Population pharmacokinetics of tacrolimus in full liver transplant patients: modelling of the post-operative clearance.
OBJECTIVE
To investigate the population pharmacokinetics of tacrolimus in an adult liver transplant cohort using routine drug monitoring data and to identify patient characteristics that influence pharmacokinetic parameters.


METHODS
Tacrolimus pharmacokinetics was studied in 37 adult patients using a population approach performed with NONMEM.


RESULTS
A one-compartment open model with linear absorption and elimination adequately described the data. The apparent clearance (CL) was approximately zero in the immediate post-operative days (PODs) and then rapidly increased as a function of POD to reach a plateau. This was modelled as a sigmoid relationship with the characteristic parameters CL(max) (plateau), TCL(50) (time to obtain 50% of the plateau) and gamma (coefficient of sigmoidicity). This clearance model was thought to describe the hepatic function regeneration after transplantation. Typical population estimates (percentage inter-individual variability) of CL(max), TCL50, and gamma and apparent distribution volumes (V) were 36 l/h (43%), 6.3 days (33%), and 4.9 l and 1870 l (49%), respectively. The CL(max) was negatively related to plasma albumin, and TCL50 was positively related to aspartate amino transferase (ASAT). Bayesian estimations performed at different POD times indicated that acceptable precisions in individual pharmacokinetic predictions could be obtained after the 15th POD.


CONCLUSIONS
Tacrolimus clearance modelling showed that there was a large variation in individual CL estimates up to the 15th day post-surgery. After this period, the mean error resulting from the Bayesian estimation was strongly decreased and this estimation method could be applicable and should limit tacrolimus monitoring.
Department of Pharmacy, Pitié Salpêtrière hospital, 47 Bd de l'hôpital, 75013, Paris, France. marie.antignac@psl.ap-hop-paris.fr
Marie
M
Antignac
Jean Sebastien
JS
Hulot
Emmanuel
E
Boleslawski
Laurent
L
Hannoun
Yvan
Y
Touitou
Robert
R
Farinotti
Philippe
P
Lechat
Saïk
S
Urien
D001499:Bayes Theorem; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016031:Liver Transplantation; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D011184:Postoperative Period; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
D007166:Immunosuppressive Agents; D016559:Tacrolimus