Regional pharmacokinetic selectivity of intrapleural cisplatin.

The pharmacokinetics and toxicity of cisplatin were investigated in 3 patients affected by malignant mesothelioma who received 90 mg/m2 of the drug intrapleurally. The mean area under the pleural Pt concentration versus time curve (AUC) [12.83 (S.D. 4.06) mg.min/ml] was about 50 times greater than that detected in plasma [0.27 (0.03) mg.min/ml], indicating a clear pharmacological advantage for this route of administration. The mean plasma total Pt concentration was 1.1 micrograms/ml and the apparent total body clearance was 268 (101) ml/min. Platinum plasma pharmacokinetic data measured following intrapleural cisplatin administration (4 patients) were compared with those observed in 7 patients treated intravenously with the same dose of cisplatin (90 mg/m2) under the same modalities of hydration. Intrapleural administration of cisplatin resulted in significantly lower plasma total partial AUC (P less than 0.05) and prolonged plasma levels of filterable Pt compared with intravenous administration. No difference between the two routes of cisplatin administration in the renal clearance (S.D.) of filterable Pt [132 (64) ml/min and 122 (39) ml/min for intravenous and intrapleural cisplatin, respectively] were observed. None of the mesothelioma patients developed clinical symptoms or signs of pleural inflammation. The intrapleural treatment did not produce haemotoxicity and the emetic toxicity was lower compared with that observed in patients receiving cisplatin intravenously.

HPLC analysis of theophylline: bioequivalence study of two sustained-release formulations at steady state.

Theophylline is at present one of the standard drugs used for asthma and obstructive respiratory diseases but still presents clinical problems due to its narrow therapeutic range. To provide additional studies in this important field, the in vivo bioavailability of Bronchoretard, a theophylline sustained-release preparation, not available at present in Italy, has been compared with that of Diffumal, formulation of large consumption. An isocratic reverse-phase HPLC method to assess the theophylline in plasma is described. The two formulations present good bioequivalence, though Bronchoretard seems to provide little therapeutic advantage.

High doses of intrapleural cisplatin in a case of malignant pleural mesothelioma. Clinical observations and pharmacokinetic analyses.

BACKGROUND: The authors report a feasibility study of intrapleural cisplatin in a patient with inoperable malignant pleural mesothelioma. METHODS: Total and filterable platinum in pleural effusion and in plasma were monitored for two intrapleural courses of 120 mg/m2 cisplatin, and a weekly schedule was adopted. Platinum concentrations in pleural effusion, plasma, and urine were determined by flameless atomic absorption spectroscopy. RESULTS: A lower peak of filterable platinum in plasma, a decrease in systemic filterable platinum exposure (AUC [area under the concentration-time curve]), and a greater pleural exposure to filterable platinum were observed after Course 2 compared with Course 1. After the second cycle of intrapleural treatment, the systemic AUC for filterable platinum was reduced by 40%. CONCLUSIONS: The authors' findings may have some implications for the clinical use of intrapleural chemotherapy with high doses of cisplatin. Both infusions of cisplatin were generally well tolerated by the patient and were associated with the local pharmacologic advantage of sustained exposure to cisplatin of the pleural cavity. No sign of myelosuppression, neuropathy, or ototoxicity was observed, and acute toxicity consisted of mild nausea, vomiting, and prolonged anorexia. A transient presence of granular casts was the only observed nephrotoxic effect of cisplatin. Excellent local control of the disease with absence of recurrence of the effusion was observed.

Carboplatin and cisplatin pharmacokinetics after intrapleural combination treatment in patients with malignant pleural effusion.

BACKGROUND: Cisplatin (DDP) and carboplatin (CBDCA) are two of the most effective drugs in a locoregional approach. Since simultaneous combined 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 pharmacokinetics of DDP and CBDCA were studied in 10 patients with malignant pleural effusion treated intrapleurally with a combination of DDP (60 mg/m2) and CBDCA (270 mg/m2) 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 ultrafiltrates were measured by means of high performance liquid chromatography and atomic absorption spectrometry. RESULTS: Both in the plasma and pleural fluid, the total levels of free Pt represented the additive result of the individual concentrations of CBDCA and Pt-species derived from DDP. After intrapleural combination, high pleural-plasma ratios of the peak concentrations and AUCs were observed both for CBDCA and DDP-derived Pt species, highlighting a distinct local pharmacological advantage. However, the Pt species originating from DDP were absorbed more rapidly from the pleural cavity than CBDCA (Ka = 86 x 10(-3) vs. 37 x 10(-3) min-1, P < 0.05). Intrapleural combination of CBDCA and DDP produced therapeutic plasma levels of reactive (free) DDP species and increased the extent of their residence time (MRT) compared with single intravenous DDP treatment [peak concentration: 1.1 +/- 0.1 (SD) vs. 1.6 +/- 0.2 microgram/ml; MRT: 5.2 +/- 1.9 vs. 0.5 +/- 0.06 h]. Furthermore, the plasma AUC of free CBDCA after intrapleural combined treatment (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 intrapleural treatment was well tolerated by all patients. Toxicity consisted of mild nausea and vomiting (grade 1-2 according to the WHO scale) in four 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 asymptomatic minimal fluid reaccumulation not requiring drainage (partial response) was observed in four patients. CONCLUSIONS: The pharmacologic results seem to exclude a pharmacokinetic interaction between CBDCA and DDP and suggest that a dose of CBDCA 2-fold higher than that used in this study associated intrapleurally with 60 mg/m2 DDP could induce an acceptable and predictable myelosuppression.