Individualized population pharmacokinetic model with limited sampling for cyclosporine monitoring after liver transplantation in clinical practice.
BACKGROUND
We recently developed and validated limited sampling models (LSMs) for cyclosporine monitoring after orthotopic liver transplantation based on individualized population pharmacokinetic models with Bayesian modelling. Aim To evaluate LSM in practice, and to seek optimal balance between benefit and discomfort.


METHODS
In 30 stable patients, more than 6 months after orthotopic liver transplantation, previously switched from trough- to 2 h post-dose (C2)-monitoring, we switched to 3-monthly LSM 0,1,2,3 h-monitoring. During 18 months we evaluated dose, creatinine clearance, calculated area under the curve, intra-patient pharmacokinetic variability and ability to assess systemic exposure by several previously validated LSMs.


RESULTS
Within patients, there was variability of cyclosporine-area under the curve with the same dose (CV of 15%). Compared to C2-monitoring, there was no significant difference in dose (P = 0.237), creatinine clearance (P = 0.071) and number of rejections. Some models showed excellent correlation and precision with LSM 0,1,2,3 h comparing area under the curves (0,2 h: r(2) = 0.88; 0,1,3 h: r(2) = 0.91; 0,2,3 h: r(2) = 0.92, all P < 0.001) with no difference in advised dose.


CONCLUSIONS
The limited sampling model, with only trough- and 2-h sampling, yields excellent accuracy and assesses systemic exposure much better than C2 with less bias and greater precision. Considering the calculated intra-patient variability, more precision is redundant, so LSM 0,2 h seems the optimal way of cyclosporine-monitoring.
Langers
P
P
Department of Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands.
Cremers
S C L M
SC
den Hartigh
J
J
Rijnbeek
E M T
EM
Ringers
J
J
Lamers
C B H W
CB
Hommes
D W
DW
van Hoek
B
B
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001499:Bayes Theorem; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016031:Liver Transplantation / Q000534:rehabilitation*; D008297:Male; D008875:Middle Aged; D008956:Models, Chemical; D012044:Regression Analysis; D012680:Sensitivity and Specificity
D007166:Immunosuppressive Agents; D016572:Cyclosporine