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Anti-interleukin-6 antibody clazakizumab in late antibody-mediated kidney transplant rejection: effect on cytochrome P450 drug metabolism.
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.
Afiliação
  • Mühlbacher J; Department of General Surgery, Medical University of Vienna, Vienna, Austria.
  • Schörgenhofer C; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
  • Doberer K; Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
  • Dürr M; Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany.
  • Budde K; Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany.
  • Eskandary F; Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
  • Mayer KA; Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
  • Schranz S; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
  • Ely S; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
  • Reiter B; Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
  • Chong E; Vitaeris Inc. (a subsidiary of CSL Behring, King of Prussia, PA, USA), Vancouver, BC, Canada.
  • Adler SH; CSL Behring, King of Prussia, PA, USA.
  • Jilma B; Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
  • Böhmig GA; Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
Transpl Int ; 34(8): 1542-1552, 2021 Aug.
Article em En | MEDLINE | ID: mdl-34153143
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Preparações Farmacêuticas / Transplante de Rim Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Humans Idioma: En Revista: Transpl Int Assunto da revista: TRANSPLANTE Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Áustria

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Preparações Farmacêuticas / Transplante de Rim Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Humans Idioma: En Revista: Transpl Int Assunto da revista: TRANSPLANTE Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Áustria