CYP-Mediated Therapeutic Protein-Drug Interactions

Abstract

Therapeutic proteins (TPs) may affect the disposition of drugs that are metabolized by cytochrome P450 (CYP) enzymes, as is evident from a review of data in recently published literature and approved Biologic License Applications. Many TPs belonging to the cytokine class appear to differentially affect CYP activities. Cytokine modulators may affect CYP enzyme activities by altering cytokine effects on CYP enzymes. The alteration in CYP enzyme activities seems to result from changes in transcription factor activity for CYP enzyme expression or changes in CYP enzyme stability, which have been observed during altered immunological states such as infection and inflammation. Human growth hormone also appears to differentially affect CYP activities through unknown mechanisms. Because TP-drug interaction research is an evolving area, limited information is available during drug development on TP-drug interactions mediated by CYP inhibition or induction. The authors of this review suggest that effort be made to understand TP-drug interactions for the safe and effective use of TPs in combination with small-molecule drugs.

Use of a cocktail probe to assess potential drug interactions with cytochrome P450 after administration of belatacept, a costimulatory immunomodulator

“…This study used the validated, orally administered Inje cocktail to assess the effect of belatacept on the pharmacokinetics of drugs metabolized by CYP1 A2 (caffeine), CYP2C9 (losartan), CYP2C19 (omeprazole), CYP2D6 (dextromethorphan) and CYP3 A4 (midazolam). Belatacept has been shown to inhibit the production of certain cytokines during an in vitro alloimmune response, and modulation of cytokine pathways responsible for regulating CYP expression is a common means by which therapeutic proteins may influence CYP activity 8. As the half‐life of belatacept in healthy individuals approaches 10 days (t 1/2  = 9.8) 4, a single dose on Day 4 could potentially affect CYP‐substrate pharmacokinetics up to Day 11.…”

“…However, it is now known that therapeutic proteins, which are proinflammatory cytokines or cytokine modulators (e.g. monoclonal antibodies) can alter CYP expression or function and thereby interact with drugs that are CYP substrates 7, 8. Endogenous cytokines produced in response to infection and disease can downregulate transcription of specific CYP genes, and clinically relevant interactions have been reported when therapeutic cytokines such as interferon (IFN)‐α are administered with drugs that are CYP substrates 6.…”

“…Belatacept has been shown to inhibit production of certain cytokines during an in vitro alloimmune response, and modulation of cytokine pathways responsible for regulating CYP expression is a common means by which therapeutic proteins may influence CYP activity 8. As the half‐life of belatacept in healthy individuals approaches 10 days (t 1/2  = 9.8) 4, a single administered dose could potentially affect CYP pharmacokinetics during this time period.…”

Is there more to learn about cytochrome P450 enzymes?

“…It had generally been thought that therapeutic proteins such as monoclonal antibodies were unlikely to cause drug interactions by affecting CYP, principally because they are not metabolised by this system 22. However, evidence is emerging that some inflammatory diseases can alter the activity of these isoenzymes, and controlling the inflammatory processes involved with such diseases with a monoclonal antibody may have an impact on drug treatment.…”

Challenges and Opportunities in Absorption, Distribution, Metabolism, and Excretion Studies of Therapeutic Biologics

“…Drug-drug interactions: As the number of approved therapeutic biologics increases, potential drug-drug interactions (DDI) between concurrently administered drugs (small molecule-biologic drugs or biologic-biologics drugs) become a concern. The importance on therapeutic proteindrug interactions and guidance that recommends how and when to evaluate such interactions have been published recently by FDA (82,83). However, preclinical tools and in vitro test systems for assessing drug interaction potential of therapeutic proteins are limited.…”