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The Role of Transporters in Drug Development: Regulatory Science Perspectives from the FDA

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Transporters in Drug Development

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 7))

Abstract

Pharmacokinetic drug interactions can lead to altered systemic exposure and varied drug response. Evaluation of a new molecular entity’s (NME’s) drug–drug interaction (DDI) potential is therefore an integral part of drug development and regulatory review prior to its market approval. Transporters are expressed in varying abundance in all tissues in the body where they govern the access of molecules to cells or their exit from cells, thereby controlling the overall distribution of drugs to their intracellular site of action. Clinically relevant interactions mediated by transporters are of increasing interest in drug development. Research in this emerging area has revealed that drug transporters, acting alone or in concert with drug metabolizing enzymes, can play an important role in modulating drug absorption, distribution, metabolism, and excretion, thus affecting the pharmacokinetics and/or pharmacodynamics of a drug. The newly published draft drug interaction guidance by the Food and Drug Administration (FDA) in 2012 includes updated recommendations in addressing transporter-mediated drug interactions with various decision trees to help guide drug development and regulatory review. This chapter discusses, from a scientific perspective, role of transporters in drug development with a focus on transporter-mediated DDIs. First, transporter-related recommendations in the recent FDA’s draft drug interaction guidance are discussed. Second, additional transporters that are emerging to be important in drug disposition are discussed. Third, recent review examples and transporter-related labelings are presented. Finally, future directions are discussed.

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Abbreviations

ABC:

ATP-binding cassette

ADME:

Absorption, distribution, metabolism, and excretion

AUC:

Area under the plasma concentration-time curve

BCRP:

Breast cancer resistance protein

BSEP:

Bile salt export pump

CLr :

Renal clearance

CLtotal :

Total clearance

C max :

Maximal plasma concentration

cMOAT:

Canalicular multispecific organic anion transporter (also named MRP2)

DDI:

Drug–drug interaction

F a F g :

Fraction of dose of inhibitor which is absorbed

FDA:

Food and Drug Administration

f u :

Fraction unbound

GFR:

Glomerular filtration rate

[I]1 :

Mean steady state total (free and bound) C max following the highest proposed clinical dose

[I]2 :

Dose of inhibitor (in mol)/250 mL

I in,max :

Estimated maximum inhibitor concentration at the inlet to the liver

ITC:

International transporter consortium

K a :

Absorption rate constant

LST:

Liver-specific transporter

MATE:

Multidrug and toxic compound extrusion transporter

MRP:

Multidrug resistance-associated protein

NDA:

New drug application

NME:

New molecular entity

OAT:

Organic anion transporter

OATP:

Organic anion transporting polypeptide

OCT:

Organic cation transporter

PD:

Pharmacodynamics

PFiC2:

Progressive familial intrahepatic cholestasis type 2

P-gp:

P-glycoprotein

PK:

Pharmacokinetics

PMC:

Postmarketing commitment

PMR:

Postmarketing requirement

Q h :

Estimated hepatic blood flow

SGLT2:

Sodium-glucose cotransporter 2

SLC:

Solute carrier

TEA:

Tetraethyl ammonium

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Acknowledgement

The authors would like to thank members of the FDA Office of Clinical Pharmacology Transporter Scientific Interest Group for their support.

Disclaimer The views presents in this chapter are those of authors and do not necessarily reflect the official view of the FDA.

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Authors and Affiliations

  1. Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, USA

    Lei Zhang Ph.D. & Shiew-Mei Huang

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  1. Lei Zhang Ph.D.
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Correspondence to Lei Zhang Ph.D. .

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Editors and Affiliations

  1. The University of Tokyo Graduate School of Pharmac. Sciences, Tokyo, Japan

    Yuichi Sugiyama

  2. Pharma, Drug Transporters in ADME Department of Pharmacy, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark

    Bente Steffansen

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Zhang, L., Huang, SM. (2013). The Role of Transporters in Drug Development: Regulatory Science Perspectives from the FDA. In: Sugiyama, Y., Steffansen, B. (eds) Transporters in Drug Development. AAPS Advances in the Pharmaceutical Sciences Series, vol 7. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8229-1_11

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