Malnoë David, Bories Mathilde, Pierre-Jean Morgane, Marchand Tony, Le Corre Pascal
Centre Hospitalier Universitaire de Rennes, Pôle Pharmacie, Secteur Pharmacotechnie et Onco-Pharmacie, Rennes, France.
Faculté de Pharmacie, Laboratoire de Biopharmacie et Pharmacie Clinique, Université de Rennes, Rennes, France.
J Clin Pharmacol. 2025 Mar;65(3):328-339. doi: 10.1002/jcph.6141. Epub 2024 Oct 9.
Graft-versus-host disease (GVHd) remains a significant challenge following allogeneic hematopoietic stem cell transplantation (HSCT). Prevention of GVHd relies mainly on the use of calcineurin inhibitors, notably ciclosporin that exhibits complex pharmacokinetics influenced by many factors including drug-drug interactions (DDIs). Due to the downregulation of drug metabolizing enzymes and transporters, it has been postulated that inflammation may be a contributing factor to the variability observed in ciclosporin pharmacokinetics. This study aimed to assess the impact of inflammation, as indicated by C-reactive protein (CRP) levels, on the metabolism of ciclosporin in adult allogeneic HSCT recipients. A retrospective observational study was conducted at Rennes University Hospital involving 71 adult HSCT patients. The relationship between the intensity of inflammation (no-to-mild, moderate, and severe), and the metabolism of ciclosporin (estimated by the concentration/dose ratio) was assessed. Severe inflammation significantly decreased the metabolism of ciclosporin, as evidenced by higher concentration/dose ratios. Thanks to the daily dose adjustment, inflammation did not influence the blood levels of ciclosporin. Interestingly, DDIs did not emerge as a significant covariate in influencing ciclosporin metabolism. This is likely because the CYP3A4 inhibitory potential of interacting drugs may be masked in HSCT patients where metabolism is already upstream downregulated by inflammation. The study highlights the intricate relationship between inflammation and ciclosporin pharmacokinetics in HSCT patients. This underscores the necessity for therapeutic monitoring and the potential adjustment of dosage strategies based on the inflammatory status. These insights could contribute to the development of more personalized, optimized, and effective management strategies for HSCT recipients.
移植物抗宿主病（GVHd）仍然是异基因造血干细胞移植（HSCT）后的一项重大挑战。预防GVHd主要依赖于使用钙调神经磷酸酶抑制剂，尤其是环孢素，其药代动力学复杂，受包括药物相互作用（DDIs）在内的多种因素影响。由于药物代谢酶和转运体的下调，有人推测炎症可能是环孢素药代动力学变异性的一个促成因素。本研究旨在评估以C反应蛋白（CRP）水平表示的炎症对成年异基因HSCT受者中环孢素代谢的影响。在雷恩大学医院进行了一项回顾性观察研究，纳入了71例成年HSCT患者。评估了炎症强度（无至轻度、中度和重度）与环孢素代谢（通过浓度/剂量比估计）之间的关系。严重炎症显著降低了环孢素的代谢，浓度/剂量比升高证明了这一点。由于每日剂量调整，炎症并未影响环孢素的血药水平。有趣的是，DDIs并未成为影响环孢素代谢的显著协变量。这可能是因为在HSCT患者中，相互作用药物的CYP3A4抑制潜力可能被掩盖，因为其代谢已因炎症而在前期下调。该研究突出了HSCT患者中炎症与环孢素药代动力学之间的复杂关系。这强调了治疗监测的必要性以及基于炎症状态调整剂量策略的可能性。这些见解可能有助于为HSCT受者制定更个性化、优化和有效的管理策略。
