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. 2015 Jul 24;4(8):454–464. doi: 10.1002/psp4.12007

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© 2015 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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Interoccasion variability (κ, kappa) vs. time of administration of midazolam for oral bioavailability (F) (a,d), absorption rate constant (Ka) (b,e), and clearance (CL) (c,f). Left column represents IOV (κ) vs. time plots of the simple model in which no cosine function was incorporated (a–c) and right column represents IOV (κ) vs. time plots of the models after implementation of a cosine function for oral bioavailability (d), a multiplication factor at the 14:00 hour administration time for absorption rate constant (e) and a cosine function for clearance (f). The k values used in these IOV plots are empirical Bayes estimates (EBEs) of the interoccasional random effect (NONMEM ETA) in the parameter involved (oral bioavailability, absorption rate constant, or clearance).