RESUMEN
10% of young male healthy volunteers have a total bilirubin value over 20 mumol/l; thus such a value appears not relevant as screening cut off point in clinical pharmacology. This study was intended to confirm if a 27 mumol/l cut off point previously defined by the authors does not support a risk. This study dealt with 487 subjects who had together measurements of total bilirubin value and lab. tests of liver cytolysis, cholestasis or hemolysis during the selection process. 48 subjects (9.8%) had a total bilirubin value over 20 mumol/l. Correlation tests do not provide arguments of cytolysis, cholestasis or hemolysis and there was no argument in favor of Gilbert's syndrome. Out of 48 hyperbilirubinemic subjects only 22 were included in clinical pharmacology studies. In more than 60%, the total bilirubin value returned to normal spontaneously and in no case appeared a significant clinical, biological, pharmacokinetic or dynamic abnormality. Except a possible increase of slow acetylor frequency, the medical literature analysis does not show any relevant modification in metabolism, pharmacokinetics or pharmacodynamics until a 40 mumol/l value of total bilirubin. Thus, the 27 mumol/l value of total bilirubin previously proposed is confirmed as a useful limit that does not lead to an additional risk.
Asunto(s)
Bilirrubina/análisis , Ensayos Clínicos Fase I como Asunto , Voluntarios , Adulto , Humanos , MasculinoRESUMEN
All the clinical, laboratory and electrocardiographic adverse events detected during 24 Phase I studies in the same unit over a 5 y period are reported here. 430 healthy male volunteers were involved, corresponding to 5488 days of follow-up. The overall incidence of adverse events was 13.5%, with a significant difference between active drug (15.3%) and placebo (7.4%) treatments. There were 69 distinct types of adverse events. Headache was the most frequent symptom (2%). There were severe adverse events in 20 cases (0.36%), with an incidence of 20/430 per subject (4.6%). There were no deaths or life-threatening events. Although the main objective of Phase I studies is to determine the maximum dose tolerated, cause-effect relationships with adverse events are hard to establish, because of the frequency of adverse events with placebo, and because of the limited number of subjects included such studies.