Diagnostics for confounding in PK/PD models for oxcarbazepine

Statistics in Medicine
Jerry R NedelmanL B Sheiner

Abstract

One type of pharmacokinetic/pharmacodynamic (PK/PD) relationship that is used to characterize the therapeutic action of a drug is the relationship between some univariate summary of the plasma-concentration-versus-time profile and the drug effect on a response outcome. Operationally, such a relationship may be observed in a large clinical trial where randomly sampled patients are randomized to different values of the concentration summary. If, under such conditions, the relationship between concentration and effect does not depend on the dose needed to attain the target concentration, such a relationship will be called a true PK/PD relationship. When the true PK/PD relationship is assessed as an object of estimation in a dose-controlled clinical trial (i.e. when dose is randomized), observed drug concentration is an outcome variable. The estimated PK/PD relationship between observed outcome and observed concentration, which we then refer to as the conventional PK/PD relationship, may be biased for the true PK/PD relationship. Because of this bias, the conventional relationship is called confounded for the true one. We show that diagnostics for confounding can be devised under reasonable assumptions. We then apply these diagnost...Continue Reading

References

Sep 11, 2003·Clinical Pharmacology and Therapeutics·Holger KraicziCarl C Peck
May 23, 2007·Clinical Drug Investigation·Gérard Flesch

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Citations

May 13, 2015·Proceedings of the National Academy of Sciences of the United States of America·Tuan Q Phan, Edoardo M Airoldi
Apr 12, 2014·British Journal of Clinical Pharmacology·Lisa V HampsonAnne Whitehead
Sep 10, 2016·Journal of Biopharmaceutical Statistics·Donald B Rubin
Jan 20, 2019·CPT: Pharmacometrics & Systems Pharmacology·Aksana K JonesKevin J Freise
Mar 16, 2012·Journal of Biopharmaceutical Statistics·Jixian Wang
Feb 14, 2020·Statistical Methods in Medical Research·Ian WadsworthThomas Jaki
Aug 11, 2018·Frontiers in Pharmacology·Zhixin LeiQigai He
Jun 30, 2021·Journal of Clinical Pharmacology·Efthymios ManolisKristin E Karlsson

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