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.
This chapter:
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Describes how an evaluation of DDI is performed from in vitro to in vivo studies within clinical development
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Reflects recent recommendations by authorities as regards the design, conduct, and reporting of DDI studies
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Presents the requirement to assess the clinical significance of DDIs
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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
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
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/GuidanceComplianceRegulatoryInformation/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
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
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
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Stopfer, P. (2020). Drug–Drug Interaction Studies. In: Hock, F., Gralinski, M. (eds) Drug Discovery and Evaluation: Methods in Clinical Pharmacology. Springer, Cham. https://doi.org/10.1007/978-3-319-68864-0_13
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DOI: https://doi.org/10.1007/978-3-319-68864-0_13
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