21 June 2012 CPMP/EWP/560/95/Rev. 1 Corr. 2** Committee for Human Medicinal Products (CHMP) Guideline on the investigation of drug interactions Discussion in the Efficacy Working Party (EWP) June/October 1996 February 1997 Transmission to the CPMP March 1997 Transmission to interested parties March 1997 Deadline for comments September 1997 Re-submission to the EWP December 1997 Approval by the CPMP December 1997 Date for coming into operation June 1998 Draft Rev. 1 Agreed by the EWP April 2010 Adoption Rev. 1 by CHMP for release for consultation 22 April 2010 End of consultation Rev. 1 (deadline for comments) 31 October 2010 Agreed by Pharmacokinetics Working Party February 2012 Adopted by CHMP 21 June 2012 Date for coming into effect 1 January 2013 This guideline replaces guideline CPMP/EWP/560/95. Keywords Interaction, guideline, metabolism, inhibition, induction, transport, enzyme, transport protein, transporter, absorption, food, distribution, PBPK, herbal, SmPC * The correction concerns section 5.3.4.1 (p 26) and the corresponding decision tree no. 6 (p 61) to read “if the observed Ki value is lower or equal to /…/”; Appendix VII, Table 5 to read “See section 5.4.2”.* Decision tree 4. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2015. Reproduction is authorised provided the source is acknowledged. Guideline on the investigation of drug interactions Table of contents Executive summary ..................................................................................... 4 1. Introduction ............................................................................................ 4 2. Scope....................................................................................................... 5 3. Legal basis and relevant guidelines ......................................................... 5 4. Pharmacodynamic interactions................................................................ 6 5. Pharmacokinetic interactions .................................................................. 6 5.1. Effects of food intake on the pharmacokinetics of the investigational drug ................... 7 5.2. Effects of other medicinal products on the pharmacokinetics of the investigational drug 8 5.2.1. Absorption ........................................................................................................ 8 5.2.2. Distribution ....................................................................................................... 9 5.2.3. Metabolism ..................................................................................................... 10 5.2.4. Active uptake and secretion in drug elimination ................................................... 12 5.2.5. Special populations .......................................................................................... 14 5.3. Effects of the investigational drug on the pharmacokinetics of other drugs ................ 15 5.3.1. Absorption ...................................................................................................... 15 5.3.2. Distribution ..................................................................................................... 15 5.3.3. Metabolism ..................................................................................................... 15 5.3.4. Transport ....................................................................................................... 25 5.4. Design of in vivo studies ..................................................................................... 26 5.4.1. Study population ............................................................................................. 27 5.4.2. Probe drugs and cocktail studies ........................................................................ 27 5.4.3. Dose, formulation and time of administration ...................................................... 28 5.4.4. Time dependencies .......................................................................................... 30 5.4.5. Active metabolites ........................................................................................... 30 5.4.6. Pharmacokinetic parameters ............................................................................. 31 5.4.7. Population pharmacokinetic analysis .................................................................. 31 5.5. PBPK modelling and simulation ............................................................................ 32 5.6. Presentation of in vivo study results in the study report .......................................... 33 5.7. Translation into treatment recommendations ......................................................... 33 5.7.1. In vitro data ................................................................................................... 33 5.7.2. In vivo effects of other drugs on the investigational drug ...................................... 34 5.7.3. In vivo effects of the investigational drug on other drugs ...................................... 35 5.7.4. Food effects .................................................................................................... 36 6. Herbal medicinal products and specific food products ........................... 36 7. Inclusion of information and recommendations in the SmPC .............. 36 7.1. Mechanistic information and prediction of non-studied interactions ........................... 37 7.2. Presentation of study results in the SmPC ............................................................. 38 Guideline on the investigation of drug interactions CPMP/EWP/560/95/Rev. 1 Corr. 2** Page 2/59 Definitions ................................................................................................. 38 Appendix I ................................................................................................. 40 Appendix II ............................................................................................... 41 Appendix III .............................................................................................. 43 Appendix IV ............................................................................................... 44 Appendix V ................................................................................................ 46 Appendix VI ............................................................................................... 48 Appendix VII ............................................................................................. 49 Appendix VIII............................................................................................ 51 Appendix IX ............................................................................................... 52 Appendix X ................................................................................................ 53 Guideline on the investigation of drug interactions CPMP/EWP/560/95/Rev. 1 Corr. 2** Page 3/59 Executive summary The potential for pharmacokinetic interactions between new medicinal products and already marketed drugs should be evaluated. This applies to both effects of the medicinal product on other drugs as well as the effect of other drugs on the medicinal product. Furthermore the effect of concomitant food intake needs to be investigated. The drug-drug interaction potential is usually investigated through in vitro studies followed by in vivo studies. The results of interaction studies are used to predict a number of other interactions based on the mechanisms involved. Treatment recommendations are developed based on the clinical relevance of the interactions and the possibility to make dose adjustments or treatment monitoring. This document aims to provide recommendations on all these issues. General recommendations are also provided for herbal medicinal products. 1. Introduction Drug-drug interactions are a common problem during drug treatment and give rise to a large number of hospital admissions as a result of medically important, sometimes serious or even fatal adverse events. Drug-drug interactions can also cause partial or complete abolishment of treatment efficacy. The ageing European population, where polypharmacy is more frequent, increases the likelihood of such interactions and underlines the importance of a scientifically sound understanding of the potential for drug-drug interactions for all new chemical entities. A number of drugs have been withdrawn from the market as a result of drug-drug interactions that were only discovered post-marketing. The potential for drug-drug interactions is considered in the benefit-risk evaluation of a medicinal product and can negatively impact on this balance either through increased incidence of adverse events or reduced efficacy. This guideline outlines a comprehensive, systematic and mechanistic approach to the evaluation of the interaction potential of a drug during its development and offers guidance to ensure that the prescriber receives clear information on the interaction potential as well as practical recommendations on how the interactions should be managed during clinical use. The first CHMP interaction guideline was adopted in 1997 and this is the first revision of this guideline. During the past 20 years, considerable scientific progress has been made so that today clinically relevant pharmacokinetic drug interactions can be predicted from