CARBOPLATIN AND CISPLATIN PHARMACOKINETICS AFTER INTRAPLEURAL COMBINATION TREATMENT IN PATIENTS WITH MALIGNANT PLEURAL EFFUSION

Background. Cisplatin (DDP) and carboplatin (CBDCA) are two of the mos t effective drugs in a locoregional approach. Since simultaneous combi ned treatment with intrapleural DDP and CBDCA has not been reported in humans; we investigated its use in patients with malignant effusions, focusing on pharmacokinetics. Patients and methods. The pharmacokinet ics of DDP and CBDCA were studied in 10 patients with malignant pleura l effusion treated intrapleurally with a combination of DDP (60 mg/m(2 )) and CBDCA (270 mg/m(2)) and in additional patients who received the same doses of drugs administered intravenously as single agents or in combination. Platinum (Pt) species originating from DDP (metabolites plus unchanged DDP) and intact CBDCA in plasma and pleural fluid ultra -filtrates were measured by means of high performance liquid chromatog raphy and atomic absorption spectrometry. Results: Both in the plasma and pleural fluid, the total levels of free Pt represented the additiv e result of the individual concentrations of CBDCA and Pt-species deri ved from DDP. After intrapleural combination, high pleural-plasma rati os of the peak concentrations and AUCs were observed both for CBDCA an d DDP-derived Pt species, highlighting a distinct local pharmacologica l advantage. However, the Pt species originating from DDP were absorbe d more rapidly from the pleural cavity than CBDCA (K-a = 86 x 10(-3) v s. 37 x 10(-3) min(-1), P < 0.05). Intrapleural combination of CBDCA a nd DDP produced therapeutic plasma levels of reactive (free) DDP speci es and increased the extent of their residence time (MRT) compared wit h single intravenous DDP treatment [peak concentration: 1.1 +/- 0.1 (S D) vs. 1.6 +/- 0.2 mu g/ml; MRT: 5.2 +/- 1.9 vs. 0.5 +/- 0.06 h]. Furt hermore, the plasma AUC of free CBDCA after intrapleural combined trea tment (2.1 +/- 0.5 mg/ml x min) was similar to that after intravenous administration of CBDCA alone (2.1 +/- 0.2 mg/ml x min). The intrapleu ral treatment was well tolerated by all patients. Toxicity consisted o f mild nausea and vomiting (grade 1-2 according to the WHO scale) in f our patients. Myelosuppression (grade 1-2) was remarkable only in two heavily pretreated patients. No evidence of recurrence of the pleural effusion was observed in six patients (complete response), while an as ymptomatic minimal fluid reaccumulation not requiring drainage (partia l response) was observed in four patients. Conclusions. The pharmacolo gic results seem to exclude a pharmacokinetic interaction between CBDC A and DDP and suggest that a dose of CBDCA 2-fold higher than that use d in this study associated intrapleurally with 60 mg/m(2) DDP could in duce an acceptable and predictable myelosuppression.