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Considerations in Analyzing Single-Trough Concentrations Using Mixed-Effects Modeling

From the U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Office of Clinical Pharmacology and Biopharmaceutics, Rockville, Maryland.

The purpose of this study was to assess the effect of trial design and data analysis choices on the bias and precision of pharmacokinetic (PK) parameter estimation. NONMEM was used to simulate and analyze plasma concentrations collected according to a dense (five samples) or sparse (single-trough samples) sampling scheme for a one-compartment open model with intravenous administration. The results indicated that the bias on estimates of CL with only single-trough data was 17% compared to less than 1% for only dense data. The estimates of CL were improved by fixing all other parameters and estimating only mean and variance of CL (-11% to 1.4%, depending on the estimation method). Adding dense data led to further improvements (-2.3% to 0.3%, depending on further improvements). In these cases, first-order conditional estimation (FOCE) methods resulted in better estimates of CL than first-order (FO) methods. These steps also improved the Bayesian estimates of CL. These studies support the following recommendations: (1) avoid collecting single-trough concentrations unless there is reasonable knowledge about the PK of the drug; (2) if collecting single-trough concentrations is inevitable, avoid estimating all parameters when modeling single-trough concentration data; (3) use prior information by modeling the single-trough concentration data along with dense data from other studies; and (4) use Bayes estimates if the PK model and its parameters are known with reasonable certainty.

Key Words: Population pharmacokinetics • bias • trough concentrations • Bayesian estimates

Address for reprints: Brian P. Booth, PhD, Center for Drug Evaluation and Research, Office of Clinical Pharmacology and Biopharmaceutics, Division of Pharmaceutical Evaluation I, HFD-860, WOC II, 5600 Fishers Lane, Rockville, MD 20857.

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