Anti-interleukin-6 antibody clazakizumab in late antibody-mediated kidney transplant rejection: effect on cytochrome P450 drug metabolism

Abstract

Targeting interleukin-6 (IL-6) is a promising strategy to counteract antibody-mediated rejection (ABMR). In inflammatory states, IL-6 antagonism was shown to modulate cytochrome P450 (CYP), but its impact on drug metabolism in ABMR treatment was not addressed so far. We report a sub-study of a phase 2 trial of anti-IL-6 antibody clazakizumab in late ABMR (ClinicalTrials.gov, NCT03444103). Twenty kidney transplant recipients were randomized to clazakizumab versus placebo (4-weekly doses; 12 weeks), followed by a 9-month extension where all recipients received clazakizumab. To study CYP2C19/CYP3A4 metabolism, we administered pantoprazole (20 mg intravenously) at prespecified time points. Dose-adjusted C0 levels (C0 /D ratio) of tacrolimus (n = 13) and cyclosporin A (CyA, n = 6) were monitored at 4-weekly intervals. IL-6 and C-reactive protein were not elevated at baseline, the latter was then suppressed to undetectable levels under clazakizumab. IL-6 blockade had no clinically meaningful impact on pantoprazole pharmacokinetics (area under the curve; baseline versus week 52: 3.16 [2.21-7.84] versus 4.22 [1.99-8.18] μg/ml*h, P = 0.36) or calcineurin inhibitor C0 /D ratios (tacrolimus: 1.49 [1.17-3.20] versus 1.37 [0.98-2.42] ng/ml/mg, P = 0.21; CyA: 0.69 [0.57-0.85] versus 1.08 [0.52-1.38] ng/ml/mg, P = 0.47). We conclude that IL-6 blockade in ABMR - in absence of systemic inflammation - may have no meaningful effect on CYP metabolism.

Keywords: antibody-mediated rejection; clazakizumab; cytochrome P450; drug metabolism; interleukin-6; kidney transplantation.

Conflict of interest statement

E. Chong was employed by Vitaeris Inc., Vancouver, Canada (a subsidiary of CSL Behring, King of Prussia, PA, USA). S.H. Adler is employed by CSL Behring. G.A. Böhmig is member of the steering committee for an ongoing pivotal phase 3 trial evaluating clazakizumab in chronic active antibody‐mediated rejection (ClinicalTrials.gov number, NCT03744910; sponsored by CSL Behring). All remaining authors have nothing to disclose. The results presented in this paper have not been published previously in whole or part, except in abstract format.

© 2021 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.

Figures

Figure 1

Summary of trial protocol. Twenty renal allograft recipients diagnosed with late antibody‐mediated rejection (ABMR) were randomized to receive clazakizumab or placebo for 12 weeks (part A). After 12 weeks, patients entered part B and they all were scheduled to receive clazakizumab. Two patients were withdrawn from the study because of diverticular disease complications. Both completed part A, one was withdrawn shortly before, the other after the first clazakizumab dose in part B. C0, trough level; CNI, calcineurin inhibitor; CYP, cytochrome P450; D, dose; DSA, donor‐specific antibody; mTOR, mammalian target of rapamycin; PK, pharmacokinetics.

Figure 2

C‐reactive protein (CRP), interleukin‐6 (IL‐6), and liver parameters. Panel a illustrates the course of CRP and IL‐6 levels (median and interquartile range) measured at 4‐weekly intervals in patients randomized to receive clazakizumab (red line) or placebo (black line), respectively. Panel b shows levels (median, interquartile range and range) of liver parameters for patients allocated to clazakizumab (red closed boxplots) versus placebo (part A: open boxplots; part B: red hatched box plots). ALAT, alanine aminotransferase; AST, aspartate aminotransferase; CHE, cholinesterase.

Figure 3

Immunosuppressant C0 level/dose (C0/D) ratio and C0 levels. Results are shown for tacrolimus (a, median and interquartile range), cyclosporin A (b, individual course), and everolimus (c, individual course), in relation to treatment allocation (placebo: black [part A] and hatched red lines [part B]; clazakizumab: red lines [part A and part B]. For part A, data were available for all patients, and for part B, because of study withdrawal of two patients, for 18 subjects.