title: The bayesian bias correction method of the first-order approximation of nonlinear mixed-effects models for population pharmacokinetics.
abstract: Population pharmacokinetic analysis usually employs nonlinear mixed-effects models. To estimate the parameters, Beal and Sheiner (1982) proposed the first-order method that employs a first-order Taylor series expansion around the means of random individual parameters. Because of the small computational burden and the high convergence proportion of maximization of the log likelihood function, this method is often used in practice. However, it is known that the estimates are biased. This paper proposes a simple procedure to reduce the bias. The proposed method maximizes the nonapproximated log likelihood functions of each individual given estimates of the population parameters derived from the first-order method, and the derived Bayes estimates of the random individual parameters are utilized to improve the estimates of the population mean parameters. We confirmed that the proposed method reduced the bias using simulated data and actual erythropoietin concentration data.
authors.affiliation: Biometrics Department, Chugai Clinical Research Center Co., Ltd.. Tokyo. Japan. funatogawatks@chugai-pharm.co.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Funatogawa
authors.forename: Ikuko
authors.initials: I
authors.lastname: Funatogawa
mesh_terms: D001499:Bayes Theorem; D015982:Bias; D002986:Clinical Trials as Topic / Q000379:methods / Q000706:statistics & numerical data*; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D004921:Erythropoietin / Q000493:pharmacokinetics; D006397:Hematinics / Q000493:pharmacokinetics; D006801:Humans; D016013:Likelihood Functions; D008954:Models, Biological; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D010599:Pharmacokinetics; D011159:Population Surveillance; D011994:Recombinant Proteins; D012107:Research Design
chemical_list: D006397:Hematinics; D011994:Recombinant Proteins; D004921:Erythropoietin