Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: Interleukin 6 (IL-6) reduces the expression of cytochrome P450 (CYP) enzymes. The goal of the study was to evaluate: 1) the effect of sirukumab on the pharmacokinetics of probe substrates for CYP3A4, CYP2C9, CYP2C19, and CYP1A2 in patients with active rheumatoid arthritis (RA), a disease in which IL-6 is elevated; 2) the safety of a single subcutaneous high dose of sirukumab in RA patients.
Methods: This was an open-label, Phase 1 study in men and women 18-65 years of age, diagnosed with RA and with a screening CRP≥8.0 mg/L. Twelve patients, genotyped to exclude poor metabolizers of CYP2C9 and CYP2C19, were enrolled. Patients received oral “cocktail” administrations of CYP probe substrates (midazolam, warfarin, omeprazole and caffeine) at weeks -1, 1, 3, and 6 weeks relative to a single subcutaneous dose of 300 mg sirukumab. Serum sirukumab concentration and antibodies to sirukumab were analyzed. Safety was monitored through 7 weeks after sirukumab administration. Plasma levels of 4-β-hydroxycholesterol were measured.
Results: AUCinf of each probe substrate before and after sirukumab treatment showed that exposure to midazolam, omeprazole and S-warfarin was reduced modestly (<50%) at 1, 3 and 6 weeks after sirukumab treatment. CRP decreased after sirukumab administration. Mean plasma levels of 4-β-hydroxycholesterol showed an increase of about 25% over time, but the ratio of 4-β-hydroxycholesterol to cholesterol did not change. All 12 patients reported at least one non-serious adverse event, the two most frequent ones being laboratory abnormalities and mild injection site reactions. No new safety findings were observed and no SAEs were reported.
Conclusion: Consistent with its intended suppression of IL-6 effects, treatment with sirukumab may reverse IL-6-mediated suppression of CYP3A4, CYP2C9 and CYP2C19 activities in RA patients. These results suggest the possibility of potential changes in the levels of certain CYP-metabolized medications in RA patients treated with sirukumab. Single high-dose sirukumab and probe cocktail administrations were well tolerated, without new safety findings.
Table 1: Mean (SD) values for AUCinf of each probe substrate before and after sirukumab treatment
|
Probe Substrate |
Pre-sirukumab (n=12) |
1 week after sirukumab (n=12) |
3 weeks after sirukumab (n=12) |
6 weeks after sirukumab (n=12) |
|||
|
AUCinf(ng*h/mL) Day 1
|
AUCinf(ng*h/mL) Day 15 |
%change* |
AUCinf(ng*h/mL) Day 29 |
%change* |
AUCinf(ng*h/mL) Day 50 |
%change* |
|
|
Midazolam |
50.67 (24.29) |
34.34 (13.89) |
-30 |
32.63 (15.76) |
-35 |
33.80 (15.39) |
-33 |
|
Omeprazole |
3720 (2623) |
1937 (1372) |
-45 |
2130 (1537) |
-41 |
2152 (1369) |
-37 |
|
S-warfarin |
24248 (4359) |
19816 (3126) |
-18 |
19845 (3354) |
-18 |
19476 (2824) |
-19 |
|
Caffeine |
13989 (10534) |
15747 (10036) |
20 |
19538 (15794) |
34 |
17967 (13900) |
28 |
|
*calculated based on geometric mean ratio |
|||||||
Disclosure:
D. de Vries,
Janssen Research and Development, LLC,
3;
Y. Zhuang,
Janssen Research and Development, LLC,
3;
S. Marciniak,
Janssen Research and Development, LLC,
3;
Z. Xu,
Janssen Research and Development, LLC,
3;
D. Chen,
Janssen Research and Development, LLC,
3;
H. M. Davis,
Janssen Research and Development, LLC,
3;
H. Zhou,
Janssen Research and Development, LLC.,
3;
F. Leon,
Janssen Research and Development, LLC.,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/evaluation-of-the-pharmacokinetics-and-safety-of-the-interactions-between-the-anti-interleukin-6-monoclonal-antibody-sirukumab-and-cytochrome-p450-activities-in-patients-with-rheumatoid-arthritis/