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Assessing goodness-of-fit for evaluation of dose-proportionality |
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| Authors: | Martin J. Wolfsegger Alexander Bauer Detlew Labes Helmut Schütz Richardus Vonk Benjamin Lang Stephan Lehr Thomas F. Jaki Werner Engl Michael D. Hale |
| Affiliation: | 1. Baxalta Innovations GmbH, a Takeda company, Vienna, Austria;2. Consultant, Berlin, Germany;3. BEBAC – Consultancy Services for Bioequivalence and Bioavailability Studies, Vienna, Austria;4. Bayer AG, Berlin, Germany;5. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany;6. Austrian Medicines and Medical Devices Agency, Wien, Austria;7. Department of Mathematics and Statistics, Lancaster University, Lancaster, UK;8. Shire, a Takeda company, Lexington, Massachusetts, USA |
| Abstract: | For the clinical development of a new drug, the determination of dose-proportionality is an essential part of the pharmacokinetic evaluations, which may provide early indications of non-linear pharmacokinetics and may help to identify sub-populations with divergent clearances. Prior to making any conclusions regarding dose-proportionality, the goodness-of-fit of the model must be assessed to evaluate the model performance. We propose the use of simulation-based visual predictive checks to improve the validity of dose-proportionality conclusions for complex designs. We provide an illustrative example and include a table to facilitate review by regulatory authorities. |
| Keywords: | dose-proportionality linear pharmacokinetics visual predictive checks |