title: Progress in Prediction and Interpretation of Clinically Relevant Metabolic Drug-Drug Interactions: a Minireview Illustrating Recent Developments and Current Opportunities.
abstract: OBJECTIVE
  This review gives a perspective on the current "state of the art" in metabolic drug-drug interaction (DDI) prediction. We highlight areas of successful prediction and illustrate progress in areas where limits in scientific knowledge or technologies prevent us from having full confidence.
  
  
  RESULTS
  Several examples of success are highlighted. Work done for bitopertin shows how in vitro and clinical data can be integrated to give a model-based understanding of pharmacokinetics and drug interactions. The use of interpolative predictions to derive explicit dosage recommendations for untested DDIs is discussed using the example of ibrutinib, and the use of DDI predictions in lieu of clinical studies in new drug application packages is exemplified with eliglustat and alectinib. Alectinib is also an interesting case where dose adjustment is unnecessary as the activity of a major metabolite compensates sufficiently for changes in parent drug exposure. Examples where "unusual" cytochrome P450 (CYP) and non-CYP enzymes are responsible for metabolic clearance have shown the importance of continuing to develop our repertoire of in vitro regents and techniques. The time-dependent inhibition assay using human hepatocytes suspended in full plasma allowed improved DDI predictions, illustrating the importance of continued in vitro assay development and refinement.
  
  
  CONCLUSIONS
  During the past 10 years, a highly mechanistic understanding has been developed in the area of CYP-mediated metabolic DDIs enabling the prediction of clinical outcome based on preclinical studies. The combination of good quality in vitro data and physiologically based pharmacokinetic modeling may now be used to evaluate DDI risk prospectively and are increasingly accepted in lieu of dedicated clinical studies.
authors.affiliation: Pharmaceutical Research and Early Development, Roche Innovation Centre Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Stephen
authors.initials: S
authors.lastname: Fowler
authors.affiliation: Pharmaceutical Reseach and Early Development, Roche Innovation Center New York, F. Hoffmann-La Roche Ltd., 430 East 29th Street, New York City, NY USA.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Morcos
authors.affiliation: Pharmaceutical Research and Early Development, Roche Innovation Centre Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Cleary
authors.affiliation: Pharmaceutical Research and Early Development, Roche Innovation Centre Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Meret
authors.initials: M
authors.lastname: Martin-Facklam
authors.affiliation: Pharmaceutical Research and Early Development, Roche Innovation Centre Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Neil
authors.initials: N
authors.lastname: Parrott
authors.affiliation: Pharmaceutical Research and Early Development, Roche Innovation Centre Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Gertz
authors.affiliation: Pharmaceutical Reseach and Early Development, Roche Innovation Center New York, F. Hoffmann-La Roche Ltd., 430 East 29th Street, New York City, NY USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yu
keywords: Cytochrome P450; Drug-drug interaction; Metabolism; Physiologically based pharmacokinetic model; Prediction; Regulatory submission