Linear mixed-effect multivariate adaptive regression splines applied to nonlinear pharmacokinetics data.
In a frequently performed pharmacokinetics study, different subjects are given different doses of a drug. After each dose is given, drug concentrations are observed according to the same sampling design. The goal of the experiment is to obtain a representation for the pharmacokinetics of the drug, and to determine if drug concentrations observed at different times after a dose are linear in respect to dose. The goal of this paper is to obtain a representation for concentration as a function of time and dose, which (a) makes no assumptions on the underlying pharmacokinetics of the drug; (b) takes into account the repeated measure structure of the data; and (c) detects nonlinearities in respect to dose. To address (a) we use a multivariate adaptive regression splines representation (MARS), which we recast into a linear mixed-effects model, addressing (b). To detect nonlinearity we describe a general algorithm that obtains nested (mixed-effect) MARS representations. In the pharmacokinetics application, the algorithm obtains representations containing time, and time and dose, respectively, with the property that the bases functions of the first representation are a subset of the second. Standard statistical model selection criteria are used to select representations linear or nonlinear in respect to dose. The method can be applied to a variety of pharmacokinetics (and pharmacodynamic) preclinical and phase I-III trials. Examples of applications of the methodology to real and simulated data are reported.
Gries
J M
JM
Department of Biopharmaceutical Sciences, School of Pharmacy, University of California-San Francisco, 94143, USA.
Verotta
D
D
D000465:Algorithms; D000818:Animals; D003198:Computer Simulation; D008012:Lidocaine / Q000493:pharmacokinetics; D008614:Meperidine / Q000493:pharmacokinetics; D015999:Multivariate Analysis; D017711:Nonlinear Dynamics; D010599:Pharmacokinetics; D012044:Regression Analysis; D012756:Sheep
D008012:Lidocaine; D008614:Meperidine