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

Abstract

AimThis open‐label study investigated the effect of belatacept on cytokine levels and on the pharmacokinetics of caffeine, losartan, omeprazole, dextromethorphan and midazolam, as CYP probe substrates after oral administration of the Inje cocktail in healthy volunteers.MethodsTwenty‐two evaluable subjects received the Inje cocktail on Days 1, 4, 7 and 11 and belatacept infusion on Day 4.ResultsSince belatacept caused no major alterations to cytokine levels, there were no major effects on CYP‐substrate pharmacokinetics, except for a slight (16–30%) increase in omeprazole exposure, which was probably due to omeprazole‐mediated, time‐dependent CYP inhibition. Belatacept did not cause major alterations in the pharmacokinetics, as measured by the geometric mean ratios and associated 90% confidence interval for area under the plasma concentration ‐time curve from time zero to infinity on Day 7 comparing administration with and without belatacept for caffeine (1.002 [0.914, 1.098]), dextromethorphan (1.031 [0.885, 1.200]), losartan (1.016 [0.938, 1.101)], midazolam (0.968 [0.892, 1.049]) or their respective metabolites.ConclusionsTherefore, no dose adjustments of CYP substrates are indicated with belatacept coadministration.

Assessment of CYP‐Mediated Drug Interactions for Evocalcet, a New Calcimimetic Agent, Based on In Vitro Investigations and a Cocktail Study in Humans

“…A cocktail approach, involving simultaneous administration of substrates for multiple CYP isozymes to subjects, is effective for evaluation of whether a test drug has the potential for clinically significant DDIs with multiple enzymes. Many cocktail combinations have been reported and their usefulness for DDI evaluation has been proven . However, the use of repaglinide in a cocktail as a substrate for CYP2C8 and the combination of substrates used in this study for several CYP isozymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP3A) has not been reported.…”

Simultaneous Determination of Five Cytochrome P450 Probe Substrates and Their Metabolites and Organic Anion Transporting Polypeptide Probe Substrate in Human Plasma Using Liquid Chromatography-Tandem Mass Spectrometry

“…Several research studies have reported the analytical method for five P450 isoform-probe drugs and their metabolites in plasma samples using LC-MS/MS. Recently, Oh et al [ 13 ], Tanaka et al [ 32 ], Williams et al [ 16 ], and Zhang et al [ 31 ] developed an LC-MS/MS method for five P450 probe drugs (caffeine, losartan, omeprazole, dextromethorphan, and midazolam) and their metabolites, which were used in an Inje cocktail [ 15 ]. Kim et al [ 12 ] developed a simultaneous assay for four P450 probe drugs (losartan, omeprazole, dextromethorphan, and midazolam) and their metabolites as well as fexofenadine, a P-gp substrate, after protein precipitation; however, caffeine and paraxanthine were separately analyzed after liquid-liquid extraction.…”

“…Several probe substrates have been validated to assess the activity of P450s and OATP1B1. Among them, caffeine, omeprazole, dextromethorphan, and midazolam are generally the most used as probes for CYP1A2, 2C19, 2D6, and 3A, respectively [ 15 , 16 , 17 ]. However, several different probe drugs have been used for CYP2C9 and OATP1B1 phenotyping studies.…”

Therapeutic Protein Drug Interactions: A White Paper From the International Consortium for Innovation and Quality in Pharmaceutical Development

“…Any protein that interacts with the immune system has the potential to change the homeostasis of circulating cytokines. This includes Fc‐based immunoglobulin G (IgG) glycoproteins, cytokine fusion proteins, 42 and drugs targeting immune checkpoints to more complex constructs such as T‐cell and natural killer (NK)–cell engagers. It may also include monoclonal antibodies specifically designed to be antagonists to specific cytokine receptors.…”