Multicenter-Based Population Pharmacokinetic Analysis of Ciclosporin in Hematopoietic Stem Cell Transplantation Patients

• Published in: Pharmaceutical research Vol. 37; no. 1; pp. 15 - 13
• Main Authors: Xue, Ling, Zhang, Wen-juan, Tian, Ji-xin, Liu, Lin-na, Yan, Hai-hong, Zhang, Wen-wen, Ding, Xiao-liang, Zhang, Jing-jing, Miao, Li-yan
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.01.2020; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult; Aged; Analysis; Antifungal agents; Aspartate; Aspartate aminotransferase; Bioavailability; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Body Weight; Child; Child, Preschool; Creatinine; Cyclosporine; Cyclosporine - pharmacokinetics; Demography; Dose-Response Relationship, Drug; Drug Therapy, Combination - methods; Female; Fluconazole; Fluconazole - pharmacology; Hematocrit; Hematologic Neoplasms - therapy; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Humans; Immunosuppressive agents; Immunosuppressive Agents - pharmacokinetics; Indicators (Biology); Information management; Itraconazole; Itraconazole - pharmacology; Male; Medical Law; Medical records; Middle Aged; Models, Biological; Patients; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Physiological aspects; Reproducibility of Results; Research Paper; Stem cell transplantation; Stem cells; Transplantation; Transplantation Conditioning - methods; Uric acid; Voriconazole; Voriconazole - pharmacology; ciclosporin; hematopoietic stem cell transplantation; multicenter; population pharmacokinetics
• ISSN: 0724-8741; 1573-904X; 1573-904X
• DOI: 10.1007/s11095-019-2740-2

Purpose To explore the contribution of physiological characteristics to variability in ciclosporin pharmacokinetics in hematopoietic stem cell transplantation patients. Methods Clinical data from 563 patients were collected from centers in three regions. Ciclosporin concentrations were measured using immunoassays. The patients’ demographics, hematological and biological indicators, coadministered drugs, region, and disease diagnosis were recorded from medical records. Data analysis was performed using NONMEM based on a one-compartment model to describe the pharmacokinetics of ciclosporin. The reliability and stability of the final model were evaluated using bootstrap resampling, goodness-of-fit plots, and prediction-corrected visual predictive checks. Results The population estimate of the clearance (CL) was 30.4 L/h, the volume of distribution (V) was 874.0 L and the bioavailability (F) was 81.1%. The between-subject variability in these parameters was 26.3, 68.0, and 110.8%, respectively. Coadministration of fluconazole, itraconazole, or voriconazole decreased CL by 17.6%, 28.4%, and 29.2%, respectively. Females’ CL increased by approximately 12.0%. In addition, CL and V decreased with hematocrit, total protein, and uric acid increase, and CL also decreased with age and aspartate aminotransferase increase. However, CL increased with creatinine clearance increase. Conclusions A multicenter-based population pharmacokinetic model of ciclosporin was established. The pharmacokinetics of ciclosporin exhibited discrepancies among different regions.