Pemetrexed Safety and Pharmacokinetics in Patients with Third-Space Fluid

• Published in: Clinical cancer research Vol. 16; no. 10; pp. 2872 - 2880
• Main Authors: DICKGREBER, Nicolas J, BENN SORENSEN, Jens, PAZ-ARES, Luis G, KJESTRUP SCHYTTE, Tine, LATZ, Jane E, SCHNECK, Karen B, ZHENG YUAN, SANCHEZ-TORRES, José Miguel
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.05.2010
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Ascites - drug therapy; Ascites - etiology; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - complications; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Glutamates - adverse effects; Glutamates - blood; Glutamates - pharmacokinetics; Guanine - adverse effects; Guanine - analogs & derivatives; Guanine - blood; Guanine - pharmacokinetics; Humans; Lung Neoplasms - complications; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Medical sciences; Mesothelioma - drug therapy; Mesothelioma - pathology; Middle Aged; Neoplasm Staging; Pemetrexed; Peritoneal Neoplasms - drug therapy; Peritoneal Neoplasms - pathology; Pharmacology. Drug treatments; Pleural Effusion, Malignant - drug therapy; Pleural Effusion, Malignant - etiology; Pleural Neoplasms - complications; Pleural Neoplasms - drug therapy; Pleural Neoplasms - pathology; Antineoplastic agent; Antifolate; Human; Toxicity; Patient; Safety; Pharmacokinetics; Pemetrexed
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-09-3324

Pemetrexed is established as first-line treatment with cisplatin for malignant pleural mesothelioma and advanced nonsquamous non-small-cell lung cancer (NSCLC) and as single-agent second-line treatment for nonsquamous NSCLC. Because the structure and pharmacokinetics of pemetrexed are similar to those of methotrexate, and methotrexate is associated with severe toxicity in patients with third-space fluid (TSF), the safety of pemetrexed in patients with TSF was evaluated. Patients with TSF (pleural effusions, ascites) and relapsed, stage III/IV NSCLC or malignant pleural/peritoneal mesothelioma were treated with pemetrexed (500 mg/m2) on day 1 of each 21-day cycle. TSF was drained at any time only if clinically indicated. Plasma samples were collected during cycles 1 and 2 to compare pemetrexed concentrations with reference data from patients without TSF. Thirty-one patients with TSF received 123 pemetrexed doses (median, 4 cycles per patient; range, 1-11; mean dose intensity, 97.5%). Seven grade 3/4 drug-related toxicities, including four hematologic, were reported; there were no treatment-related deaths. There was no correlation between TSF amount and type, number, and sequelae of toxicities. Pemetrexed plasma concentrations were within the range of those in patients without TSF. Pemetrexed clearance and central volume of distribution were not statistically different between patients with and without TSF. No clinically relevant alterations of pemetrexed pharmacokinetics occurred in patients with TSF. Pemetrexed was well tolerated; toxicities were expected and manageable. The standard pemetrexed dose recommendations were adequate for patients with TSF in this study. These data suggest that draining TSF before administering pemetrexed is unnecessary.