Abstract
Renal dysfunction and drug-drug interactions (DDIs) can affect the clearance of various drugs from the body; however, these effects are difficult to sufficiently evaluate in clinical studies. This article outlines our recent approaches to improve the method of evaluating and providing the drug information on the effects of renal dysfunction and DDIs. These approaches aim to optimize the drug regimens of patients with renal dysfunction and to improve the management of DDIs. The renal excretion ratio (RR) is required to predict alterations in drug clearance in patients with renal dysfunction. However, the estimation of RR requires pharmacokinetic information that is not always provided in the Japanese drug package inserts or interview forms.
A systematic approach to predict changes in drug clearance due to DDIs of the cytochrome p450 (CYP) is described. Uniquely, this method uses a small number of parameters, which are only obtained by in vivo DDI studies, i.e., the contribution ratio of CYPs to oral clearance of substrates (CR), the inhibition ratio of inhibitors (IR) or the increase in clearance by induction (IC). Changes in oral clearance for any combination of drugs can be predicted once these parameters have been calculated for each drug. These predictions were used to construct a pharmacokinetic interaction significance classification system (PISCS) to evaluate the clinical risk of DDIs in daily therapy.
