Role of Transporters in Drug Development

Transporters are membrane-bound proteins that play a key role in the absorption, distribution, metabolism (by altering the access of drugs to metabolizing enzymes), and excretion of drugs.1-3 In 2010 and 2013 a International Transporter Consortium (ITC) published articles to underscore the scientific rationale for evaluating the most clinically important drug transporters, various in vitro assays that may be appropriate for evaluating the potential for drug-drug interactions (DDIs), and what "cutoff" criteria may be used to determine if follow-up clinical DDI studies are needed.4, 5 Evaluating the role of transporters in mediating DDIs and altering the efficacy and safety profile of drugs has also been of regulatory interest.6 The results of a survey of prescribing information ("labels") of 183 new molecular entities (NMEs) approved between 2003 and 2011 suggested that the incorporation of transporter-related information increased from 24% in 2003–2006 to 56% in 2007–2011.7 The authors attributed this increased incorporation of transporter-related information to various factors such as advances in transporter research and evaluation and the 2006 FDA draft guidance on evaluation of DDIs, which recommended evaluation of transporter-based DDIs as part of overall DDI evaluation. The 2012 FDA draft Guidance for Industry: Drug Interaction Studies—Study, Design, Data Analysis, Implications for Dosing, and Labeling Recommendations, the FDA website on drug-drug interactions, and guidance documents from other regulatory agencies such as the European Medicines Agency and Pharmaceutical Medical Devices Agency (PMDA) have provided a regulatory framework on the need and timing of the assessment of the most clinically relevant transporters.8-10 In some instances a evaluation of transporter-mediated DDIs has continued beyond regulatory approval. Fan et al summarize the content and status of transporter-related postmarketing requirement/postmarketing commitment studies in new drug applications (NDAs) and discuss the various reasons for requesting such studies.11 Further, these authors discuss the impact of postmarketing requirement/postmarketing commitment study results on labeling to guide the optimal use of drugs. The authors conclude that the results from transporter-related postmarketing requirement/postmarketing commitment studies are important for dose optimization and have been used to revise drug product labeling. The involvement of hepatic drug transporters in influencing the movement of drugs across the hepatocyte and modulating the access of drug to metabolizing enzymes is also being increasingly recognized.12, 13 Liu and Sahi14 and Patel et al15 provide a comprehensive summary of the role of hepatic drug transporters in the disposition of drugs and their metabolites and the application of different in vitro experimental systems used to investigate the relative contributions of various transporters to overall hepatic uptake. One of the most widely evaluated families of hepatic uptake transporters is the organic anion transport polypeptides (OATPs).16, 17 In addition to the transport of exogenously administered drugs, OATP transporters also play a critical role in transport of endogenous compounds such as bile acids, conjugated steroids, and thyroid hormones. Considering the important role played by OATP transporters, regulatory agencies recommend evaluating the potential of a drug to be a substrate of OATP transporters and to assess whether a drug has the potential to inhibit OATP transporters in vivo. Vaidyanathan and colleagues describe a comparison of the prediction performance of various "cutoff" criteria (based on in vitro data and pharmacokinetic properties of the drug) recommended by different regulatory agencies to assess the potential of a drug to inhibit OATP transporters in vivo.18 A critical evaluation of the strength and limitation of each prediction criterion may support efforts toward development of a harmonized decision criterion and facilitate global drug development. The effect of variability in transporter expression on drug response and in vitro–to–in vivo extrapolations has recently gained widespread attention.19-21 The impact of variability in the expression levels of OATP, a genetically polymorphic hepatic transporter, on response to therapy by HMG-CoA reductase inhibitors ("statins") in particular and on the hepatic drug uptake in general, has been well documented in the literature.22-24 Interestingly, Sugiyama and colleagues have shown that, in addition to differences in allelic frequencies of OATP transporters, intrinsic ethnic variability in the activity of OATP1B1 should also be considered to fully understand the ethnic variability in the plasma exposure of statins.25 McLean et al provide an assessment of potential impact of known polymorphisms in drug transporters and discuss if there is sufficient evidence to incorporate these polymorphisms in the drug development process.26 Using rosuvastatin (a substrate of OATP transporters) as an example, Riedmaier et al discuss the utility of a physiologically based pharmacokinetic (PBPK) approach in conjunction with a power calculation algorithm to evaluate the required sample size to detect the effects of OATP1B1 polymorphisms.27 Various disease states can alter the expression and activity of drug transporters.28 The increased levels of proinflammatory cytokines in disease states can affect drug response by modulating the expression and activity of drug transporters.29 Atilano-Roque et al discuss the effect of disease pathologies on transporter expression and function.30 The authors focus on various uptake and efflux transporter proteins in liver, kidney, and brain and discuss mechanisms