Critical limits to define a lab adverse event during phase I studies: a study in 1134 subjects

European Journal of Clinical Pharmacology
Michel SibilleD Vital Durand

Abstract

The first goal of phase I drug development is the determination of maximal tolerated dose, which must be established by case-by-case analysis, sometimes using a laboratory adverse event. Since no accurate rule defining lab adverse events, has been validated yet, we propose a new "combined method" based on combination of two thresholds: inclusion values and magnitude of variation. Using this combined method, the label "lab adverse event" is applied if any lab value exceeds the inclusion threshold and is associated with a variation from baseline exceeding the variation threshold defined from reference change limit. Thus, this study aimed to test this combined method on a large healthy volunteer population, studied in 19 phase I centres worldwide, and on five lab parameters: alanine amino transferase, aspartate amino transferase, alkaline phosphatases, creatinine and polymorphonuclear leukocytes. The inclusion threshold from each center was used. Reference change limits were defined from volunteers previously included in comparable studies and were expressed as absolute values: increases of 10 IU.l-1 for alanine amino transferase or aspartate amino transferase, 15 IU.l-1 for alkaline phosphatases, 15 mumol.l-1 for creatinine and a...Continue Reading

Citations

May 9, 2014·The International Journal of Psycho-analysis·Edmundo Gómez Mango
Jun 26, 2014·The International Journal of Psycho-analysis·Catalina Bronstein
Jan 9, 2017·European Journal of Clinical Pharmacology·Kerstin Breithaupt-GroeglerGeorg Wensing
May 20, 2003·Journal of Clinical Pharmacology·Camilla BuöenMikael S Thomsen

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