Clinical pharmacological approaches to optimize anticancer drug dosing

Abstract

The treatment of cancer is increasingly personalized, with dose optimization being an important factor. In this thesis, a number of factors is studied to determine how these factors can be used to optimize the dose. First, the effect of drugs inhibiting or inducing the enzyme CYP3A is considered, when combined with anticancer drugs. The reason for this is that anticancer drugs are often broken down by the CYP3A enzyme. We give recommendations how to deal with drug-drug interactions for these two types of drugs in case the information available from scientific studies is insufficient. Second, in previous studies it was shown that patients with a low muscle mass experience more side effects of chemotherapy and live shorter. We studied whether this relationship could be explained by an altered distribution of drugs in the body in patients with a low muscle mass. This was indeed found to be the case for some of the drugs. However, the relationship was not strong enough to use muscle mass to adjust the dose. Lastly, we show that drug concentrations can be measured in tumor and in saliva. Concentrations at the site of action can potentially be used to predict whether a drug will be effective or cause side effects. The dosage could be adjusted accordingly.