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.