrazoxane suggests its distribution primarily in the total body water (25 L/m2). The mean systemic clearance and steady-state volume of distribution of dexrazoxane in two Asian female patients at 500 mg/m2 dexrazoxane along with 50 mg/m2 doxorubicin were 15.15 L/h/m2 and 36.27 L/m2, respectively, but their elimination half-life and renal clearance of dexrazoxane were similar to those of the ten Caucasian patients from the same study. Qualitative metabolism studies with Zinecard 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 the 500 mg/m2 dose of Zinecard was excreted in the urine.
Protein Binding
In vitro studies have shown that Zinecard is not bound to plasma proteins.
Special Populations
Pediatric
The pharmacokinetics of Zinecard have not been eva luated in pediatric patients.
Gender
Analysis of pooled data from two pharmacokinetic studies indicate that male patients have a lower mean clearance value than female patients (110 mL/min/m2 versus 133 mL/min/m2). This gender effect is not clinically relevant.
Renal Insufficiency
The pharmacokinetics of Zinecard were assessed following a single 15 minute IV infusion of 150 mg/m2 of dexrazoxane in male and female subjects with varying degrees of renal dysfunction as determined by creatinine clearance (CLCR) based on a 24-hour urinary creatinine collection. Dexrazoxane clearance was reduced in subjects with renal dysfunction. Compared with controls, the mean AUC0–inf value was twofold greater in subjects with moderate (CLCR 30–50 mL/min) to severe (CLCR <30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC0–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 PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Hepatic Insufficiency
The pharmacokinetics of Zinecard have not been eva luated in patients with hepatic impairment. The Zinecard dose is dependent upon the dose of doxorubicin (see DOSAGE AND ADMINISTRATION). Since a doxorubicin dose reduction is recommended in the presence of hyperbilirubinemia, the Zinecard dosage is proportionately reduced in patients with hepatic impairment.
Drug Interactions
There was no significant change in the pharmacokinetics of doxorubicin (50 mg/m2) and its predominant metabolite, doxorubicinol, in the presence of dexrazoxane (500 mg/m2) in a crossover s |
