Relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity after intravenous infusions of cisplatin to cancer patients

Purpose: The relationships between pharmacokinetic parameters of unchanged cisplatin (CDDP) and several markers for nephrotoxicity after CDDP infusion (80mg/m(2)) over 2 and 4 h were quantitated in patients with Various cancers (lung, stomach and colon cancers and mediastinal tumor). Methods: Plasma and urinary levels of unchanged CDDP were measured using a specific high-performance liquid chromatography method. Pharmacokinetic parameters were calculated according to the model-independent method. The nephrotoxicity markers, blood urea nitrogen (BUN), serum creatinine (SCr), plasma and urinary beta(2)-microglobulin (BMG(p) and BMG(u)), urinary N-acetyl-beta-D-glucosaminidase (NAG) and creatinine clearance (CCR) were monitored for 30 days following CDDP administration. Results: The maximum plasma concentration (C-max), maximum urinary excretion rate (dAe/dt(max)), area under the plasma concentration-time curve from time zero to infinity (AUC), cumulative amount excreted in urine from time zero to infinity (Ae), total clearance (Clt), renal clearance (Clr) and plasma half-life (t(1/2)) of unchanged CDDP were not significantly different between the 2-h and 4-h infusion schedules. The values of the nephrotoxicity markers changed significantly following CDDP administration, suggesting that CDDP chemotherapy (80 mg/m(2)) caused nephrotoxicity. The C-max of unchanged CDDP was the most informative pharmacokinetic parameter for nephrotoxicity. C-max was related to maximum BUN, maximum SCr and minimum CCR levels in 27 CDDP treatments according to an exponential model. Conclusion: In order to attain more effective CDDP chemotherapy with minimum nephrotoxicity, the present pharmacokinetic and pharmacodynamic studies suggest that the C-max or steady-state plasma level of unchanged CDDP should be maintained between 1.5 and 2 mu g/ml in a standard continuous infusion schedule over 2 h and 4 h.