10th International Marbach Castle DDI Workshop May 26th – 28th, 2019


The 10th Anniversary of the International Drug-Drug Interaction (DDI) Workshop at Marbach Castle Enjoyed Continued Attention, Appreciation and Endorsement by International Academic, Industry and Regulatory Scientists


More than 80 experts attended the 10th International DDI Workshop and discussed current topics of regulatory requirements and scientific aspects of drug-drug interactions. The meeting was once again fully booked several weeks in advance, indicating that the DDI Workshop series has become a focal point in the calendar for those concerned with the topic and its unmet needs. Thus, the workshop continues to enjoy from an unbroken popularity, appreciation and endorsement by the participating speakers and attendees.


The meeting began with a session on ‘Past, Present and Future of the Investigations of DDIs’ and was started with a historical perspective by Prof. Malcolm Rowland from the University of Manchester who led the audience through 50 years of DDI investigations. Prof. Rowland gave numerous examples. Often regarded clinically as all or none phenomena, drug-drug interactions (DDI) are graded with the extent varying with the concentrations of the interacting species and hence with their pharmacokinetics (PK) and dosage regimens. Initially, DDIs were identified from clinical observations, often adverse outcomes, and sometimes even drug withdrawals. Their origins were often unbeknown pharmacokinetic. To minimize such problems, studies in healthy subjects became part of drug development, with choice of study often governed by the high likelihood that the drugs would be co-administered in the patient population, rather than based on scientific principles. Changes were driven with improvements in analytical methods and mechanistic understanding of ADME processes, coupled with increasing adoption of physiologically based organ models, linking in vitro investigations with in vivo observations, heralding in the era of in vitro-in vivo extrapolation (IVIVE). Originally confined primarily to studies of competitive metabolic inhibition in preclinical species they rapidly extended to non-competitive inhibition and enzyme induction, and while animal studies were used to test methodologies underlining IVIVE, the availability of human tissue and cell-based systems allowed prediction of events in human. Early PK models assumed perfusion rate limited tissue distribution, which needed to be extended to allow for a membrane permeability rate limitation, increasingly apparent with larger and less lipophilic compounds, and a realization of the role of transporters, sometimes coupled with metabolic events. And while the use of in vitro findings was helping to identify likely risks of a DDI in vivo, incorporated into regulatory guidances, there was still much concern for false negatives, and false positives. As such, emphasis remained on undertaking clinical DDI investigations, but now on a more mechanistic basis. Also, many drugs produced multiple interactions at multiple sites within the body, which could no longer be considered discretely, a problem addressed with the use of whole body physiologically based PK (PBPK) models, dynamic models that integrated biochemical, physiological, pathophysiological, genetic and ontological information with drug specific information. However, with concerns for ensuring quality of associated studies and the PBPK software platforms, regulators have issued PBPK guidances, in which issues of validation and qualification play a significant part. Still, confidence is sufficiently high in many cases to both avoid the need for undertaking some DDI studies and allow statements to be made in the label based on PBPK predictions. The next presentations in the regulatory session was on ‘An industry view on the evolution of modelling and simulation in drug development with emphasis on DDI studies over the past decade’ given by Dr. Richard Lalonde, University of Florida. He showed numerous examples how modeling and simulation has made the drug development process more evidence-based and unbiased.


In the second session on “Changes in the International Regulatory DDI Landscapes” there were presentations on ‘Update on EMA Guidances Impacting the Assessment of DDIs’ given by Kevin Blake, PhD,  from the EMA and on ‘The Japanese (PMDA) DDI Guideline and application of PBPK’ by Kiyomi Ito, PhD, Musashino University, Tokyo, Japan, followed by a lively discussion.


The subsequent program on Day 1 consisted of two more scientific sessions, as well as a concluding Questions & Answer session.


The third session of Day 1 was called ‘PBPK Modeling of Metabolism-Based DDIs’ with a presentation on ‘Predicting DDI with Integrated MiDD Capability’ given by Ping Zhao, PhD, Bill and Melinda Gates Foundation, Seattle.


The fourth session was about ‘Clinical Management of DDIs’ and featured presentations on ‘Getting Over Fatigue of DDI Warnings: What the Future Decision Support Tools Hold for Clinicians in the Era of Precision Dosing’ by Jean-Luc Reny, MD, Geneva University Hospital, Geneva, as well as ‘Late Breaking Topic! Ketoconazole and Liver Injury – A Five-Year Update’ by Gerd Mikus, MD, Heidelberg University Hospital where he made a strong point against banning ketoconazole in favor of itraconazole in DDI studies.


Day 2 started with a session titled ’Transporter-Based DDIs Revisited’. The first presentation was on ‘The Role of Intestinal Influx Transporters in Drug-Nutrient, Drug-Excipient and Drug-Drug Interactions’ presented by Kathleen Giacomini, PhD, University of California at San Francisco.  Intestinal transporters play critical roles in the absorption of drugs and nutrients. Drug-drug interactions, mediated by intestinal transporters, are widely recognized as important determinants of drug toxicity and/or non-response. In marked contrast, transporter-mediated excipient drug interactions in which excipients co-formulated with therapeutic drugs inhibit intestinal drug transporters are less well studied, and very little is known about transporter-mediated drug-nutrient interactions in the intestine. Dr. Giacomini described excipient drug interactions with the intestinal absorptive transporter, OATP2B1. She demonstrated the complex interplay between formulation and drug absorption and suggested that intestinal transporters are important determinants of not only drug-drug interactions, but drug-nutrient and drug-excipient interactions.


The next presentations in that session was on the question ‘Can Endogenous Biomarkers be Applied in Phase I Clinical Trials to Facilitate Subject Phenotyping and DDI Prediction?’ by Yuichi Sugiyama, PhD; RIKEN, Yokohama.  He showed recent progress in using endogenous compounds as biomarkers for assessing DDI susceptibility of compounds and genetic polymorphism based interindividual differences involving hepatic transporters in humans. Use of multiple biomarkers will enhance the confidence in the prediction of clinical DDI using endogenous biomarkers. The session concluded with a presentation by Peter Stopfer, PhD, Boehringer Ingelheim on ‘The Effect of Inhibitors of Drug Transport on a Probe-Drug Cocktail Consisting of Digoxin, Furosemide, Metformin, and Rosuvastatin.’


The final session of the meeting was titled ‘DDIs with Hormonal Contraceptives Revisited’ and featured presentations on ‘Regulatory Guidance Versus Clinical Guidance on Drug Interactions of Combined Hormonal Contraceptives’ by Larry Lesko, PhD, University of Florida, ‘Closing the Knowledge Gap on Potential Differences in the Sensitivity to CYP3A4 Induction between Common Progestins used in Oral Contraceptives Relative to Midazolam’ by Joachim Höchel, PhD, and Herbert Wiesinger, PhD, Bayer AG, and ‘Assessment of Drug Interactions with Oral Contraceptives using PBPK Modelling: A Best Practice Approach Using Case Studies’ by Karen Rowland Yeo, PhD,  Certara, Sheffield.


The meeting then concluded with five excellent presentations from selected posters presentations and as usual, the final wrap-up discussion of the workshop. As in every year, a wide variety of DDI-related topics were discussed including experimental, clinical and regulatory issues.


Finally, this meeting report would not be complete without mentioning the beautiful Fingerstyle Guitar and Soul, Pop & Jazz Double Concert by Simon Wahl, Michael Diehl and 2enjoy as well as the many networking opportunities for the attendance to engage in informal interaction with colleagues form industry, academia and the regulatory agencies.



Workshop Programme 2019