title: Utility of population pharmacokinetic modeling in the assessment of therapeutic protein-drug interactions.
abstract: Assessment of pharmacokinetic (PK) based drug-drug interactions (DDI) is essential for ensuring patient safety and drug efficacy. With the substantial increase in therapeutic proteins (TP) entering the market and drug development, evaluation of TP-drug interaction (TPDI) has become increasingly important. Unlike for small molecule (e.g., chemical-based) drugs, conducting TPDI studies often presents logistical challenges, while the population PK (PPK) modeling may be a viable approach dealing with the issues. A working group was formed with members from the pharmaceutical industry and the FDA to assess the utility of PPK-based TPDI assessment including study designs, data analysis methods, and implementation strategy. This paper summarizes key issues for consideration as well as a proposed strategy with focuses on (1) PPK approach for exploratory assessment; (2) PPK approach for confirmatory assessment; (3) importance of data quality; (4) implementation strategy; and (5) potential regulatory implications. Advantages and limitations of the approach are also discussed.
authors.affiliation: Quantitative Pharmacology, Department of Pharmacokinetics & Drug Metabolism, Amgen, Inc., Thousand Oaks, CA, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chow
authors.affiliation: Office of Clinical Pharmacology & Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, MD, USA.
authors.forename: Justin C
authors.initials: JC
authors.lastname: Earp
authors.affiliation: Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Lawrenceville, NJ, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Gupta
authors.affiliation: PK/PD and Drug Metabolism, Merck & Co, West Point, PA, USA.
authors.forename: William
authors.initials: W
authors.lastname: Hanley
authors.affiliation: Biologics Clinical Pharmacology, Janssen Research and Development LLC, Spring House, PA, USA.
authors.forename: Chuanpu
authors.initials: C
authors.lastname: Hu
authors.affiliation: Clinical Pharmacology, Oncology Business Unit, Pfizer, La Jolla, CA, USA.
authors.forename: Diane D
authors.initials: DD
authors.lastname: Wang
authors.affiliation: PK/PD and Drug Metabolism, Merck & Co, West Point, PA, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zajic
authors.affiliation: Quantitative Pharmacology, Department of Pharmacokinetics & Drug Metabolism, Amgen, Inc., Thousand Oaks, CA, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
mesh_terms: D004347:Drug Interactions; D006801:Humans; D008954:Models, Biological; D011506:Proteins / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D011506:Proteins
keywords: TP–drug interaction; confirmatory PPK approach; drug–drug interaction; population pharmacokinetic model; therapeutic protein