Pharmacokinetics of intrapleural recombinant interleukin-2 in immunotherapy for malignant pleural effusion

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Abstract
Background. The authors measured pharmacokinetic parameters before, during, and after immunotherapy by continuous intrapleural infusion of recombinant interleukin‐2 (rIL‐2) and correlated the resulting data with clinical effects in nine patients with malignant pleural effusion. Methods. The underlying disease was malignant mesothelioma in five patients and adenocarcinoma in four patients. Continuous intrapleural infusion of rIL‐2 was performed for 5 days at 21 × 106 IU/m2/day. Maximum tolerated dose previously was determined to be 24 × 106 IU/m2/day in a Phase I study. Peak levels, the areas under the concentration curve (AUC), and drug half‐lives were measured in pleural fluid and plasma samples collected at 0 (baseline), 12, 24, 48, 72, 96, and 120 hours during infusion and at 2, 6, 8, 32, 44, 56, 80, and 120 hours after the end of infusion. Results. High and prolonged intracavitary drug levels were achieved in all but two patients, with a statistically significant correlation between peak values and AUC. Four patients achieved objective responses according to World Health Organization criteria. Neither of the patients with undetectable rIL‐2 levels had response to therapy. Serum rIL‐2 levels were low regardless intrapleural levels. Mean AUC was lower in the plasma than in the pleural fluid. Conclusions. This study demonstrates that continuous intrapleural infusion of rIL‐2 is an active method of treatment for malignant pleural effusion. The low serum levels associated with this method greatly improve tolerance. The results also indicate that the concentration and duration of intrapleural rIL‐2 levels may depend on the extent of pleural invasion. Additional study is needed to confirm this finding.