Understanding individual drug response variation: Pharmacokinetic analysis of diabetes trials

Kidney disease is an ever-increasing problem worldwide in patients with diabetes. Diabetic kidney disease is associated with a high risk to end in chronic dialysis, transplantation or death. Early detection of patients with type 2 diabetes at risk for progression of kidney complications combined with effective individualized therapies are key steps to slow or even reverse disease progression. Many clinical trials have been initiated over the past decades to evaluate new drugs to decrease the residual risk in patients with diabetic kidney disease. However, they still targeted the same drug at the same dose to a large population without taking into account how individual patients responded. Drug response variability can be a result of many factors. Previous studies have focused on individual's unique characteristics. However, there remains a dearth of knowledge on which specific patient characteristics predict the individual’s response to a drug. From a clinical pharmacological perspective, studying the exposure of an individual to a drug and associating the exposure to the pharmacodynamic response may provide further insight in underlying factors involved in the variability between individuals in drug response. The overarching aim of this thesis was to determine to what extent the between-patient variability in drug exposure explains and contributes to the between-patient variability in pharmacodynamic drug response.