title: Optimized Cocktail Phenotyping Study Protocol Using Physiological Based Pharmacokinetic Modeling andIn silicoAssessment of Metabolic Drug-Drug Interactions Involving Modafinil.
abstract: In vivococktail pathway phenotyping (ICPP) is routinely used to assess the metabolic drug-drug interaction (mDDI) potential of new drug candidates (NDC) during drug development. However, there are a number of potential limitations to this approach and the use of validated drug cocktails and study protocols is essential. Typically ICPP mDDI studies assess only the impact of interactions following multiple postulated perpetrator doses and hence the emphasis in terms of validation of these studies has been ensuring that there are no interactions between probe substrates. Studies assessing the comparative impact of single and multiple doses of the postulated perpetrator have the potential to provide richer information regarding both the clinical impact and mechanism of mDDIs. Using modafinil as a model compound, we sought to develop an optimized ICPP mDDI study protocol to evaluate the potential magnitude and clinical relevance of mDDIs using a physiologically based pharmacokinetic modeling approach.
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Flinders University Adelaide, SA, Australia.
authors.forename: Angela
authors.initials: A
authors.lastname: Rowland
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Flinders UniversityAdelaide, SA, Australia; Precision Medicine Group, Flinders Center for Innovation in Cancer, School of Medicine, Flinders University AdelaideSA, Australia.
authors.forename: Arduino A
authors.initials: AA
authors.lastname: Mangoni
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Flinders UniversityAdelaide, SA, Australia; Precision Medicine Group, Flinders Center for Innovation in Cancer, School of Medicine, Flinders University AdelaideSA, Australia.
authors.forename: Ashley
authors.initials: A
authors.lastname: Hopkins
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Flinders UniversityAdelaide, SA, Australia; Precision Medicine Group, Flinders Center for Innovation in Cancer, School of Medicine, Flinders University AdelaideSA, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sorich
authors.affiliation: Department of Clinical Pharmacology, School of Medicine, Flinders UniversityAdelaide, SA, Australia; Precision Medicine Group, Flinders Center for Innovation in Cancer, School of Medicine, Flinders University AdelaideSA, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rowland
keywords: cocktail phenotyping; metabolic drug–drug interactions; modafinil; physiological based pharmacokinetic modeling; study protocol