title: Incorporation of concentration data below the limit of quantification in population pharmacokinetic analyses.
abstract: Handling of data below the lower limit of quantification (LLOQ), below the limit of quantification (BLOQ) in population pharmacokinetic (PopPK) analyses is important for reducing bias and imprecision in parameter estimation. We aimed to evaluate whether using the concentration data below the LLOQ has superior performance over several established methods. The performance of this approach ("All data") was evaluated and compared to other methods: "Discard," "LLOQ/2," and "LIKE" (likelihood-based). An analytical and residual error model was constructed on the basis of in-house analytical method validations and analyses from literature, with additional included variability to account for model misspecification. Simulation analyses were performed for various levels of BLOQ, several structural PopPK models, and additional influences. Performance was evaluated by relative root mean squared error (RMSE), and run success for the various BLOQ approaches. Performance was also evaluated for a real PopPK data set. For all PopPK models and levels of censoring, RMSE values were lowest using "All data." Performance of the "LIKE" method was better than the "LLOQ/2" or "Discard" method. Differences between all methods were small at the lowest level of BLOQ censoring. "LIKE" method resulted in low successful minimization (<50%) and covariance step success (<30%), although estimates were obtained in most runs (∼90%). For the real PK data set (7.4% BLOQ), similar parameter estimates were obtained using all methods. Incorporation of BLOQ concentrations showed superior performance in terms of bias and precision over established BLOQ methods, and shown to be feasible in a real PopPK analysis.
authors.affiliation: Department of Bioengineering & Therapeutic Sciences, University of California San Francisco Box 2911, San Francisco, California, 94143 ; Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
authors.forename: Ron J
authors.initials: RJ
authors.lastname: Keizer
authors.affiliation: Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Jansen
authors.affiliation: Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
authors.forename: Hilde
authors.initials: H
authors.lastname: Rosing
authors.affiliation: Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: Thijssen
authors.affiliation: Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute Louwesweg 6, 1066 EC, Amsterdam, The Netherlands ; Division of Drug Toxicology, Section of Biomedical Analysis, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University Utrecht, The Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Division of Drug Toxicology, Section of Biomedical Analysis, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University Utrecht, The Netherlands ; Division of Clinical Pharmacology, Department of Medical Oncology, Antoni van Leeuwenhoek, Hospital/the Netherlands Cancer Institute Amsterdam, The Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
keywords: BLOQ; Bioanalysis; limit of quantification; pharmacometrics; population pharmacokinetics