Factors influencing pharmacokinetics of tacrolimus during the early liver post-transplantation period: a population analysis
C. Gérard (1), C. Verstuyft (2), J. Stocco (3), A. Hulin (4), B. Blanchet (5), M. Tod (1)
(1) Université de Lyon, Lyon, F-69003, France, (2) Pharmacologie, Paris, F-75011, France, (3) Pharmacie, Hôpital Beaujon, APHP, Clichy, F-92110, France, (4) Toxicologie, Hôpital Henri Mondor, APHP, Créteil, F-94010, France, (5) Toxicologie, Hôpital Cochin, APHP, Paris, F-75014, France.
Objectives: Tacrolimus (TAC) is an immunosuppressive agent used for the prevention of acute rejection after liver transplantation. Clearance and bioavailability of TAC are controlled by the activity of P-glycoprotein (P-gp) and CYP3A5 in the gut and the liver. P-gp and CYP3A5 are polymorphic, and the genotype of the donor and the recipient may differ. The objective was to investigate the population pharmacokinetics (PK) of TAC during the first 15 days post-transplantation and identify recipient and donor characteristics that influence PK parameters.
Methods: This was a prospective multicentric study (3 sites). 65 adult patients receiving oral TAC after liver transplantation were included. For each patient, at least 3 blood samples were taken at J2, J7 and J14. Patients characteristics collected and tested were: age, body weight, total plasmatic proteins, albumin concentration, coagulation factor V, prothrombin time, total and conjugated bilirubin, alkaline phosphatase (AP), Gamma Glutamyl Transferase, ALAT, ASAT, serum creatinine concentration (SCR), red blood cell count and haematocrit. Genetic factors were also collected for each donor and transplant recipient : CYP3A5 (intron 3) and P-gp (3435C_T in exon 26) genotypes. PK analysis was carried out by using Monolix V3.1.
Results: Mean patient age and body weight were 52.9 ± 10.1 years and 70.8 ± 13.4 kg, respectively. Mean dosage regimen of TAC was 0.074 ± 0.059 mg/kg per day. A one compartment model with first order absorption and elimination adequately described the data. Typical population estimates (relative standard error) of absorption rate constant, apparent distribution volume and apparent clearance (CL) were 0.91 h-1 (216%), 486 L (21%) and 11.7 L/h (14%), respectively. CL of TAC was negatively related to AP, ASAT and SCR. CYP3A5 donor and P-gp recipient genotypes were significant covariates of CL. Mean CL was lower when the donor was CYP3A5*3/*3 homozygote rather than carrying at least one CYP3A5*1 allele : 12.6 ± 4.6 vs 24.8 ± 3.1 L/h (p<0.005). For P-gp, there was a significant difference between the mean CL of the 3 types of patients : 13.7±6.1 for T/T homozygotes ("mutant" alleles) ; 14.2±4.6 for C/T heterozgygotes and 18.5±5.3 for C/C homozygotes (p< 0.05).
Conclusions: During the early post-transplant period, some biological parameters but especially CYP3A5 and P-gp genotypes, should be taken into account because of their effect on the CL and consequently on the initial dosage regimen of TAC.