title: Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy.
abstract: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The population pharmacokinetics and limited sampling strategies for ciclosporin monitoring have been extensively studied in renal and liver transplant recipients. Little is known about the pharmacokinetics of ciclosporin in patients undergoing haematopoietic allogeneic stem cell transplantation (HSCT). • It is anticipated that there is a difference in pharmacokinetics in patients after kidney or liver transplantation compared with patients undergoing stem cell transplantation, because of mucositis and interacting drugs (e.g. fluconazole). • Data on the pharmacokinetics of ciclosporin and the relationship between its systemic exposure, as reflected by the area under the curve (AUC), and the biological effect as graft vs. host-disease (GVHD) prophylaxis and graft vs. tumour (GVT) response are scarce in patients after HSCT. WHAT THIS STUDY ADDS • A pharmacokinetic model was developed for orally and intravenously administered ciclosporin, enabling an adequate estimate of the systemic exposure of ciclosporin in patients after HSCT. A limited sampling strategy was tested that may serve as a tool to study the optimum systemic exposure (AUC) of ciclosporin in HSCT to prevent GVHD but establish adequate GVT response and to guide therapeutic drug monitoring. AIM To develop a population pharmacokinetic model of ciclosporin (CsA) in haematopoietic allogeneic stem cell transplantation to facilitate a limited sampling strategy to determine systemic exposure (area under the curve [AUC]), in order to optimize CsA therapy in this patient population. METHODS The pharmacokinetics of CsA were investigated prospectively in 20 patients following allogeneic haematopoietic stem cell transplantation (HSCT). CsA was given twice daily, as a 3 h i.v. infusion starting at day 1 of the conditioning scheme, and orally later on, when oral intake was well tolerated. Fluconazole was given as antimycotic prophylaxis. Pharmacokinetic parameter estimation was performed using nonlinear mixed effect modelling as implemented in the NONMEM program. A first order absorption model with lag time was compared with Erlang frequency distribution and Weibull distribution models. The influence of demographic variables on the individual empirical Bayesian estimates of clearance and distribution volume was tested. Subsequently two limited sampling strategies (LSS) were evaluated: posterior Bayesian fitting and limited sampling equations. RESULTS Twenty patients were included and 435 samples were collected after i.v. and oral administration of CsA. A two compartment model with first order absorption best described the data. Clearance (CL) was 21.9 l h(-1)  (relative standard deviation [RSD]± 5.2%) with an inter-individual variability of 21%. The central volume of distribution (V(c) ) was 18.3 l (RSD ± 8.7%) with an inter-individual variability of 29%. Bioavailability (F) was 0.71 (RSD ± 9.9%) with and inter-individual variability of 25% and lag time (t(lag) ) was 0.44 h (RSD 5.5%). Weight, body surface area, haematocrit, albumin, ALAT and ASAT had no significant influence on pharmacokinetic parameters. The best multiple point combination for posterior Bayesian fitting, in terms of estimating systemic CsA exposure, appeared to be C0 + C2 + C3. Two selected LSS two time point equations and all selected three and four time point equations predicted de all AUC(0,12 h) within 15% bias and prediction. CONCLUSIONS The i.v. and oralcurves were best described with a two compartment model with first-order absorption with lag time. With the Bayesian estimators from this model, the area under the concentration-time curve in HSCT patients taking fluconazole can be estimated with only three blood samples (0, 2, 3 h) with a bias of 1% and precision of 4%.
authors: Department of Clinical Pharmacology and Pharmacy, VU University Medical Centre, Amsterdam, the Netherlands. aj.wilhelm@vumc.nl
authors: Abraham J
authors: AJ
authors: Wilhelm
authors: Peer
authors: P
authors: de Graaf
authors: Agnes I
authors: AI
authors: Veldkamp
authors: Jeroen J W M
authors: JJ
authors: Janssen
authors: Peter C
authors: PC
authors: Huijgens
authors: Eleonora L
authors: EL
authors: Swart
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001499:Bayes Theorem; D001682:Biological Availability; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011446:Prospective Studies; D012494:Sampling Studies; D014184:Transplantation, Homologous / Q000379:methods; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine