MJ GarcÃa1, D Santos Buelga1, A Blázquez2, A Torregrosa2, J Manzanares2, P Urruzuno2, E Medina2, and C Manzanares2
1Pharmacy Department, University of Salamanca; 2Biochemistry and Pediatric Gastroenterology Services, Hospital 12 de Octubre, Madrid. Spain
Tacrolimus (FK) can be used as rescue therapy for reversal of acute or chronic rejection and CsA toxicity, representing a significant advance in the prevention of graft failure. The aim of this study was to determine the influence of variables such as age, body weight, time after initiation of treatment, haematocrit, albumin, AST, ALT, g GT, FAlc, bilirubin, serum creatinine and corticosteroid doses on the tacrolimus clearance in liver transplanted paediatric patients, treated with FK as rescue therapy, during a period of time between 2 and 24 months. 273 steady-state blood FK concentrations were obtained from 19 children (7.5 ± 4.9 years) receiving the drug orally. The influence of covariates on FK clearance was investigated with NONMEM program.
Results show that clearance (CL) linearly depends on body weight (BW), bilirubin (BIL) and time after initiation of treatment (T) and CL decreases when ALT increased, according the following model:
CL = (0.262BW – 0.0036T – 0.046BIL) (1- 0.12ALT)
Age is highly correlated with BW, and AST and g GT with ALT. We choose BW and ALT because they explain more variability. Serum creatinine (CRE) and haematocrit (HTC) remained relatively stable during the observation period (CRE = 0.66 ± 0.26; HTC = 33.81± 4.71), that is why they do not entry in the model. From the model, it is observed a clear tendency toward a decrease in FK clearance along the T. No influence was found for any other variables.
According proportional error models, both interindividual and residual variabilities were reduced from 50.4% and 49.3% in basic to 37.0% and 29.1% in final model, respectively.
Thus, it seems that BW, T, BIL and ALT significantly influence FK disposition and they should be considered in programming dosage regimens. However, the use of this model in “a priori” dosage recommendations should be taken with caution because of the remanent unexplained CL variability, so we recommended a closely monitoring of FK whole blood levels.
Reference: PAGE 8 (1999) Abstr 151 [www.page-meeting.org/?abstract=151]
Poster: poster