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

ABSTRACT: AIM:This 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. METHODS:Twenty-two evaluable subjects received the Inje cocktail on Days 1, 4, 7 and 11 and belatacept infusion on Day 4. RESULTS:Since 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. CONCLUSIONS:Therefore, no dose adjustments of CYP substrates are indicated with belatacept coadministration.

SUBMITTER: Williams D

PROVIDER: S-EPMC5237687 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Williams Daphne D Tao Xiaolu X Zhu Lili L Stonier Michele M Lutz Justin D JD Masson Eric E Zhang Sean S Ganguly Bishu B Tzogas Zoe Z Lubin Susan S Murthy Bindu B

British journal of clinical pharmacology 20161102 2

<h4>Aim</h4>This 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.<h4>Methods</h4>Twenty-two evaluable subjects received the Inje cocktail on Days 1, 4, 7 and 11 and belatacept infusion on Day 4.<h4>Results</h4>Since belatacept caused no major alterations to cytokine levels, there were ...[more]

PMID: 27552251

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Project description:PurposeProbe substrates are used routinely to assess transporter function in vitro. Administration of multiple probe substrates together as a "cocktail" in sandwich-cultured human hepatocytes (SCHH) could increase the throughput of transporter function assessment in a physiologically-relevant in vitro system. This study was designed to compare transporter function between cocktail and single agent administration in SCHH.MethodsRosuvastatin, digoxin, and metformin were selected as probe substrates of hepatic transporters OATP1B1, OATP1B3, BCRP, P-gp, and OCT1. Total accumulation (Cells+Bile) and biliary excretion index (BEI) values derived from administration of the cocktail were compared to values obtained after administration of single agents in the absence and presence of a model inhibitor, erythromycin estolate.ResultsFor rosuvastatin and metformin accumulation, the ratio of means [90% confidence interval (CI)] for cocktail to single agent administration was 100% [94%, 106%] and 90% [82%, 99%], respectively. Therefore, the cocktail and single-agent mode of administration were deemed equivalent per standard equivalence criterion of 80-120% for rosuvastatin and metformin accumulation, but not for digoxin accumulation (77% [62%, 92%]). The ratio of means [90% CI] for rosuvastatin BEI values between the two administration modes (105% [97%, 114%]) also was deemed equivalent. The ratio for digoxin BEI values between the two administration modes was 99% [78%, 120%]. In the presence of erythromycin estolate, the two administration modes were deemed equivalent for evaluation of rosuvastatin, digoxin, and metformin accumulation; the ratio of means [90% CI] was 104% [94%, 115%], 94% [82%, 105%], and 100% [88%, 111%], respectively. However, rosuvastatin and digoxin BEI values were low and quite variable in the presence of the inhibitor, so the BEI results were inconclusive.ConclusionsThese data suggest that rosuvastatin and metformin can be administered as a cocktail to evaluate the function of OATP1B1, OATP1B3, BCRP, and OCT1 in SCHH, and that digoxin may not be an ideal component of such a cocktail.

Dataset Information

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

Publications

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

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