PHARMACOKINETICS AND PHARMACODYNAMICS OF CARBOPLATIN ADMINISTERED IN A HIGH-DOSE COMBINATION REGIMEN WITH THIOTEPA, CYCLOPHOSPHAMIDE AND PERIPHERAL STEM-CELL SUPPORT

The aim of this pharmacokinetic/pharmacodynamic study was to define th e relationships of the carboplatin exposure with the toxicity in patie nts treated with high dose carboplatin (400 mg m(-2) day(-1)), cycloph osphamide (1500 mg m(-2) day(-1)) and thiotepa (120 mg m(-2) day(-1)) for four consecutive days, followed by peripheral stem cell transplant ation. Exposure to carboplatin was studied in 200 treatment days by me asuring the area under the carboplatin plasma ultrafiltrate (pUF) conc entration vs time curve (AUG). The AUC was obtained by using a previou sly validated limited sampling model. A total of 31 patients was studi ed who received one, two or three courses of this high-dose chemothera py reigmen. The unbound, plasma ultrafiltrate carboplatin was almost c ompletely cleared from the body before each next treatment day in a co urse; the day-to-day AUC variation was 3.3%. The mean cumulative AUC o ver 4 days was 19.6 (range 14.1-27.2) mg ml(-1) min(-1). In 97 treatme nt days the carboplatin dose was calculated using the Calvert formula with the creatinine clearance as the measure for the glomerular filtra tion rate (GFR). For these courses, the inter-patient variability in p harmacokinetics was significantly reduced from 21% to 15% (P = 0.007) in comparison with the schemes where it was given as a fixed dose of 4 00 mg m(-2). There were no relationsips found between toxicity and the AUC of carboplatin, which may be due to the influence of overlapping toxicities of cyclophosphamide and thiotepa. However, the ototoxicity was strongly related to the cumulative carboplatin AUC. This toxicity was dose limiting for carboplatin in this schedule. It appeared that t he carboplatin pharmacokinetics in these regimens were similar to thos e reported at conventional dosages. To reduce the inter-patient variat ion, the carboplatin dose can be calculated using the Calvert-formula with the creatinine clearance as the measure for the GFR.