Abstract CN04-01: Contribution of polymorphic transporters to oncology drug disposition and safety.

The last two decades has seen a substantial change in the approaches to the clinical development of drugs. This paradigm shift was instigated by the discovery of a significant number of highly innovative and distinct classes of molecules in terms of both mechanism of action and chemical structure, along with the deployment of an array of new approaches to clinical trial design. Moreover, a rising understanding of the relationships between pharmacokinetics and pharmacodynamics has encouraged a more systematic and rigorous analysis of the potential role of clinical pharmacology in the day-to-day management of patients. Historically, pharmacokinetic studies have been an important integrated component of the various stages of drug development, have demonstrated utility as a guide to dose escalation strategies, trial design issues associated with dosing frequency, and have provided pertinent information on interindividual pharmacokinetic variability of novel agents. It was previously suggested that lack of efficacy and/or inadequate safety of investigational agents are currently the primary reasons for attrition in drug development, with poor pharmacokinetic properties representing only less than 10% of total attrition (1). However, it has become widely appreciated at the same time that the relatively narrow therapeutic index of many drugs demands that a rigorous effort be made to characterize their pharmacokinetic properties, optimize their regimens, and that the failure to recognize this early on during drug development may lead to suboptimal dosing strategies, eventually resulting in lack of efficacy. Drug transporter proteins are of increasing interest in this context due to their role both in processes regulating pharmacokinetic properties of drugs (absorption, distribution, and elimination) and the development of cellular drug resistance through decreased uptake or increased efflux in the target organ. The ubiquitous distribution of drug transporters, and their role in the cellular uptake and efflux of both endogenous compounds and xenobiotics give strength to the supposition that transporters play a crucial role in the therapeutic effects of multiple drugs used clinically. In particular, variation in drug transporter activity and/or expression in organs such as the intestine, kidney, and liver, leading to transporter malfunction, is now increasingly recognized to have a significant role as a determinant of intersubject variability in response to various commonly prescribed oncology drugs. The most extensively studied class of drug transporters are those encoded by the family of ATP-binding cassette (ABC) genes. Among the 48 currently known ABC gene products, ABCB1 (P-glycoprotein), ABCC1 (MRP1) and its homologue ABCC2 (MRP2; cMOAT), and ABCG2 (BCRP) are known to influence the oral absorption and disposition of a wide variety of drugs. As a result, variable expression levels of these proteins in humans, due to inherited factors (pharmacogenetics) and/or environmental factors (e.g. drug-drug interactions), can have important consequences for an individual9s susceptibility to certain drug-induced side effects and treatment efficacy (2). Inherited differences in activity of transporter proteins are occasionally responsible for extensive interpatient variability in drug disposition (systemic exposure) and/or effects (normal and target tissue exposure). The importance and detectability of genetic variants for a given protein depends on the contribution of the variant gene product to pharmacological response, the availability of alternative pathways of elimination for a given drug, and the frequency of occurrence of the least common variant allele. In recent years, many substrates have been identified for known polymorphic drug transporters, and the contribution of a genetically-determined source of interindividual pharmacokinetic variability is now being rapidly established for an ever increasing number of agents. Various recent publications highlight this principle, for example in the case of genetic variation in ABCG2 in relation to the gefitinib-induced diarrhea (3), and the finding that ABCB1 polymorphism in cancer patients may adversely influence the QTc-prolongation observed with clinical usage of the cyclic depsipeptide romidepsin (4). Nonetheless, most of currently known cases where pharmacogenetics has made a clinical impact involve agents for which elimination is critically dependent on a rate-limiting breakdown by a polymorphic enzyme rather than on transport, or when a polymorphic enzyme is involved in the formation of a toxic metabolite. Similar to the discoveries of functional genetic variations in drug efflux transporters of the ABC family, there have been considerable advances in the identification of inherited variants in transporters that facilitate cellular drug uptake in tissues that play an important role in drug elimination, such as the liver and kidney (2). These transporters comprise over 350 proteins organized into 51 distinct families, and are commonly classified as passive transporters, ion coupled transporters, or exchangers. Among these, members of the organic anion-transporting polypeptides (OATP), organic anion transporters, and organic cation transporters (OCT) can mediate the cellular uptake of a large number of structurally diverse compounds. Accordingly, functionally relevant polymorphisms in these influx carriers may contribute to interindividual and interethnic variability in drug disposition and response; for example, recent work has identified OCT1 function as a critical regulator of imatinib uptake into chronic myeloid leukemia cells, and as such OCT1 malfunction has been identified as a factor contributing to suboptimal response to treatment in patients receiving imatinib (5). Investigations into how ABC transporters and solute carriers impact drug distribution, toxicity, efficacy, and drug resistance has become the focus of many efforts to now also rapidly expand knowledge of other oncology drugs, both investigational and approved. Specific examples from our recent ventures in this field that will be presented include preliminary data from preclinical studies indicating (i) an unexpected contribution of ABCC4 (MRP4), a highly polymorphic transporter, to the gastric absorption of dasatinib that impacts oral bioavailability, and (ii) a dominant role of specific solute carriers in the intracellular accumulation of sorafenib into human epidermal keratinocytes. The use of animal models deficient in certain transporters has historically provided invaluable information on the normal physiological function of these proteins. For example, mice deficient in ABCB1, a transporter involved in the extrusion of many different substances out of cells, are known to be extremely sensitive to certain neurotoxins. In recent years, mouse models have been generated for nearly all ABC transporters and solute carriers currently known to be of relevance to anticancer drugs. It should be emphasized that there are sometimes complications in translating preclinical findings to the clinic, and these can be explained in part by differences in tissue localization and/or substrate recognition of transporters between humans and animals. An example of this was recently reported for OATPs of putative relevance to the oral absorption of imatinib (6). Future studies could use humanized transgenic mice to possibly improve animal-to-human translational findings, and some of these have already become available. Future utility and refinement of these model systems, for example by the generation of mouse models carrying mutant human transporters, will likely shed important light on the role of individual polymorphic transporters to the absorption and disposition of multiple oncology products and their associated pharmacodynamic effects. References: 1. Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 204;3:711–15. 2. Franke RM, Gardner ER, Sparreboom A. Pharmacogenetics of drug transporters. Curr Pharm Design 2010;16:220–30. 3. Cusatis G, Gregorc V, Li J, Spreafico A, Ingersoll RG, Verweij J, Ludovini V, Villa E, Hidalgo M, Sparreboom A, Baker SD. Pharmacogenetics of ABCG2 and adverse reactions to gefitinib. J Natl Cancer Inst 2006;98:1739–42. 4. Sissung TM, Gardner ER, Piekarz RL, Howden R, Chen X, Woo S, Franke RM, Clark JA, Miller-De Graff L, Steinberg SM, Venzon D, Liewehr D, Kleeberger SR, Bates SE, Price DK, Rosing DR, Cabell C, Sparreboom A, Figg WD. Impact of ABCB1 allelic variants on QTc interval prolongation. Clin Cancer Res 2011;17:937–46. 5. Eechoute K, Sparreboom A, Burger H, Franke RM, Schiavon G, Verweij J, Loos WJ, Wiemer EA, Mathijssen RH. Drug transporters and imatinib treatment: implications for clinical practice. Clin Cancer Res 2011;17:406–15. 6. Eechoute K, Franke RM, Loos WJ, Boere I, Verweij J, Gurney H, Scherkenbach LA Kim RB, Tirona RG, Mathijssen RH, Sparreboom A. Environmental and genetic factors affecting transport of imatinib by OATP1A2. Clin Pharmacol Ther 2011;89:816–20. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr CN04-01.