9th International Marbach Castle DDI Workshop May 27-29, 2018

The 9th 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 9th 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 ‘Changes in the US/EU Regulatory Landscapes’ and was started with a presentation by Dr. Joseph Grillo from the FDA on ‘Drug Interactions From Lab to Labeling: A Regulatory Perspective’.

Dr. Grillo pointed out that unanticipated, unrecognized, or mismanaged drug-drug interactions (DDIs) are major causes of preventable morbidity and mortality, and have occasionally caused the withdrawal of approved drugs from the US market. The overarching goal of FDA’s DDI program is to promote public health by effectively leveraging the totality of information submitted or reported throughout a drug or biologic product life-cycle to determine the potential for clinically significant DDI, develop appropriate management strategies for them, and effectively convey this information to the healthcare provider and ultimately the public. In December 2017, FDA published two draft guidances to update and replace the 2012 revised draft DDI guidance for industry. The “In Vitro Metabolism and Transporter-Mediated Drug-Drug Interaction Studies” draft guidance focuses on in vitro experimental approaches for evaluating metabolizing enzyme- and transporter-based drug interaction potential and how to extrapolate in vitro data to decide on the need for clinical DDI studies. The “Clinical Drug Interactions Studies—Study Design, Data, Analysis, and Clinical Implications” draft guidance focuses on clinical studies that evaluate the potential for DDIs and advises sponsors on the timing and design of the clinical studies, interpretation of the results, and options for managing DDIs in patients. A DDI-specific prescription drug labeling and other problem specific “modular” guidances are also planned to support these foundational documents. In the US, the prescription drug labeling is the primary mechanism through which FDA and drug manufacturers communicate essential, science-based prescribing information to healthcare providers. The prescription drug labeling should include a summary of essential DDI information that is needed for the safe and effective use of the drug by the healthcare provider. This information can include data and results from prospective clinical DDI studies, population-based analyses, modeling and simulations, postmarketing reports, or data extrapolated from other information. As part of the Agency’s labeling initiative, guidances and best labeling practices for communicating DDI-related information in prescription drug labeling are planned or being created as well as innovative approaches to enhance clarity, utility, and comprehension (e.g., tables, figures, structured text, etc.).

The next presentations in the regulatory session was on ‘The new FDA Guidance on In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Studies’ given by Aleksandra Galetin, PhD, Centre for Applied Pharmacokinetic Research, The University of Manchester, and on ‘The new FDA In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Guidance – A Perspective from Practice’ given by Andrew Parkinson, PhD, XPD Consulting, Shawnee KS, USA.

The three presentations were followed by an intense podium discussion. One focus was the call for even more harmonization between the different guidances to avoid unnecessary duplication of work and different interpretation of the same scientific data in different parts of the world.

In the second part of this Session on “Changes in the US/EU Regulatory Landscapes” there were presentations on ‘PBPK Model Qualification and Reporting Procedures for Regulatory Submissions: A Consortium Perspective’ given by Edgar L. Schuck, PhD, Modeling and Simulation, Clinical Pharmacology Sciences, MDC, Eisai, USA. The next presentation focused on ‘Dynamic Drug Labels for Optimal Management of DDIs in Patient Care’ and was given by David Burger, PharmD, Radboud University Medical Center, Nijmegen, The Netherlands. The session then concluded with a presentation on ‘Assessment of Two DDIs Involving a Distinct Enzyme and Their Consequences on Morbi-Mortality’ given by Béatrice Saint-Salvi, PhD, DDI Unit, ANSM, France. These presentations again were followed by a lively podium discussion with the three speakers.

The subsequent program consisted of three more scientific sessions, as well as selected oral presentations of some of the poster presentations and a concluding Questions & Answer session.

The first session was called ‘Phenotyping Revisited’ with two presentations on ‘Can DDIs of Direct-Acting Oral Anticoagulants (DOACs) be Predicted by Using a Micro-Dosed DOAC Cocktail Approach?’ given by Gerd Mikus, MD, Heidelberg University Hospital, Heidelberg, Germany, and another on ‘Mechanistic Assessment of Pharmacokinetic DDIs – Phenotyping Revisited’ by Uwe Fuhr, MD, University of Cologne, Cologne, Germany.

The second session was about ‘Sensitivity Assessment in PBPK: Foe or Friend’ and featured presentations on  ‘Deciphering Sensitivity Analysis in PBPK: Model Credibility, Uncertainty, Verification and Validation’ by George D. Loizou, PhD, Head of Computational Toxicology Team, Health Risks, HSL: HSE‘s Health & Safety Laboratory, Buxton, Derbyshire, UK, as well on ‘In Search of Sensitive Endogenous Markers for Transporter DDIs – Mechanistic Models for Creatinine and Coproporphyrin I’ by Aleksandra Galetin, PhD, Centre for Applied Pharmacokinetic Research, The University of Manchester, Manchester, UK.

The final session on ‘Non-CYP Related Metabolic DDIs’ featured a presentation onNon-CYP Related Metabolic DDIs with Particular Emphasis on UGT-based DDIs’ by Janne T. Backman, MD, Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

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 guitar concert by Eckhard Freund and Özkan Yalkinoglu with inspiring and meditative guitar music, as well as the many networking opportunities for the attendance to engage in informal interaction with colleagues form industry, academia and the regulatory agencies.

The Workshop Organizers

Hartmut Derendorf, PhD, FCP 
Robert Hermann, MD, FCP 
Amin Rostami-Hodjegan, PhD, FCP       
Oliver von Richter, PhD, FCP

Workshop Programme 2018