Creatinine clearance as a predictor of ultrafilterable platinum disposition in cancer patients treated with cisplatin: relationship between peak ultrafilterable platinum plasma levels and nephrotoxicity.

Ultrafilterable platinum (UP) disposition was studied in 22 cancer patients receiving their first course of cisplatin (50 to 140 mg/m2) by two-hour infusion. UP plasma and urinary platinum levels were quantitated using a high-performance liquid chromatographic (HPLC) assay, which was selective for cisplatin and active platinum metabolites. Creatinine clearance was determined in all patients at the time of the pharmacokinetic studies and ranged from 58 to 214 mL/min. Creatinine clearance was a poor predictor of UP disposition in patients, probably as a consequence of the complex renal clearance mechanism for UP in the human kidney, which involves both tubular secretion and reabsorption. However, the peak plasma level of UP was closely related to the area under curve (AUC) of UP (r2 = .831), P less than .0001) and was significantly correlated with the decline in creatinine clearance observed after four courses of cisplatin therapy to 12 of the patients (r2 = .727, P less than .005). Cisplatin dose and the AUC of UP were less satisfactory predictors of the change in creatinine clearance with four courses of therapy (r2 = .488, P less than .025 and r2 = .623, P less than .005). The large interpatient variability in all the parameters of cisplatin disposition measured in this study suggested that there may be a role for individualization of cisplatin dosage based on a peak level obtained in the first course of therapy. Longer term infusion of cisplatin could also be justified.

Reduced ability to clear ultrafilterable platinum with repeated courses of cisplatin.

Ultrafilterable plasma and urinary levels of platinum were quantitated for 24 hours after the first- and fourth-course infusion of cisplatin (CDDP) to seven patients. Four patients received 80 mg/m2 and three patients received 100 mg/m2 CDDP as a 2-hour infusion. The area under the curve (AUC) of ultrafilterable platinum, average renal clearance (CIR) of ultrafilterable platinum, and percentage of the platinum dose excreted in urine (% E) were determined for each infusion over the 26-hour period of the study. The AUC was higher in all patients after the fourth-course infusion, with a median increase of 74%. The median CLR was 494 mL/min (range, 214 to 996 mL/min) for the first course and decreased to 156 mL/min (range, 108 to 271 mL/min) for the fourth-course infusion (P less than .02). The median % E was 29.2% (range, 19.6% to 37.7%) for the first course and decreased to 19.9% (range, 12.4% to 25.9%) for the fourth-course infusion (P less than .02). There was no difference in creatinine clearance for the two infusions (median, 94 mL/min; P greater than .05). Urinary excretion of B2-microglobulin (B2-MG) and N-acetyl-B-glucosaminidase (NAG) was highly variable between patients and did not provide a useful predictor of changes in renal function. Four courses of CDDP therapy resulted in significantly reduced renal elimination of platinum in patients, probably through a reduction in the secretion of the drug in the proximal tubule of the kidney. The results suggest that increased antitumor effect and toxicity could occur in patients receiving sequential courses of cisplatin.