Pharmacokinetics of cis-diammine-1,1-cyclobutane dicarboxylate platinum(II) in patients with normal and impaired renal function.

Abstract

cis-Diammine-1,1-cyclobutane dicarboxylate platinum(II) (CBDCA, JM8) is a nonnephrotoxic analogue of cisplatin currently undergoing clinical evaluation. Pharmacokinetic studies have been performed in patients receiving CBDCA (20 to 520 mg/sq m) as a 1-hr infusion without hydration or diuresis. Following the end of the infusion, plasma levels of total platinum and ultrafilterable (Mr less than 50,000) platinum (free platinum) decayed biphasically with first-order kinetics (total platinum t alpha 1/2 = 98 min; t beta 1/2 range, 399 to greater than 1440 min; free platinum t alpha 1/2 = 87 min; t beta 1/2 = 354 min). During the first four hr, binding of platinum to plasma protein was limited (24%), with most of the free platinum in the form of unchanged CBDCA (94%). However, by 24 hr, the majority of platinum was protein bound (87%). The major route of elimination was renal, 65% of the platinum administered being excreted in the urine within 24 hr, with 32% of the dose excreted as unchanged CBDCA. No evidence was found from studies on the renal clearance of free platinum to indicate renal tubular secretion (mean free platinum renal clearance, 69 ml/min). However, the plasma clearance of free platinum did correlate positively with glomerular filtration rates (p = 0.005). None of the pharmacokinetic parameters determined were dose dependent. In vitro studies with plasma and urine demonstrated that, in contrast to cisplatin, CBDCA is a stable complex [t 1/2 - 37 degrees; plasma, 30 hr, and urine (range), 20 to 460 hr]. The differences in the pharmacokinetics of cisplatin and CBDCA may explain why the latter complex is not nephrotoxic.