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Drug–Drug Interaction Studies

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Drug Discovery and Evaluation: Methods in Clinical Pharmacology

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Abstract

Drug drug interaction (DDI) can result when one drug alters the pharmacokinetics of another drug or its metabolites. The assessment of pharmacokinetic DDIs during clinical development is a part of the general clinical pharmacology and safety assessment of a new investigational compound. Market withdrawals of drugs were frequently caused by DDIs which underlines the importance of addressing these issues during drug development. This is also reflected by the latest DDI (DDI) guidelines from European Medicines Agency EMA (2012), Food and Drug Administration (FDA) (2012), and Pharmaceuticals and Medical Devices Agency (2014). The details of all aspects which have to be considered in the design of DDI studies are outlined in the respective guidelines from EMA (2012), FDA (2012), and PMDA (2014). This section is aiming to give a summary of the respective considerations of these guidelines for the design of DDI studies and also contains many aspects of the respective guidelines including the most relevant decision trees and tables.

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Abbreviations

ABC:

ATP-binding cassette

AhR:

Aryl hydrocarbon receptor

AUC:

Area under the plasma concentration-time curve

BCRP:

Breast cancer resistance protein

BSEP:

Bile salt export pump

CAR:

Constitutive androstane receptor

CYP:

Cytochrome P450

FMO:

Flavin monooxygenase

MAO:

Monoamine oxidase

MATE:

Multidrug and toxin extrusion

MRP:

Multidrug resistance-associated protein

NTR:

Narrow therapeutic range

OAT:

Organic anion transporter

OATP:

Organic anion transporting polypeptide

OCT:

Organic cation transporter

PBPK:

Physiologically-based pharmacokinetic

PD:

Pharmacodynamics

P-gp:

P- glycoprotein

PK:

Pharmacokinetics

PXR:

Pregnane X receptor

SLC:

Solute carrier

TDI:

Time dependent inhibition

UGT:

Uridine diphosphate (UDP)-glucuronosyl transferase

XO:

Xanthine oxidase

References and Further Reading

  • EMA-CHMP (2012) Guideline on the investigation of drug interactions: final (CPMP/EWP/560/95/Rev. 1 corr. 2). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf. Accessed 13 Mar 2017

  • Huang S-M, Zhao H, Lee J, Reynolds KS, Zhang L, Temple R, Lesko LJ (2010) Therapeutic protein drug interactions and impacts on drug development, Clin Pharmacol Ther 87:497–503

    Article  CAS  PubMed  Google Scholar 

  • Le Vee M, Lecureur V, Stieger B, Fardel O (2009) Regulation of drug transporter expression in human hepatocytes exposed to the proinflammatory cytokines tumor necrosis factor-alpha or interleukin-6, Drug Metab Dispos 37:685–693

    Article  PubMed  Google Scholar 

  • PMDA. Pharmaceuticals & Medical Device Agency-Japan (2014) Drug interaction guideline for drug development and labeling recommendations (draft for public comment) 2014. http://www.solvobiotech.com/documents/Japanese_DDI_guideline_(draft)_2014Jan.pdf. Accessed 13 Mar 2017

  • US-FDA (2012) Guidance for industry: drug interaction studies – study design, data analysis, implications for dosing, and labeling recommendations (draft guidance). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo rmation/Guidances/ucm292362.pdf. Accessed 13 Mar 2017

  • Zhang L, Zhang Y, Zhao P, Huang S-M (2009a) Predicting drug-drug interactions: An FDA perspective, The AAPS Journal 11(2):300–306

    Google Scholar 

  • Zhang L, Zhang Y, Huang S-M (2009b) Scientific and regulatory perspectives on metabolizing enzyme-transporter interplay and its role in drug interactions - challenges in predicting drug interaction, Molecular Pharmaceutics 6(6):1766–1774

    Google Scholar 

  • Zhao P, Ragueneau-Majlessi I, Zhang L, Strong J, Reynolds K, Levy R, Thummel K, Huang S-M (2009) Quantitative evaluation of pharmacokinetic inhibition of CYP3A substrates by ketoconazole – a simulation study, J Clin Pharmacol 49(3):351–359, 2143

    Google Scholar 

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Author information

Authors and Affiliations

  1. Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

    Peter Stopfer

Authors
  1. Peter Stopfer
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Corresponding author

Correspondence to Peter Stopfer .

Editor information

Editors and Affiliations

  1. CorDynamics , Dieburg, Germany

    Franz J. Hock

  2. CorDynamics , Chicago, Illinois, USA

    Michael R. Gralinski

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Stopfer, P. (2018). Drug–Drug Interaction Studies. In: Hock, F., Gralinski, M. (eds) Drug Discovery and Evaluation: Methods in Clinical Pharmacology. Springer, Cham. https://doi.org/10.1007/978-3-319-56637-5_13-1

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  • DOI: https://doi.org/10.1007/978-3-319-56637-5_13-1

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-56637-5

  • Online ISBN: 978-3-319-56637-5

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

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