PHARMACOKINETICS OF CARBOPLATIN WITH AND WITHOUT AMIFOSTINE IN PATIENTS WITH SOLID TUMORS

We showed previously that amifostine (WR 2721; Ethyol), a protector ag ainst carboplatin-induced toxicities, changed the pharmacokinetics of carboplatin in tumor-bearing nude mice, In the present study, the infl uence of amifostine on the pharmacokinetics of carboplatin was studied in patients when carboplatin was given in combination with three dose s of amifostine, administered just before the carboplatin infusion and 2-4 h thereafter, Compared with a control group of patients who recei ved carboplatin alone, the patients receiving the combination had a lo nger final half-life of ultrafilterable platinum species [5.0 h versus 3.5 h in patients with a normal creatinine clearance (Clcr > 80 ml/mi n); 5,6 h versus 4.2 h in those with an impaired renal function (50 < Clcr < 80 ml/min)l. This might be caused by an influence of amifostine on the renal clearance of carboplatin as suggested by a transient inc rease in serum creatinine levels 24 h after treatment in the patients receiving the combination (mean +/- SD: 34.1% +/- 17.2% versus -1,8% /- 16.5% in patients treated with carboplatin alone), The impact of th ese changes on the area under the concentration-time curves of the ult rafilterable platinum species was hardly noticeable in patients with a normal renal function but led to a significant increase in patients w ith an impaired renal function (395 +/- 59 mu mol/l.h versus 280 +/- 6 2 mu mol/l.h in patients receiving carboplatin alone), The clinical re levance of this influence is unclear, although theoretically it may re sult in an increase in the efficacy of carboplatin, as has been observ ed in tumor-bearing nude mice.