Potential roles for preclinical pharmacology in phase I clinical trials.

TLDR

Preclinical pharmacology has shaped anticancer drug use, yet most animal data become available only after clinical trials, limiting opportunities to compare human pharmacokinetics with mouse data during phase I dose‑escalation studies. The study aims to develop strategies that adjust dose‑escalation rates using pharmacokinetic data from mice and humans. Current phase I trials use a universal modified Fibonacci escalation scheme applied to all drugs without pharmacology‑based adjustments, which the authors propose to modify based on PK determinations. Because the starting dose often lies far from the maximum tolerated dose, patients receive subtherapeutic doses and resources are stretched, but retrospective analyses suggest that 20–50 % fewer dose escalations could be achieved.

Abstract

Concepts elucidated from preclinical pharmacology studies have made a substantial impact on the clinical use of anticancer drugs. However, the majority of animal pharmacology results have not been available until after drugs have entered clinical trials. Since clinical pharmacokinetic measurements are already part of many phase I trials, human data could be directly compared with mouse data if mouse pharmacology studies were completed before clinical trials were initiated. Once the starting dose in a phase I clinical trial has been evaluated, subsequent doses are escalated until the maximum tolerated dose is reached. The rate of escalation is empirically defined by a modified Fibonacci series. This universal escalation scheme is applied to all drugs, with no modifications based upon pharmacology or other factors. If the starting dose is far removed from the maximum tolerated dose, a large number of dose escalations are required. Consequently, most patients receive subtherapeutic doses, and the amount of resources allocated to each drug increases. We are exploring potential strategies for controlling the rate of dose escalation based upon pharmacokinetic determinations in mouse and man. Retrospective analyses indicate that 20%-50% savings in the total number of dose escalations are possible.