Open AccessAnti‐interleukin‐6 antibody clazakizumab in late antibody‐mediated kidney transplant rejection: effect on cytochrome P450 drug metabolism
Author(s) -
Mühlbacher Jakob,
Schörgenhofer Christian,
Doberer Konstantin,
Dürr Michael,
Budde Klemens,
Eskandary Farsad,
Mayer Katharina A.,
Schranz Sabine,
Ely Sarah,
Reiter Birgit,
Chong Edward,
Adler Scott H.,
Jilma Bernd,
Böhmig Georg A.
Publication year - 2021
Publication title -
transplant international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.998
H-Index - 82
eISSN - 1432-2277
pISSN - 0934-0874
DOI - 10.1111/tri.13954
Subject(s) - medicine , tacrolimus , calcineurin , cyp3a4 , pharmacokinetics , gastroenterology , placebo , drug metabolism , pharmacology , pharmacodynamics , pantoprazole , kidney transplantation , kidney , cytochrome p450 , drug , transplantation , omeprazole , metabolism , pathology , alternative medicine
Summary 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 C 0 levels (C 0 /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 C 0 /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.