Bayesian dose-finding phase I trial design incorporating pharmacokinetic assessment in the field of oncology.

Abstract

The main purpose of a phase I dose-finding study in the field of oncology is to evaluate toxicity and pharmacokinetic (PK) data and to estimate the optimal dose (OD) for subsequent clinical trials. From a pharmacological perspective, PK information is considered as an appropriate indicator for evaluating the degree of drug intervention in humans. Dose proportionality is typically assessed to investigate the PK properties of a drug. If we rely solely on the dose-exposure relationship, then when this relationship is not proportional, eg, if there is saturation of drug elimination or absorption, the performance of OD selection may be affected. This may be because any exposure ratio between two dose levels differs from the dose ratio between the dose levels. In addition, large inter-individual variability in exposure affects the occurrence of toxicity. Therefore, incorporating PK assessment in a phase I dose-finding trial may enable us to more precisely estimate OD. In most oncology dose-finding clinical trials, however, the result of PK analysis is not explicitly incorporated in the dose-finding determination analysis. In this study, we propose a Bayesian approach to incorporating PK assessment into OD estimation in a dose-finding trial. Our proposed approach incorporates into the statistical model an adjustment based on the latest area under the time-concentration curve assessment. The simulation study shows that compared with standard methods, the proposed method may be better able to select the correct ODs across a variety of realistic settings.