An exposure-response analysis based on rifampin suggests CYP3A4 induction is driven by AUC: an in vitro investigation.
1. Induction is an important mechanism contributing to drug-drug interactions. It is most commonly evaluated in the human hepatocyte assay over 48-h or 72-h incubation period. However, whether the overall exposure (i.e. Area Under the Curve (AUC) or Cave) or maximum exposure (i.e. Cmax) of the inducer is responsible for the magnitude of subsequent induction has not been thoroughly investigated. Additionally, in vitro induction assays are typically treated as static systems, which could lead to inaccurate induction potency estimation. Hence, European Medicines Agency (EMA) guidance now specifies quantitation of drug levels in the incubation. 2. This work treated the typical in vitro evaluation of rifampin induction as an in vivo system by generating various target engagement profiles, measuring free rifampin concentration over 3 d of incubation and evaluating the impact of these factors on final induction response. 3. This rifampin-based analysis demonstrates that the induction process is driven by time-averaged target engagement (i.e. AUC-driven). Additionally, depletion of rifampin in the incubation medium over 3 d as well as non-specific/specific binding were observed. 4. These findings should help aid the discovery of clinical candidates with minimal induction liability and further expand our knowledge in the quantitative translatability of in vitro induction assays.
a Systems Modeling and Simulation Group , Pharmacokinetics, Dynamics & Metabolism - NCE, Medicine Design, Worldwide Research and Development, Pfizer Inc. , Groton, CT 06340 , USA and.
Cheng
C
Chang
b Enzymology and Transporter Group , Pharmacokinetics, Dynamics & Metabolism - NCE, Medicine Design, Worldwide Research and Development, Pfizer Inc. , Groton, CT 06340 , USA.
Xin
X
Yang
b Enzymology and Transporter Group , Pharmacokinetics, Dynamics & Metabolism - NCE, Medicine Design, Worldwide Research and Development, Pfizer Inc. , Groton, CT 06340 , USA.
Odette A
OA
Fahmi
b Enzymology and Transporter Group , Pharmacokinetics, Dynamics & Metabolism - NCE, Medicine Design, Worldwide Research and Development, Pfizer Inc. , Groton, CT 06340 , USA.
Keith A
KA
Riccardi
b Enzymology and Transporter Group , Pharmacokinetics, Dynamics & Metabolism - NCE, Medicine Design, Worldwide Research and Development, Pfizer Inc. , Groton, CT 06340 , USA.
Li
L
Di
b Enzymology and Transporter Group , Pharmacokinetics, Dynamics & Metabolism - NCE, Medicine Design, Worldwide Research and Development, Pfizer Inc. , Groton, CT 06340 , USA.
R Scott
RS
Obach
D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology*; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D012293:Rifampin / Q000494:pharmacology*
D065701:Cytochrome P-450 CYP3A Inducers; D051544:Cytochrome P-450 CYP3A; D012293:Rifampin
CYP3A4; drug–drug interaction; exposure–response relationship; induction; pharmacokinetics pharmacodynamics (PKPD)