Cyclosporine A monitoring ? how to account for twice and three times daily dosing

Abstract

Cyclosporine A (CsA) dose-interval pharmacokinetic profiles, performed 1-4 years post-transplantation, were collected from 74 renal transplanted children. Forty patients were on three times daily dosing (t.i.d.) and 34 on twice daily dosing (b.i.d.). Regression models for prediction of area under the curve (AUC) using 1-3 concentration time points as independent variables were developed. With similar weight-adjusted single doses (mg kg(-1)) of CsA, t.i.d. dosing resulted in a trough-concentration (C0) similar to that from b.i.d. dosing, but a 30% lower 2 h post-dose concentration (C2). For b.i.d. dosing the relationship between C0 and AUC was poor (r2=0.23) and the prediction error was large (5.8+/-33.5%). For t.i.d. dosing the relationship was better (r2=0.79), but prediction error was still large (4.5+/-24.9%). For C2 relationships were similar to those for the b.i.d. (r2=0.59) and t.i.d. (r2=0.63) groups, but explained modestly the variations of AUC (prediction error=2.6+/-16.8% b.i.d., 4.8+/-23.2% t.i.d.). Both C0 and C2 are useful monitoring methods when CsA is administered t.i.d. If the aim is similar specified daily drug exposure, the target C2 should be roughly 30% smaller in t.i.d. dosing than in b.i.d. dosing and the target C0 could be similar. The prediction error of AUC can be large in individual patients when using single time-point determinations, however. The use of multiple time points reduces the variation, but is less feasible.

Cyclosporin twice or three times daily dosing in pediatric transplant patients – It is not the same!

“…Nowadays complete 24-h PK profiles would rarely be conducted. For CYA-ME, both in our study and in the previously mentioned cross-sectional study (2), similar weight-adjusted doses resulted in comparable trough levels. However, dose-normalized trough levels and dose-normalized exposure were significantly reduced on t.i.d.…”

“…dosing in order to reduce the peak concentration. In a recent publication, Fanta et al (2) taught us how to account for t.i.d. dosing of CyA‐ME.…”

Developmental pharmacokinetics of ciclosporin – a population pharmacokinetic study in paediatric renal transplant candidates

“…Moreover, because the V /BW did not change with age (Figure 3D), it can be estimated that the half‐life of ciclosporin is about 20% shorter in younger than in older patients. To compensate for the rapid elimination in prepubertal children (≤8 years), ciclosporin dosing can be increased from twice daily dosing by administering a third daily dose, to achieve drug exposures (average daily concentrations) similar to those in older patients with slower elimination [10, 31].…”

“…Dose requirement calculations Dose requirement calculations were made to demonstrate the influence of the covariates on oral dosing. A target ciclosporin exposure [area under the concentration–time curve (AUC) of 2500 µg l −1 h, approximating the target AUC of a dose interval when ciclosporin is administered three times daily to stable kidney transplant patients [31]] was chosen. Doses were calculated on the basis of (i) the EBE estimates (true dose required), (ii) the population model and all covariate information and (iii) the population model and information on BW.…”

Renal transplantation in infants

“…In our center, the early immunosuppressive protocol is still CsA-based, as the dosing in the smallest recipients is easier and more accurate with CsA as compared to tacrolimus. Due to the faster metabolic capacity of smaller children, CsA is at first given to the infants three times a day [43]. Steroid-free protocols are successfully used in many transplant centers to avoid the side effects of glucocorticoids Fig.…”