PEDIATRIC PHASE-I DRUG TOLERANCE - A REVIEW AND COMPARISON OF RECENT ADULT AND PEDIATRIC PHASE-I TRIALS

Purpose: We evaluated the ratio of pediatric to adult maximum tolerate d doses (MTDs) from 70 Phase I studies conducted between 1975 and 1995 . The aim of this study was to determine whether previously observed d ifferences in drug tolerance between adult and pediatric Phase I patie nts have persisted over the 20-year period of this analysis. Patients and Methods: Phase I trials of pediatric and adult patients with solid tumors as the predominant diagnosis and sharing similar dosing regime ns were evaluated. For consistent comparison between Phase I studies, the MTD was defined as the drug dose one level below that yielding dos e-limiting toxicity in >30% of patients. The ratio of pediatric to adu lt MTDs was calculated and plotted chronologically by year of pediatri c study closure. Statistical evaluation of MTD ratios included regress ion and correlation analysis. The extent of therapy before Phase I stu dy entry was also examined. Results: Ninety-three Phase I studies were reviewed. Twenty-one drugs (70 studies) met our criteria for paired r eview of MTDs and analysis of the variation of ratio with time. The pe diatric to adult MTD ratios ranged from 0.4 to 2.8, with a median of 1 .2. Regression analysis of the ratio of MTD versus date of pediatric s tudy closure supports a linear relationship of decreasing ratio with t ime (p<0.01). Analysis of the regression line predicts MTD ratios of 2 .02 and 0.76 for 1974 and 1995, respectively. Of patients included in this analysis, 37.1% and 68.6% of adult and pediatric patients, respec tively, were considered to have been heavily pretreated before study e ntry. A significant (p<0.001) downward trend with time was observed in the proportion of adult patients entering Phase I studies who had rec eived both radiation and chemotherapy. Conclusions: The results of thi s review continue to show an equal or greater drug tolerance in the pe diatric population when compared with adult patients for most drugs st udied during Phase I trials. However, there appears to be a significan t trend of decreasing differences in drug tolerance between pediatric and adult Phase I patients with time, as defined by the descent of the MTD ratio toward values <1.0. Mechanisms to explain greater drug tole rance in children and the observation of decreasing maximum tolerated dose ratios with time are discussed. Limited data suggest that changes in degree of therapy before Phase I study entry may be influencing th e MTD ratio.