title: Population pharmacokinetics and individualized dosage prediction of cyclosporine in allogeneic hematopoietic stem cell transplant patients.
abstract: BACKGROUND
  Cyclosporine (CsA), a potent immunosuppressive agent used to prevent rejection, is characterized by large individual variability. The purpose of this study was to explore the pharmacokinetic characteristics of CsA and establish a CsA population pharmacokinetic model that could be used for personalized therapy in allogeneic hematopoietic stem cell transplant (allo-HSCT) patients.
  
  
  METHODS
  Clinical data were obtained from 117 allo-HSCT patients. The data analysis was performed using NONMEM software. A first-order conditional estimation with interaction (FOCE-I) method within NONMEM was used to estimate the parameters. The covariates, including demographics, hematological indices, biochemical levels, concurrent drugs, and genetic polymorphisms of CYP3A4, CYP3A5, and ABCB1, were evaluated quantitatively. The stability of the final model was validated by a nonparametric bootstrap procedure.
  
  
  RESULTS
  A total of 1,571 observed concentrations were collected. A 1-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of CsA. The typical values for clearance (CL), volume of distribution (V), and bioavailability were 29.6 L/hr, 605 L, and 0.619, respectively. The interindividual variability of these parameters was 20.4, 66.1, and 30.4%, respectively. The residual error was 31.4% and 23.7 ng/mL. The duration of CsA therapy, hematocrit, antifungal agent administration, triglycerides, and weight were identified as the main covariates that influenced CL, and hematocrit had a significant effect on V. The internal validation showed that the final model was stable and accurate.
  
  
  CONCLUSIONS
  This study established a population pharmacokinetic model of CsA in allo-HSCT patients that could provide the foundation for personalized use of CsA in the clinic.
authors.affiliation: Department of Clinical Pharmacology (LX, W-WZ, X-LD, J-JZ, J-AB, L-YM), The First Affiliated Hospital of Soochow University, Suzhou, China; and Department of Pharmaceutics, College of Pharmaceutical Sciences (LX, W-WZ, X-LD, J-JZ, L-YM), Soochow University, Suzhou, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Xue
authors.forename: Wen-Wen
authors.initials: WW
authors.lastname: Zhang
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Ding
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Zhang
authors.forename: Jian-An
authors.initials: JA
authors.lastname: Bao
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Miao
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000741:Anemia, Aplastic / Q000628:therapy; D015331:Cohort Studies; D016572:Cyclosporine / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D006402:Hematologic Diseases / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000628:therapy; D015470:Leukemia, Myeloid, Acute / Q000628:therapy; D008297:Male; D008954:Models, Biological; D009190:Myelodysplastic Syndromes / Q000628:therapy; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000628:therapy; D014184:Transplantation, Homologous
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D007166:Immunosuppressive Agents; D016572:Cyclosporine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human