Time shift in ciclosporin metabolism downregulation by inflammation in allogeneic hematopoietic cell transplantation: A time-dependent transduction modelling PK-PD approach

Abstract

Ciclosporin is a major immunosuppressant in allogeneic hematopoietic stem cell transplantation (HSCT), with a narrow therapeutic index and high interindividual variability. We previously showed that severe inflammation significantly reduces cytochrome P450 3A4 (CYP3A4)-mediated ciclosporin metabolism, as reflected by an increased concentration-to-dose (C/D) ratio. However, the temporal dynamics between inflammation and ciclosporin metabolism remain poorly understood. This study aimed to characterize the time-dependent effect of inflammation—quantified by C-reactive protein (CRP) levels—on CYP3A4-mediated ciclosporin metabolism using a signal transduction pharmacokinetic-pharmacodynamic (PK-PD) modeling approach in HSCT patients. We selected 10 HSCT patients with a single moderate-to-severe inflammatory episode (CRP > 40 mg/L) and modeled CRP kinetics alongside ciclosporin C/D ratios using a transduction model. Key parameters included the maximum effect (E_max), the CRP concentration at 50% of E_max (EC₅₀), and the time delay (τ) between CRP and metabolism variations. External validation was performed using published time profiles from Chen et al. 1994 and 2 patients with potential drug–drug interactions (pDDI) involving letermovir from our cohort. The model captured a 4.7-fold increase in C/D ratio at an EC₅₀ of 120 mg/L of CRP, with a time delay of 6 days between CRP peak and C/D ratio peak. External validation confirmed strong predictive performance. In patients with moderate-to-severe inflammation, inflammation-driven CYP3A4 downregulation appeared to outweigh the impact of letermovir-mediated DDI. Our results provide the first quantitative evidence of time-dependent inhibition due to inflammation of ciclosporin metabolism. This quantitative modeling framework may inform dose adjustment and DDI risk evaluation in inflammatory conditions, particularly in allogeneic HSCT patients.