UPPER LIMIT OF PLASMA ALANINE AMINO TRANSFERASE DURING PHASE-I STUDIES

In Phase I clinical studies, the maximum tolerated dose has to be dete rmined by a case by case analysis sometimes using a laboratory adverse effect, e. g. an increase in alanine amino transferase (ALT). For thi s reason a threshold to discriminate between significant or non signif icant adverse changes in ALT is required particularly in Phase I studi es, in order to deal with the very common ''close to the limit values' '. Previous methods (limit of normal range or normal range plus an arb itrary margin) do not solve this problem. The authors propose a new me thod taking into account the threshold used as inclusion criteria for ALT (R) and the range of spontaneous variations measured under identic al Phase I study conditions (V). The (R) and (V) thresholds. respectiv ely, are defined as 50 IU.l(-1) and a 50 % increase, from baseline. Th us an ALT value is recognized as a ''significant adverse experience'' if it exceeds 50 IU.l(-1) above an increase from baseline exceeding 50 % of the baseline value. To highlight the value of the method, it was implemented in a one year period including 8 studies and 134 subjects . The sensitivity, specificity and positive predictive value of variou s methods were compared. The results showed the following: Six out of 134 subjects had significant adverse changes in ALT (4 %); and all the se 6 subjects were detected by the proposed new method without error. Eight subjects including two false positives, were detected by an use of the normal range limit, and only 4 were detected using, the 10 % ma rgin. Thus, use of the new method showed 1. keeping the normal range l imit as the detection threshold led to preserved sensitivity; 2. it re duced the background noise of false positive results related to chance variation around the upper limit, mainly in subjects with a baseline Value close to the limit; 3. it allowed better judgment of the signifi cance of a value which lay just beyond the limit when variation from t he baseline exceeding the normal range. The new method produced the be st combination of sensitivity, specificity and positive predictive val ue. Given the small number of subjects in the study, further evaluatio n with a larger population is required. Finally, the proposed new meth od seems to be a tool easy to use determining the significance of adve rse changes in ALT when the values are close to the limit that is comm on in Phase I studies.