title: Third-space fluid distribution of pemetrexed in non-small cell lung cancer patients.
abstract: OBJECTIVE
  Hydrophilic drugs particularly those with low plasma protein binding may accumulate in third-space fluid in the body. Cytotoxic drugs like methotrexate (MTX) cause damage in the tissue, and evacuation of the third-space fluid in pleura is strongly recommended before new dosing. Pemetrexed (PEM) is a multi-targeted antifolate similar to MTX approved for the treatment for malignant pleural mesothelioma and non-small cell lung cancer. Current recommendations for patients receiving treatment with PEM prescribe draining of the pleural fluid. This is based upon the recommendations for MTX and not directly to any specific findings relating to PEM. The recommendations are the same because PEM is an analogue of MTX; the molecular structures and pharmacokinetic parameters are similar. However, since draining the pleural fluid is painful and cancer patient are particularly susceptible to infection subsequently, it is relevant to examine the recommendations for PEM explicitly.
  
  
  METHODS
  Eight patients treated with a 500 mg/m(2) PEM combined with platinum salt were examined. Plasma samples were first collected in relation to the start of PEM infusion. Thereafter, plasma and pleura samples were taken at various times after drug infusion from each patient; in two patients, sampling was done twice but on different occasions. The quantitative determination of PEM was performed with reversed-phase high-performance liquid chromatography, and sample preparation was performed using protein precipitation with perchloric acid. Pharmacokinetic analysis was performed using a non-compartment method as well a two-compartment model.
  
  
  RESULTS
  The results were calculated from 10 samples taken from eight patients, where data from one patient point were excluded as the patient had impaired renal function, and three samples were reported as below limit of quantification. The plasma PEM pharmacokinetics calculated showed an elimination half-life (t ½ elimination) of 3.2 h and distribution half-life (t ½-distribution) of 6 min. Clearance (CL) was 5.1 L/h, central volume of distribution (V(central)) 23.2 L and peripheral volume distribution (V(peripheral)) 10.6 L, and the area under the curve was 186 μg h/mL. Using non-compartment methods, an elimination half-life of 3.1 h and an apparent CL of 3.2 L/h were measured, whereas an apparent steady-state volume became 14.2 L. The pleura concentrations were only half of simultaneous plasma concentrations, and elimination half-life was 3.15 h.
  
  
  CONCLUSIONS
  Pemetrexed is not likely to accumulate in the pleural fluid, and evacuation of fluid might not be necessary. Further investigation is needed to recommend no drainage of the fluid, i.e., in patients with renal impairment.
authors.affiliation: Systems Pharmacology, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark, peh@sund.ku.dk.
authors.forename: Per Hartvig
authors.initials: PH
authors.lastname: Honoré
authors.forename: Sigrid Jóhansdóttir
authors.initials: SJ
authors.lastname: Joensen
authors.forename: Michelle
authors.initials: M
authors.lastname: Olsen
authors.forename: Steen Honoré
authors.initials: SH
authors.lastname: Hansen
authors.forename: Anders
authors.initials: A
authors.lastname: Mellemgaard
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000068437:Pemetrexed; D016066:Pleural Effusion, Malignant / Q000378:metabolism*; D011379:Prognosis; D014018:Tissue Distribution
chemical_list: D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D016190:Carboplatin; D002945:Cisplatin