Keywords: dose escalation, PK, model based analysis, Bayesian
The objective of phase 1 clinical trials is to obtain the information on safety, tolerability and pharmacokinetics (PK) of the drug candidate and determine the maximum tolerated dose (MTD). Nowadays, dose escalation process is often guided by modeling dose-toxicity relationship. PK data is usually analyzed separately and used in subjective manner during the dose escalation process to aid the decision making process. Attempt to formally incorporate PK data in determining the next dose during the dose escalation process is rarely made and not many tools are publicly available to facilitate this process. Combining dose finding and PK analysis would make decision making process more efficient, increase the precision of next recommended dose and lead to better estimation of dose toxicity curve in general. Several methods of incorporating of PK data into dose-toxicity modeling were proposed in a single agent setting. (Ursino et.al. 2017,Toumazi et.al.) Bayesian design for the dual-agent setting incorporating PK data and historical data from single agents was also proposed. (Cotterill et.al. 2015) The quality of such designs tends to be evaluated via simulation and practical implementations as a clinical study are rare. The discussion on methodology and details of implementation of such designs would help disseminating the idea among clinical statisticians; sharing experience on applicability and usefulness of these model based approaches might lead to wider design acceptance in practice.