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Clin Pharmacol Ther. 2018 Nov;104(5):781-784. doi: 10.1002/cpt.1082. Epub 2018 May 15.

ITC Commentary on Metformin Clinical Drug-Drug Interaction Study Design That Enables an Efficacy- and Safety-Based Dose Adjustment Decision.

Author information

1
Quantitative Drug Disposition, GlaxoSmithKline plc, King of Prussia, Pennsylvania, USA.
2
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc, Kenilworth, New Jersey, USA.
3
Clinical Pharmacology, Global Product Development, Pfizer Inc., Groton, Connecticut, USA.
4
Clinical Pharmacology, Gilead Sciences Inc., Foster City, California, USA.
5
Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK.
6
Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, California, USA.
7
Drug Metabolism and Clinical Pharmacology, DMPK Solutions, San Diego, California, USA.
8
Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, Washington, USA.
9
Clinical Research, Gilead Sciences, Inc., Foster City, California, USA.
10
Clinical Pharmacology, Genentech, South San Francisco, California, USA.
11
Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
12
Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.

Abstract

Metformin drug-drug interaction (DDI) studies are conducted during development of drugs that inhibit organic cation transporters and/or multidrug and toxin extrusion proteins (OCTs/MATEs). Monitoring solely changes in systemic exposure, the typical DDI study endpoint appears inadequate for metformin, which is metabolically stable, has poor passive membrane permeability, and undergoes transporter-mediated tissue distribution and clearance. Evaluation of renal clearance, antihyperglycemic effects, and potentially lactate as an exploratory safety marker, can support rational metformin dose adjustment. The proposed DDI study design aims to adequately inform metformin dosing during comedication.

PMID:
29761830
DOI:
10.1002/cpt.1082

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