Thirdspace fluid distribution of pemetrexed in no

Authors: Per Hartvig Honoré Sigrid Jóhansdóttir Joensen Michelle Olsen Steen Honoré Hansen Anders Mellemgaard

Publish Date: 2014/06/17

Volume: 74, Issue: 2, Pages: 349-357

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Abstract

Hydrophilic drugs particularly those with low plasma protein binding may accumulate in thirdspace fluid in the body Cytotoxic drugs like methotrexate MTX cause damage in the tissue and evacuation of the thirdspace fluid in pleura is strongly recommended before new dosing Pemetrexed PEM is a multitargeted antifolate similar to MTX approved for the treatment for malignant pleural mesothelioma and nonsmall 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 explicitlyEight patients treated with a 500 mg/m2 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 reversedphase highperformance liquid chromatography and sample preparation was performed using protein precipitation with perchloric acid Pharmacokinetic analysis was performed using a noncompartment method as well a twocompartment modelThe 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 halflife t ½ elimination of 32 h and distribution halflife t ½distribution of 6 min Clearance CL was 51 L/h central volume of distribution V central 232 L and peripheral volume distribution V peripheral 106 L and the area under the curve was 186 μg h/mL Using noncompartment methods an elimination halflife of 31 h and an apparent CL of 32 L/h were measured whereas an apparent steadystate volume became 142 L The pleura concentrations were only half of simultaneous plasma concentrations and elimination halflife was 315 h

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