on behalf of the International Transporter ConsortiumDrug transporters can govern the absorption, distribution, metabolism, and excretion of substrate drugs and endogenous substances. Investigations to examine their potential impact to pharmacokinetic (PK) drug-drug interactions (DDIs) are an integral part of the risk assessment in drug development. To evaluate a new molecular entity as a potential perpetrator of transporters, use of well characterized and/or clinically relevant probe substrates with good selectivity and sensitivity are critical for robust clinical DDI assessment that could inform DDI management strategy in the product labeling. The availability of endogenous biomarkers to monitor transportermediated DDIs in early phases of clinical investigations would greatly benefit downstream clinical plans. This article reviews the state-of-the-art in transporter clinical probe drugs and emerging biomarkers, including current challenges and limitations, delineates methods and workflows to identify and validate novel endogenous biomarkers to support clinical DDI evaluations, and proposes how these probe drugs or biomarkers could be used in drug development.Drug transporters can modulate the absorption, distribution, metabolism, and excretion (ADME) of substrate drugs and endogenous substances, ultimately determining their exposure in systemic circulation and tissues. 1 Transporter substrate or modulator (inhibitor or inducer) drugs can become clinical victims or perpetrators of drug-drug interactions (DDIs), respectively, when the transporter in question is a substantial contributor to the pharmacokinetics (PK) of the victim drug and can be inhibited or induced in the clinical setting. For example, lapatinib, a P-glycoprotein (P-gp) inhibitor, increased digoxin exposure by 2.8-fold (TYKERB labeling at Drugs@FDA), whereas tipranavir/ ritonavir, a P-gp inducer, decreased saquinavir/ritonavir exposure by 76% (APTIVUS labeling at Drugs@FDA). Understanding DDIs is an integral part of risk assessment in drug development considering the common practice of concomitant use of multiple medications. 1-3

Background: Rivaroxaban is an oral Factor Xa inhibitor. The primary objective of this communication was to quantitatively predict changes in rivaroxaban exposure when individuals with varying degrees of renal impairment are co-administered with another drug that is both a P-gp and a moderate CYP3A4 inhibitor. Methods: A physiologically based pharmacokinetic (PBPK) model was developed to simulate rivaroxaban pharmacokinetics in young (20-45 years) or older (55-65 years) subjects with normal renal function, mild, moderate and severe renal impairment, with or without concomitant use of the combined P-gp and moderate CYP3A4 inhibitor, erythromycin. Results: The simulations indicate that combined factors (i.e., renal impairment and the use of erythromycin) have a greater impact on rivaroxaban exposure than expected when the impact of these factors are considered individually. Compared with normal young subjects taking rivaroxaban, concurrent mild, moderate or severe renal impairment plus erythromycin resulted in 1.9-, 2.4-or 2.6-fold increase in exposure, respectively in young subjects; and 2.5-, 2.9-or 3.0-fold increase in exposure in older subjects. Conclusions: These simulations suggest that a drug-drug-disease interaction is possible, which may significantly increase rivaroxaban exposure and increase bleeding risk. These simulations render more mechanistic insights as to the possible outcomes and allow one to reach a decision to add cautionary language to the approved product labeling for rivaroxaban. Copyright © 2012 John Wiley & Sons, Ltd.

Recently, increased interest in drug transporters and research in this area has revealed that drug transporters play an important role in modulating drug absorption, distribution, and elimination. Acting alone or in concert with drug metabolizing enzymes they can affect the pharmacokinetics and pharmacodynamics of a drug. This commentary will focus on the potential role that drug transporters may play in drug-drug interactions and what information may be needed during drug development and new drug application (NDA) submissions to address potential drug interactions mediated by transporters.