Critical Review of Preclinical Approaches to Investigate Cytochrome P450–Mediated Therapeutic Protein Drug-Drug Interactions and Recommendations for Best Practices: A White Paper

Abstract

Drug-drug interactions (DDIs) between therapeutic proteins (TPs) and small-molecule drugs have recently drawn the attention of regulatory agencies, the pharmaceutical industry, and academia.

Development of a Physiologically Based Pharmacokinetic Model to Predict Disease-Mediated Therapeutic Protein–Drug Interactions: Modulation of Multiple Cytochrome P450 Enzymes by Interleukin-6

“…These values were similar to the observed AUC 0- AUC area under plasma concentration versus time curves, RA rheumatoid arthritis a AUC (ng*h/mL) are presented as mean (SD) of 0 to infinity values b AUC ratio is presented as geometric mean ratio (90% CI) c Patients received an oral cocktail of CYP probe subs at 1 week prior to (day 1) and 3 weeks after (day 29) a single subcutaneous dose of 300 mg sirukumab 24 h and the post-/pre-treatment AUC ratio values, which were 102 ± 44 ng*h/mL, 42.3 ± 18 ng*h/mL, and 43% (90% CI 34-55%), respectively (8). The PBPK model prediction also suggested that anti-IL-6R treatment by tocilizumab may cause a 34% (90% CI 23%-46%) decrease in systemic exposure to omeprazole, which is also similar to the observed value (28%) in RA patients (31).…”

“…Interleukin-6 has been generally considered as a suppressor for CYP enzymes (31). In vitro studies have shown that CYP3A4, CYP2C19, CYP2C9, and CYP1A2 expression and activities were suppressed at high IL-6 concentrations (>100 pg/mL) (5,6).…”

“…As a result, the development of a PBPK model can also reasonably characterize the TP-DI in RA patients between CYP enzyme substrates and tocilizumab, an IL-6R antibody that blocks IL-6 binding to soluble and membrane-expressed IL-6R and the downstream signaling (8). It has been reported that tocilizumab treatment caused 57 and 28% decreases in system exposure to CYP3A4 substrate simvastatin and CYP2C19 substrate omeprazole, respectively (8,31). The results from our model validation process also reasonably captured such trends, which showed that blockage of IL-6 pathway caused 49% (90% CI 42-58% and 34% (90% CI 23-46%) decreases in systemic exposure to simvastatin and omeprazole, respectively.…”

“…Subsequently, plasma concentration profiles of the CYP substrates in RA patients before sirukumab treatment from the sirukumab clinical cocktail TP-DI study (10) were simulated with the developed virtual RA patient population and the optimized CYP substrate profiles. Model (8,31). All PK simulations were conducted using 10 trials containing 10 subjects each with CYP substrates orally administered on day 31 or day 39 of simulation to ensure the regulatory effect of IL-6 on the expression levels of all hepatic CYP enzymes reached SS at time of dosing.…”

Anti-CD28 Monoclonal Antibody–Stimulated Cytokines Released from Blood Suppress CYP1A2, CYP2B6, and CYP3A4 in Human Hepatocytes In Vitro

“…Although the absorption, distribution, metabolism, and excretion properties of small-molecule drugs and therapeutic proteins (also known as biologic drugs) are distinct, the two classes of drugs can alter each other's disposition, and therefore have the potential for drug-drug interactions (DDIs) (Evers et al, 2013). Changes in the clearance of small-molecule drugs caused by certain therapeutic proteins can be a consequence of the suppression of drug-metabolizing enzymes (DMEs) or transporters Lee et al, 2010;Zhou and Mascelli, 2011).…”