Population pharmacokinetics of ciclosporin in allogeneic hematopoietic stem cell transplant recipients: C‐reactive protein as a novel covariate for clearance

Abstract

What is known and objectives Ciclosporin (CsA), a potent immunosuppressive agent used to prevent graft‐versus‐host disease in allogeneic hematopoietic stem cell transplant (allo‐HSCT) recipients, is characterized by large inter‐individual variability and a narrow therapeutic range. The aim of this study was to develop a population pharmacokinetic model for CsA in Chinese allo‐HSCT recipients and to identify covariates influencing CsA pharmacokinetics. Methods A total of 758 retrospective drug monitoring data points were collected after intravenous infusion or oral administration of CsA from 59 patients. Population pharmacokinetic analysis was performed using nonlinear mixed effects modelling expressed by differential equations. Monte Carlo simulation was applied to optimize dosage regimens. The final model was validated using bootstrap and normalized prediction distribution errors. Results and discussion The results showed that the daily CsA dose, haematocrit, total bile acid, C‐reactive protein (CRP) and co‐administration of triazole antifungal agent were identified as significant covariates for clearance (CL) of CsA. The typical value of CL was 19.8 L/h with an inter‐individual variability of 13.1%. The volume of distribution was 1340 L. Bioavailability was 67.2% with an inter‐individual variability of 8.5%. Dosing simulation based on the developed model indicated that patients with high CRP concentration required a higher daily dose to attain the therapeutic trough concentration. The influence of CRP ultimately on the therapy outcome of CsA is not clear, which needs further study. What is new and conclusion CRP concentration was identified as a novel marker associated with CsA pharmacokinetics, which should be considered when determining the appropriate dosage of CsA in allo‐HSCT recipients.

A Drug Safety Concept (I) to Avoid Polypharmacy Risks in Transplantation by Individual Pharmacotherapy Management in Therapeutic Drug Monitoring of Immunosuppressants

“…For example, a more individualized pharmacokinetic dosing of vancomycin in a critically ill patient contributed to a faster achievement of the target value without increased nephrotoxicity [ 30 ]. Recently, the patient C-reactive protein (CRP) was identified as a significant covariate affecting the pharmacokinetics of CsA, indicating that a higher daily dose is required to achieve therapeutic trough concentrations at high CRP levels [ 31 ]. Since each patient has unique characteristics, immunosuppression has to be questioned to follow a uniform regimen [ 32 ].…”

Population Pharmacokinetics of Cyclosporine in Chinese Pediatric Patients With Acquired Aplastic Anemia

“…Concomitant drugs, such as anabolic steroids ( Ni et al, 2013 ) and triazole antifungal agents ( Zhou et al, 2012 ; Li et al, 2019 ; Ling et al, 2021 ), have been reported to affect CsA PK exposure. Children undergoing IST often receive steroids as a concomitant drug ( Ettenger, 1998 ; Benfield et al, 1999 ; Clucas et al, 2019 ).…”

Assessment of risk factors for acute graft-versus-host disease post-hematopoietic stem cell transplantation: a retrospective study based on a proportional odds model using a nonlinear mixed-effects model

“… 2 , 9 , 16 CsA has high interindividual variability, 17 and its pharmacokinetics are affected by numerous factors, including demographic characteristics, hematocrit, liver function, and triazole antifungal agents. 18 – 21 In a previous study, a population pharmacokinetic (PopPK) model for CsA was established in Chinese HSCT patients, 18 and the exposure (area under the concentration–time curve, AUC) of CsA could be estimated by this model. Some previous studies have explored the relationship between the concentration of CsA and the occurrence of aGVHD.…”