title: Practical recommendations for population PK studies with sampling time errors.
abstract: OBJECTIVE
  Population pharmacokinetic (PK) data collected from routine clinical practice offers a rich source of valuable information. However, in observational population PK data, accurate time information for blood samples is often missing, resulting in measurement errors (ME) in the sampling time variable. The goal of this study was to investigate the effects on model parameters when a scheduled time is used instead of the actual blood sampling time, and to propose ME correction methods.
  
  
  METHODS
  Simulation studies were conducted based on two major factors: the curvature in PK profiles and the size of ME. As ME correction methods, transform both sides (TBS) models were developed with application of Box-Cox power transformation and Taylor expansion. The TBS models were compared to a conventional population PK model using simulations.
  
  
  RESULTS
  The most important determinant of bias due to time ME was the degree of curvature (nonlinearity) in PK profiles; the smaller the curvature around sampling times, the smaller the associated bias. The second important determinant was the magnitude of ME; the larger the ME, the larger the bias. The proposed TBS models performed better than a conventional population PK modeling when curvature and ME were substantial.
  
  
  CONCLUSIONS
  Time ME in sampling time can lead to bias on the parameter estimators. The following practical recommendations are provided: 1) when the curvature of PK profiles is small, conventional population PK modeling is robust to even large ME; and 2) when the curvature is moderate or large, the proposed methodology reduces bias in parameter estimates.
authors: Department of Biostatistics, School of Medicine, Vanderbilt University, 1161 21st Avenue South, Medical Center North, S-2323, Nashville, TN, 37232, USA, leena.choi@vanderbilt.edu.
authors: Leena
authors: L
authors: Choi
authors: Ciprian M
authors: CM
authors: Crainiceanu
authors: Brian S
authors: BS
authors: Caffo
mesh_terms: D006801:Humans; D008954:Models, Biological; D010599:Pharmacokinetics; D012107:Research Design; D013997:Time Factors
references: Biometrics. 2004 Jun;60(2):451-60
references: 15180671
references: Biostatistics. 2003 Apr;4(2):297-312
references: 12925523
references: Biometrics. 2000 Jun;56(2):368-75
references: 10877291
references: Biometrics. 2004 Mar;60(1):1-7
references: 15032767
references: Eur J Clin Pharmacol. 2013 Jan;69(1):53-63
references: 22660440
references: Clin Pharmacol Ther. 2010 Jun;87(6):727-34
references: 20410877
references: Clin Pharmacol Ther. 2006 Oct;80(4):331-45
references: 17015051
references: Biometrics. 2007 Jun;63(2):342-50
references: 17688487