{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T02:14:24Z","timestamp":1724292864572},"reference-count":32,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2003,1,1]],"date-time":"2003-01-01T00:00:00Z","timestamp":1041379200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2003,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The goals of the present study were to model the population kinetics of in vivo influx and efflux processes of grepafloxacin at the serum-cerebrospinal fluid (CSF) barrier and to propose a simulation-based approach to optimize the design of dose-finding trials in the meningitis rabbit model. Twenty-nine rabbits with pneumococcal meningitis receiving grepafloxacin at 15 mg\/kg of body weight (intravenous administration at 0 h), 30 mg\/kg (at 0 h), or 50 mg\/kg twice (at 0 and 4 h) were studied. A three-compartment population pharmacokinetic model was fit to the data with the program NONMEM (Nonlinear Mixed Effects Modeling). Passive diffusion clearance (CL\n            <jats:sub>diff<\/jats:sub>\n            ) and active efflux clearance (CL\n            <jats:sub>active<\/jats:sub>\n            ) are transfer kinetic modeling parameters. Influx clearance is assumed to be equal to CL\n            <jats:sub>diff<\/jats:sub>\n            , and efflux clearance is the sum of CL\n            <jats:sub>diff<\/jats:sub>\n            , CL\n            <jats:sub>active<\/jats:sub>\n            , and bulk flow clearance (CL\n            <jats:sub>bulk<\/jats:sub>\n            ). The average influx clearance for the population was 0.0055 ml\/min (interindividual variability, 17%). Passive diffusion clearance was greater in rabbits receiving grepafloxacin at 15 mg\/kg than in those treated with higher doses (0.0088 versus 0.0034 ml\/min). Assuming a CL\n            <jats:sub>bulk<\/jats:sub>\n            of 0.01 ml\/min, CL\n            <jats:sub>active<\/jats:sub>\n            was estimated to be 0.017 ml\/min (11%), and clearance by total efflux was estimated to be 0.032 ml\/min. The population kinetic model allows not only to quantify in vivo efflux and influx mechanisms at the serum-CSF barrier but also to analyze the effects of different dose regimens on transfer kinetic parameters in the rabbit meningitis model. The modeling-based approach also provides a tool for the simulation and prediction of various outcomes in which researchers might be interested, which is of great potential in designing dose-finding trials.\n          <\/jats:p>","DOI":"10.1128\/aac.47.1.138-143.2003","type":"journal-article","created":{"date-parts":[[2002,12,24]],"date-time":"2002-12-24T04:39:08Z","timestamp":1040704748000},"page":"138-143","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":10,"title":["Modeling of Transfer Kinetics at the Serum-Cerebrospinal Fluid Barrier in Rabbits with Experimental Meningitis: Application to Grepafloxacin"],"prefix":"10.1128","volume":"47","author":[{"given":"Marc","family":"Pfister","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Biopharmaceutical Sciences, University of California, San Francisco, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Biopharmaceutical Sciences, University of California, San Francisco, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margareta","family":"Hammarlund-Udenaes","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy, University of Uppsala, Uppsala, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lewis B.","family":"Sheiner","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Biopharmaceutical Sciences, University of California, San Francisco, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cynthia M.","family":"Gerber","sequence":"additional","affiliation":[{"name":"Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin G.","family":"Ta\u0308uber","sequence":"additional","affiliation":[{"name":"Institute of Microbiology and Infectious Diseases, Inselspital, University of Berne, Berne, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philippe","family":"Cottagnoud","sequence":"additional","affiliation":[{"name":"Department of Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1046\/j.1365-2125.1998.00780.x","volume":"46","year":"1998","unstructured":"Anderson, B. 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