title: Dose selection method for pharmacokinetic study in hemodialysis patients using a subpharmacological dose: oseltamivir as a model drug.
abstract: BACKGROUND
  Dose selection is an important step in pharmacokinetic (PK) studies of hemodialysis patients. We propose a simulation-based dose-selection method for PK studies of hemodialysis patients using a subpharmacological dose of oseltamivir as a model drug.
  
  
  METHODS
  The concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were measured by liquid chromatography-tandem mass spectrometry. To determine a low oseltamivir dose exhibiting PK linearity, a pilot low dose determination investigation (n = 4) was performed using a single administration dose-escalation study. After the dose was determined, a low dose study (n = 10) was performed, and the optimal dose required to reach the hypothetical target OC exposure (area under the concentration-time curve [AUC] of 60,000 ng · hr/mL) was simulated using a nonparametric superposition method. Finally, observed PKs at the optimal dose were compared to the simulated PKs to verify PK predictability.
  
  
  RESULTS
  In the pilot low dose determination study, 2.5 mg of oseltamivir was determined to be the low dose. Subsequently, we performed a single-dose PK study with the low oseltamivir dose in an additional group of 10 hemodialysis patients. The predicted AUC last of OC following continuous oseltamivir doses was simulated, and 35 mg of oseltamivir corresponded to the hypothetical target AUC last of OC. The observed PK profiles of OC at a 35-mg oseltamivir dose and the simulated data based on the low dose study were in close alignment.
  
  
  CONCLUSIONS
  The results indicate that the proposed method provides a rational approach to determine the proper PK dose in hemodialysis patients.
authors.forename: Dong Ki
authors.initials: DK
authors.lastname: Kim
authors.forename: Jay Wook
authors.initials: JW
authors.lastname: Lee
authors.forename: Kwang-Hee
authors.initials: KH
authors.lastname: Shin
authors.forename: Sejoong
authors.initials: S
authors.lastname: Kim
authors.forename: Kook-Hwan
authors.initials: KH
authors.lastname: Oh
authors.forename: Myounghee
authors.initials: M
authors.lastname: Kim
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
authors.forename: Jung Pyo
authors.initials: JP
authors.lastname: Lee
authors.forename: Chun-Soo
authors.initials: CS
authors.lastname: Lim
authors.forename: Yon Su
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea. junephro@paran.com.
authors.forename: Kwon Wook
authors.initials: KW
authors.lastname: Joo
mesh_terms: D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D004360:Drug Therapy, Computer-Assisted / Q000379:methods*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000097:blood* / Q000175:diagnosis / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D053139:Oseltamivir / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006435:Renal Dialysis / Q000379:methods*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D053139:Oseltamivir