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Solving a Mystery Using PBPK: How Drug-excipient Complexes Can Confound a Metabolic DDI Result

Assessment of drug-drug interaction (DDI) liabilities is an important safety component of any drug development program. Itraconazole, a selective strong inhibitor of CYP3A, has been widely employed to determine the maximum drug interaction risk with new molecular entities as CYP3A substrates. Hydroxypropyl-β-cyclo-dextrin (HP-β-CD) is used as an excipient in the itraconazole solution for oral dosing (Sporanox).

Fenebrutinib is being developed as a potential therapy for autoimmune diseases. It is a CYP3A substrate and time-dependent inhibitor in vitro. Prospective PBPK simulations predicted increases in both fenebrutinib maximum plasma concentration (Cmax) and area under the curve (AUC) in the presence of itraconazole. However in the clinical DDI study, while multiple doses of 200 mg itraconazole solution increased fenebrutinib AUC, there was an unexpected decrease in Cmax and a delay in time to reach Cmax (Tmax). Understanding the cause of this clinical observation was important to determine CYP3A’s contribution to fenebrutinib clearance, and subsequently the DDI between fenebrutinib and other CYP3A inhibitors and/or inducers.

Here, we presented an integrated approach to support PBPK model-informed fenebrutinib drug development. AUltimately, with better mechanistic understanding, PBPK model-based approaches may facilitate developing clinical recommendations for concomitant medication use for fenebrutinib, without requiring additional clinical DDI studies.

About our Speaker

Dr. Yuan Chen is a Principal Scientist in the Department of Drug Metabolism and Pharmacokinetics at Genentech. She has nearly 20 years of experience in broad areas of drug discovery and development in Roche and Genentech. Yuan has been in project lead role for many discovery and early development projects, and contributed to the clinical candidate nomination and filing of IND /CTA and NDA to the regulatory authorities. Yuan’s scientific expertise is on physiologically-based pharmacokinetic (PBPK) modeling for the prediction of human PK, absorption, and CYP-and transporter-mediated drug-drug interactions etc. She leads PBPK effort at Genentech, oversees PBPK strategy and support to all projects, and has great experiences in interactions with regulators for PBPK application in drug labeling. In addition, Yuan has been an active member on the IQ PBPK expert working groups and contributed to several PBPK white papers.

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