title: Pediatric phase I drug tolerance: a review and comparison of recent adult and pediatric phase I trials.
abstract: OBJECTIVE
  We evaluated the ratio of pediatric to adult maximum tolerated doses (MTDs) from 70 Phase I studies conducted between 1975 and 1995. The aim of this study was to determine whether previously observed differences in drug tolerance between adult and pediatric Phase I patients have persisted over the 20-year period of this analysis.
  
  
  METHODS
  Phase I trials of pediatric and adult patients with solid tumors as the predominant diagnosis and sharing similar dosing regimens were evaluated. For consistent comparison between Phase I studies, the MTD was defined as the drug dose one level below that yielding dose-limiting toxicity in >30% of patients. The ratio of pediatric to adult MTDs was calculated and plotted chronologically by year of pediatric study closure. Statistical evaluation of MTD ratios included regression and correlation analysis. The extent of therapy before Phase I study entry was also examined.
  
  
  RESULTS
  Ninety-three Phase I studies were reviewed. Twenty-one drugs (70 studies) met our criteria for paired review of MTDs and analysis of the variation of ratio with time. The pediatric 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 study closure supports a linear relationship of decreasing ratio with time (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, respectively, were considered to have been heavily pretreated before study entry. A significant (p<0.001) downward trend with time was observed in the proportion of adult patients entering Phase I studies who had received both radiation and chemotherapy.
  
  
  CONCLUSIONS
  The results of this review continue to show an equal or greater drug tolerance in the pediatric population when compared with adult patients for most drugs studied during Phase I trials. However, there appears to be significant 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 tolerance 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 the MTD ratio.
authors.affiliation: Department of Pediatric Hematology, University of Texas Southwestern Medical Center, Dallas, USA.
authors.forename: L
authors.initials: L
authors.lastname: Carlson
authors.forename: P
authors.initials: P
authors.lastname: Ho
authors.forename: M
authors.initials: M
authors.lastname: Smith
authors.forename: J
authors.initials: J
authors.lastname: Reisch
authors.forename: S
authors.initials: S
authors.lastname: Weitman
mesh_terms: D000328:Adult; D000367:Age Factors; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002648:Child; D017321:Clinical Trials, Phase I as Topic; D004361:Drug Tolerance; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D012044:Regression Analysis
chemical_list: D000970:Antineoplastic Agents