title: Estimation of feasible solution space using Cluster Newton Method: application to pharmacokinetic analysis of irinotecan with physiologically-based pharmacokinetic models.
abstract: BACKGROUND
  To facilitate new drug development, physiologically-based pharmacokinetic (PBPK) modeling methods receive growing attention as a tool to fully understand and predict complex pharmacokinetic phenomena. As the number of parameters to reproduce physiological functions tend to be large in PBPK models, efficient parameter estimation methods are essential. We have successfully applied a recently developed algorithm to estimate a feasible solution space, called Cluster Newton Method (CNM), to reveal the cause of irinotecan pharmacokinetic alterations in two cancer patient groups.
  
  
  RESULTS
  After improvements in the original CNM algorithm to maintain parameter diversities, a feasible solution space was successfully estimated for 55 or 56 parameters in the irinotecan PBPK model, within ten iterations, 3000 virtual samples, and in 15 minutes (Intel Xeon E5-1620 3.60GHz × 1 or Intel Core i7-870 2.93GHz × 1). Control parameters or parameter correlations were clarified after the parameter estimation processes. Possible causes in the irinotecan pharmacokinetic alterations were suggested, but they were not conclusive.
  
  
  CONCLUSIONS
  Application of CNM achieved a feasible solution space by solving inverse problems of a system containing ordinary differential equations (ODEs). This method may give us reliable insights into other complicated phenomena, which have a large number of parameters to estimate, under limited information. It is also helpful to design prospective studies for further investigation of phenomena of interest.
authors.forename: Kenta
authors.initials: K
authors.lastname: Yoshida
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Akihiko
authors.initials: A
authors.lastname: Konagaya
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001650:Bile Duct Neoplasms / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055808:Drug Discovery; D005240:Feasibility Studies; D006801:Humans; D000077146:Irinotecan; D008954:Models, Biological
chemical_list: D000970:Antineoplastic Agents; D000077146:Irinotecan; D002166:Camptothecin