Profile Likelihood-Based Confidence Intervals Using Monte Carlo Integration for Population Pharmacokinetic Parameters

ABSTRACT

Population pharmacokinetic (PPK) analysis usually employs nonlinear mixed effects models using first-order linearization methods. It is well known that linearization methods do not always perform well in actual situations. To avoid linearization, the Monte Carlo integration method has been proposed. Moreover, we generally utilize asymptotic confidence intervals for PPK parameters based on Fisher information. It is known that likelihood-based confidence intervals are more accurate than those from the usual asymptotic confidence intervals. We propose profile likelihood-based confidence intervals using Monte Carlo integration. We have evaluated the performance of the proposed method through a simulation study, and analyzed the erythropoietin concentration data set by the method.

Keywords:

• Confidence interval
• Monte Carlo integration
• Nonlinear mixed effects model
• Population pharmacokinetics
• Profile likelihood

ACKNOWLEDGMENTS

We would like to thank the editor and the anonymous referees for their valuable comments, which have greatly improved the manuscript, and Dr. Langman for correcting the English.

Notes

∗The proportion of simulated data that each method satisfies the convergence criterion.

^†The proportion that the true values are included in the 95% confidence intervals.