Journal of Pharmacokinetics and Biopharmaceutics, Vol. 20, No. 5, 1992

PHARMACOMETRICS

Smooth Nonparametric Maximum Likelihood
Estimation for Population Pharmacokinetics, with
Application to Quinidine

Marie Davidian and A. Ronald Gallant

Received May 12, 1992--Final September 24, 1992

The seminonparametric (SNP) method, popular in the econometrics literature, is proposed for use in population pharmacokinetic analysis. For data that can be described by the nonlinear mixed effects model, the method produces smooth nonparametric estimates of the entire random effects density and simultaneous estimates of fixed effects by maximum likelihood. A graphical model-building strategy based on the SNP method is described. The methods are illustrated by a population analysis of plasma levels in 136 patients undergoing oral quinidine therapy.

KEY WORDS: population pharmacokinetics; nonlinear mixed effects models; density estimation; nonparametric estimation; maximum likelihood; quinidine.