Prediction of Area under the Cyclosporine Concentration Versus Time Curve in Children Undergoing Hematopoietic Stem Cell Transplantation

Abstract

This prospective study aimed to validate a previously developed first-dose limited sampling strategy (LSS) to predict the area under the cyclosporine concentration-versus-time curve (AUC) and to develop and then validate an LSS to predict cyclosporine AUC at steady state. This two-center Canadian study included children (ages .4 to 17.2 years) undergoing myeloablative allogeneic hematopoietic stem cell transplantation receiving cyclosporine for acute graft-versus-host disease prophylaxis. There were three cohorts, each incorporating 24 AUC determinations: first-dose LSS validation, steady-state LSS development, and steady-state LSS validation. Patients contributing data to either of the development cohorts were excluded from the corresponding validation group. Cyclosporine was given every 12 hours as a 2-hour infusion. Cyclosporine AUC was determined after administration of the first cyclosporine dose (8 samples) and then once weekly (9 samples) until engraftment. Steady-state LSSs were developed using stepwise multiple linear regression. An LSS was considered to provide an acceptable estimate of AUC if the lower limit of the 95% confidence limit (CL) of the intraclass coefficient was .8 or higher and both bias and precision were 15% or less. Fifty-three children age .4 to 18 years participated. Cyclosporine concentrations drawn up to 4 hours from the start of the infusion correlated most strongly with AUC. The previously developed first-dose LSSs and three steady-state LSSs met criteria for acceptability. The intraclass coefficients of the three-point first-dose LSS validation cohort, three-point steady-state LSS development cohort, and three-point steady-state LSS validation cohort were .974 (95% CL: .941 to .988), .984 (95% CL: .965 to .993), and .993 (95% CL: .984 to .997), respectively. The three-point first-dose (2, 6, and 8 hours) and steady-state (2, 2.5, and 8 hours) LSSs are valid measures of cyclosporine AUC after intravenous administration over 2 hours. Their use in a prospective evaluation of the relationship between cyclosporine AUC and hematopoietic stem cell transplantation clinical outcomes in children is suggested.

Cyclosporine use in Hematopoietic Stem Cell Transplantation: Pharmacokinetic Approach

“…It is notable that referring to C 2 samples as C max or peak has been criticized, although some authors stated about well accordance of levels at 2 h postdose samples with maximal observed concentrations [103,151]. There are other single time points proposed by BMT studies like C 3 or C 8 for prediction of AUC but generalization for their application requires further investigations [54,131,132].…”

“…Currently iv. twice daily 1.5 mg/kg dose is commonly applied that could be safely administered with 2 h infusion, although conclusive data for shorter infusion times is lacking [54]; Higher doses per kg usually proposed for children to reach target AUC [161]. Optimal trough target levels by efficacy and toxicities introduced to be 200-300 ng/ml during the initial 21-28 days, and 100-200 ng/ml afterward until about 90 days with provisions of free GvHD, toxicity or decreased chimerism period [8].…”

“…Estimation of the true AUC will be more reliable with increase in number of samples [27] but this fact significantly decrease the practical applicability [22]. In addition some trials did not find an association between AUC and clinical outcomes like occurrence of GvHD or its severity [4,54]. Currently data for precise therapeutic ranges for parameters other than trough levels are lacking.…”

Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I

“…To choose the appropriate target trough concentration for an individual patient, the pharmacodynamic association of CNI concentrations with clinical outcomes must be interpreted cautiously with respect to the alloHCT characteristics (detailed in Section 2), the methods and timing of pharmacokinetic sampling, 83 the and the analytical method used for quantification of the CNI concentrations. Artificially high cyclosporine concentrations may be due to desorption of cyclosporine from the material of central venous catheters.…”

“…To choose the appropriate target trough concentration for an individual patient, the pharmacodynamic association of CNI concentrations with clinical outcomes must be interpreted cautiously with respect to the alloHCT characteristics (detailed in Section 2) and with respect to the pharmacokinetic sampling techniques 83,84 and the quantification method. The historic pharmacodynamic data of cyclosporine with outcomes have been reviewed previously; 115 the results of pharmacodynamic studies reported within the past decade are summarized in Table 3.…”