of altered transporter expression and function secondary to disease. The authors also underscore the development and implementation of quantitative proteomics, in vitro–in vivo extrapolation, and modeling to help advance the understanding of how functional changes in transporters can impact the pharmacokinetics of drugs in various disease states. Rodieux et al discuss the causes and consequences of variability in drug transporter activity in the treatment of pediatric patients.31 Through an extensive review of literature, the authors describe the impact and interdependence of various factors such as developmental differences, genetic factors, and comorbidities that may influence drug transporter activity. Further, the authors underscore the utility of PBPK approaches in integrating drug- and patient-specific parameters, including drug transporter ontogeny, to further improve the predictions of pharmacokinetics in pediatric patients. Drug transporters in the kidney have been shown to influence the disposition of several drugs and endogenous compounds. The uptake and efflux transporters located in the basolateral and apical membrane of the proximal tubule, respectively, work in concert to move drugs from the blood into the urine. Lepist and Ray explore the clinical relevance of renal transporter-based DDIs, highlight the populations that may be more sensitive to renal transporter-based DDIs, and discuss key knowledge gaps that may lead to underappreciation of renal transporter-based DDIs.32 The use of mechanistic, static, and PBPK models in the quantitative prediction of transporter-mediated DDIs and in delineating the interplay between enzymes and transporters has gained widespread attention.33, 34 Varma and El-Kattan extensively discuss the Extended Clearance Classification System (ECCS), a framework that can be used to predict the predominant rate-determining clearance mechanism based on physicochemical and in vitro properties, ionization, molecular weight, and permeability.35 Further, the review provides insight into how ECCS can be used to quantitatively predict the magnitude of DDIs due to "enzyme-transporter" interplay. Feng and Varma provide an overview of the PBPK modeling-based approaches and outline some challenges and knowledge gaps for predicting renal transporter-based DDIs.36 Pan et al provide a concise literature review of PBPK modeling to evaluate the contributions of various transporters and summarize regulatory submissions in which PBPK modeling was used to evaluate the role of intestinal, hepatic, and renal transporters.37 The importance of assessing intracellular drug concentrations for predicting DDIs and the associated challenges of quantifying intracellular concentrations are widely recognized. Because information on intracellular drug concentrations is not easily available, plasma concentrations are used to make assessments regarding the absence or presence of a DDI. In some cases, however, DDIs can lead to changes in tissue concentrations without a significant change in plasma concentration. In addition to the use of PBPK modeling to predict tissue concentrations, the role of noninvasive imaging methods such as positron emission tomography (PET) in assessing tissue uptake and interplay between various transporters has been reported in the literature.38-40 In this supplement, Langer provides an overview of the use of PET imaging to assess the effect of transporter-mediated DDIs on drug disposition in various organs such as brain, liver, and kidneys.41 Further, the author postulates that given the growing importance of membrane transporters with respect to drug safety and efficacy, use of PET in assessment of transporter-mediated DDIs is expected to play an increasingly important role. Disruption of transporter activity can also lead to organ toxicity.42 For example, inhibition of the bile salt export pump (BSEP), a transporter responsible for efflux of bile salts from the hepatocyte into the bile canniculus, and multidrug resistance-associated proteins (MRP) 3 and 4 may be risk factors for development of cholestatic drug-induced liver injury (DILI).43, 44 Hucke and Ciarimboli present an overview of the role of transporters in the toxicity of chemotherapeutic drugs and emphasize the importance of knowledge regarding transporter expression, function, and regulation under normal and pathologic conditions.45 Despite the widespread recognition of the important role played by transporters, there are still several challenges associated with evaluating transporter-based DDIs. One of the challenges is identifying probe inhibitors and substrates for assessing transporter-based DDIs. Momper et al highlight the advantages and disadvantages of probe substrates and probe inhibitors for various transporters used for in vivo DDI studies and describe how the lack of probe specificity complicates interpretation of in vivo assessments.46 In conclusion, this supplementary issue is the result of collaborative efforts of an interdisciplinary group of scientists who have provided their perspectives on transporters. The supplementary issue focuses on several key areas such as basic research on transporters, the role of clinically important transporters in various tissues, in vitro–in vivo correlations to predict the need for in vivo DDI studies, novel methodologies for assessing the role of transporters in modulating tissue concentrations of drugs, and how PBPK modeling can be used to quantitatively predict transporter (and enzyme-transporter) DDIs. We strongly believe that the various topics covered in this supplement will shed further light on the pivotal role played by drug transporters in modulating DDIs, efficacy, and safety. The authors declare no financial conflicts of interest.