Estimation and inference for a spline-enhanced population pharmacokinetic model

Lang Li, Morton B. Brown, Kyung Hoon Lee, Suneel Gupta

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

This article is motivated by an application where subjects were dosed three times with the same drug and the drug concentration profiles appeared to be the lowest after the third dose. One possible explanation is that the pharmacokinetic (PK) parameters vary over time. Therefore, we consider population PK models with time-varying PK parameters. These time-varying PK parameters are modeled by natural cubic spline functions in the ordinary differential equations. Mean parameters, variance components, and smoothing parameters are jointly estimated by maximizing the double penalized log likelihood. Mean functions and their derivatives are obtained by the numerical solution of ordinary differential equations. The interpretation of PK parameters in the model and its flexibility are discussed. The proposed methods are illustrated by application to the data that motivated this article. The model's performance is evaluated through simulation.

Original languageEnglish (US)
Pages (from-to)601-611
Number of pages11
JournalBiometrics
Volume58
Issue number3
DOIs
StatePublished - Sep 2002

Fingerprint

Pharmacokinetics
Splines
pharmacokinetics
Spline
Population
Ordinary differential equations
Time-varying
Drugs
Ordinary differential equation
drugs
Model
Variance Components
Spline Functions
Smoothing Parameter
Cubic Spline
Performance Model
Pharmaceutical Preparations
Lowest
Dose
Likelihood

Keywords

  • Double penalized log-likelihood function
  • Multicompartment models
  • Natural cubic spline
  • Runge-Kutta method

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Public Health, Environmental and Occupational Health
  • Agricultural and Biological Sciences (miscellaneous)
  • Applied Mathematics
  • Statistics and Probability

Cite this

Estimation and inference for a spline-enhanced population pharmacokinetic model. / Li, Lang; Brown, Morton B.; Lee, Kyung Hoon; Gupta, Suneel.

In: Biometrics, Vol. 58, No. 3, 09.2002, p. 601-611.

Research output: Contribution to journalArticle

Li, Lang ; Brown, Morton B. ; Lee, Kyung Hoon ; Gupta, Suneel. / Estimation and inference for a spline-enhanced population pharmacokinetic model. In: Biometrics. 2002 ; Vol. 58, No. 3. pp. 601-611.
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