Use of Pharmacokinetics and Pharmacodynamics in Preclinical Studies to Guide Dosage Escalation Schemes in Phase I Studies of Anticancer Drugs

Abstract

For the concept of pharmacologically-guided clinical trials with new anticancer drugs, the principal focus has been development of links between preclinical testing and Phase I clinical trials. Recent experiences with very lengthy Phase I trials for at least 8 drugs have provided particular impetus for the project. The specific concept was that dose-limiting toxicity is predicted by drug concentrations in plasma, and that the quantitative relationship between drug exposure (as measured by plasma drug concentration times time, or CxT) and toxicity holds across species. As a consequence, dose escalations in man could safely be based on measurements of drug levels in plasma, rather than on empirical escalation schemes. Although the concept is still relatively new, practical results have already been achieved. Examples will be given of Phase I trials which were completed with a savings of 12–24 months. Overall, there is now a substantial collection of data which demonstrates that coordination with preclinical pharmacology and toxicology studies can save both time and resources in early clinical trials without a loss of safety.