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. AIMTo 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. METHODSThe 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. RESULTSTwenty 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] Ϯ 5.2%) with an inter-individual variability of 21%. The central volume of distribution (Vc) was 18.3 l (RSD Ϯ 8.7%) with an inter-individual variability of 29%. Bioavailability (F) was 0.71 (RSD Ϯ 9.9%) with and inter-individual variability of 25% and lag time (tlag) was 0.44 h (RSD 5.5%). Weight, body surface area, haematocrit, albumin, ALAT...

Pharmacokinetic tools for the dose adjustment of ciclosporin in haematopoietic stem cell transplant patients

“…The half-life of CsA in these studies was about 10-fold higher than the one estimated in the present study whatever the method used. Similarly to Wilhelm et al [6] and Eljebari et al [5], no covariate was included in our three final models, although for NONMEM a significant decrease of the OFV was found when introducing the haematocrit on apparent clearance. Haematocrit is a clinically relevant covariate due to the fixation of CsA on red blood cells, but its introduction in the model was associated with a worse estimation of IPV.…”

“…Using data collected from 18 HSCT recipients given oral CsA, Wilhelm et al . developed a PK model using nonmem . In a second step, the authors employed a Bayesian fitting procedure using the MW/PHARM program and determined that a C 0‐ C 2‐ C 3 sampling schedule allowed AUC estimation with a reasonable bias.…”

“…Similarly to Wilhelm et al . and Eljebari et al . , no covariate was included in our three final models, although for nonmem a significant decrease of the OFV was found when introducing the haematocrit on apparent clearance.…”

“…Even if sometimes helpful when rigorously validated and appropriately used, multiple linear regression equations are not pharmacokinetic tools as they do not refer to any kind of pharmacokinetic model or parameters. Using data collected from 18 HSCT recipients given oral CsA, Wilhelm et al developed a PK model using NONMEM [6]. In a second step, the authors employed a Bayesian fitting procedure using the MW/PHARM program and determined that a C0-C2-C3 sampling schedule allowed AUC estimation with a reasonable bias.…”

On the importance of blood sampling for ciclosporin pharmacokinetic studies

“…We read the interesting paper recently published by Wilhelm et al [1]. Measured blood concentrations of ciclosporin (CsA) reported in Figure 2 seem very high with regards to the daily dose administered.…”