title: A semi-physiological population pharmacokinetic model describing the non-linear disposition of indisulam.
abstract: The pharmacokinetic profile of the anti-cancer agent indisulam is non-linear. In addition to non-linear clearance, this may partially be explained by saturable distribution to red blood cells and saturable plasma protein binding. The aims of this study were to develop a semi-physiological population pharmacokinetic model of indisulam and to examine the impact of protein binding and distribution to red blood cells. Indisulam concentrations in plasma, plasma ultrafiltrate and in red blood cells from multiple phase I studies in Caucasian and Japanese patients were used to develop a pharmacokinetic model using NONMEM. This model comprised four physiological compartments: plasma, red blood cells, interstitial fluid and tissue. A simulation study was performed to examine the contribution of physiological processes in indisulam pharmacokinetics. Plasma albumin concentrations were predictive for the maximal protein binding capacity and considerably influenced total plasma concentrations of indisulam, whereas free plasma concentrations remained relatively unaffected. The maximal specific red blood cell binding capacity was 64.0 ( +/-5.9) mg/L and corresponded to the typical red blood cell carbonic anhydrase concentration. Simulation studies demonstrated that the hematocrit does not have a clinically relevant impact on indisulam disposition. This semi-physiological model allowed adequate prediction of the time profiles of indisulam concentrations in all monitored compartments for a large range of dose levels and several treatment regimens. The model has elucidated the mechanism and the role of saturable plasma protein binding and saturable distribution to red blood cells in indisulam pharmacokinetics and provides a basis for rationale PK-PD relationships.
authors.affiliation: Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands. apaza@slz.nl
authors.forename: Anthe S
authors.initials: AS
authors.lastname: Zandvliet
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: William
authors.initials: W
authors.lastname: Copalu
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D044466:Asian People; D001798:Blood Proteins / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000378:metabolism; D017321:Clinical Trials, Phase I as Topic; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000378:metabolism; D045604:Extracellular Fluid / Q000378:metabolism; D006801:Humans; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D015999:Multivariate Analysis; D011485:Protein Binding; D012044:Regression Analysis; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D044465:White People
chemical_list: D000970:Antineoplastic Agents; D001798:Blood Proteins; C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; D013449:Sulfonamides; D002256:Carbonic Anhydrases