Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies: experience and recommendations

B73 Phase I clinical trials of novel anticancer agents are increasingly important extensions of the preclinical drug development process, and offer exciting opportunities for measuring parameters such as molecular target expression, pharmacokinetic (PK) behavior, and pharmacodynamic (PD) endpoints. Such endpoints are essential in both the preclinical and clinical stages of drug development, and can be linked to measures of clinical effect. However, the development and implementation of PK/PD endpoints can be challenging due to the need for sensitive, specific and reproducible assays. Logistical and ethical considerations also need to be taken into account when incorporating these possibly invasive studies into early stage trial design. The disappointingly low utilization of PK/PD endpoints in phase I clinical trials can probably be explained by the many challenges inherent in their development and implementation. The use of less invasive methodologies therefore has many advantages. Here we present the experience and recommendations in this area of the Pharmacodynamic/ Pharmacokinetic Technologies Advisory Committee of Cancer Research UK. We have found that submissions for phase I trials of new cancer drugs in the United Kingdom have frequently lacked detailed information about PK and/or PD endpoints, which leads to suboptimal information being obtained in those trials or to delays in starting the trials while PK/PD methods are developed and validated. The development of a new generation of molecular therapeutics offers opportunities to measure specific molecular target effects by examining PK/PD endpoints. This approach is certainly desirable, however it may not be the most valuable use of resource, since methods would need to be developed individually for each class of agent. Rather, it may be preferable to focus on the development of generic assays that measure biological processes affected by different drug classes, e.g. apoptosis, angiogenesis, proliferation, metastasis and invasion. We have reviewed the value of minimally invasive PK/PD technologies in early stage clinical trials, updating our recent review of the area (Workman et al, JNCI 98: 580-598, 2006) with emphasis on magnetic resonance spectroscopy and positron emission tomography. We highlight the need for more extensive use of PK/PD endpoints in preclinical and clinical anticancer drug development, and encourage the timely development, validation, and application of minimally invasive PK/PD methods. We will illustrate our experience with up-to-date examples and summarize our recommendations for the role of imaging technologies in early clinical trials.