Towards a Best Practice Approach in PBPK Modeling: Case Example of Developing a Unified Efavirenz Model Accounting for Induction of CYPs 3A4 and 2B6

• Main Authors: A Ke (Author), Z Barter (Author), K Rowland‐Yeo (Author), L Almond (Author)
• Format: Book
• Published: Wiley, 2016-07-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2163-8306; 10.1002/psp4.12088
• Keywords: Therapeutics. Pharmacology; RM1-950
• Source: CPT: Pharmacometrics & Systems Pharmacology, Vol 5, Iss 7, Pp 367-376 (2016)

In this study, we present efavirenz physiologically based pharmacokinetic (PBPK) model development as an example of our best practice approach that uses a stepwise approach to verify the different components of the model. First, a PBPK model for efavirenz incorporating in vitro and clinical pharmacokinetic (PK) data was developed to predict exposure following multiple dosing (600 mg q.d.). Alfentanil i.v. and p.o. drug‐drug interaction (DDI) studies were utilized to evaluate and refine the CYP3A4 induction component in the liver and gut. Next, independent DDI studies with substrates of CYP3A4 (maraviroc, atazanavir, and clarithromycin) and CYP2B6 (bupropion) verified the induction components of the model (area under the curve [AUC] ratios within 1.0-1.7‐fold of observed). Finally, the model was refined to incorporate the fractional contribution of enzymes, including CYP2B6, propagating autoinduction into the model (Racc 1.7 vs. 1.7 observed). This validated mechanistic model can now be applied in clinical pharmacology studies to prospectively assess both the victim and perpetrator DDI potential of efavirenz.