Simulation of sirolimus exposures and population variability immediately post renal transplantation: importance of the patient's CYP3A5 genotype in tailoring treatment.
The rapid achievement of efficacious exposure to sirolimus (SRL) after renal transplantation is crucial. However, there is high unpredictability in the dose to exposure relationship. Part of the variation is related to patients originating from subpopulations of fast or slow metabolizers via the CYP3A5*1/*3 genotype. The probability of achieving therapeutic SRL blood concentrations for each subpopulation under two equal-intensity increasing-frequency protocols after the start of treatment was explored with Monte Carlo simulation. The population pharmacokinetic model and inter-patient variability distributions of Djebli et al. (DRH2006) were sampled. They developed a base and final model with a genotype covariate for CL/F in patients receiving calcineurin inhibitor (CNI)-free therapy with SRL, mycophenolate mofetil and corticosteroids. Fast metabolizers (expressers) had a CL/F of 28.3 l/h whilst slow metabolizers (non-expressers) had a CL/F of 14.1 l/h. Here, in simulation, a standard 10 mg QD SRL was contrasted with a higher frequency of 5 mg BID SRL as related to the proportion of next dosed patients being within the 15-30 ng/ml trough levels on day 7 after transplantation. Near 0% of expressers on either regimen reached or exceeded the 30 ng/ml trough on day 7. Expressers showed protocol dependence for the chance of being within the 15-30 ng/ml range with the 5 mg BID protocol doubling those chances. Non-expressers appeared less protocol dependent for the probability of being above or below the 15-30 ng/ml range. The ability to determine the genotype early on may help to rationalize the initial titration of individual patients receiving CNI-free renal transplantation treatment with SRL.
Lukas
John C
JC
Pharsight Corporation, Mountain View, CA, USA. jlukas@dynakin.com
Calvo
Rosario
R
Zografidis
Anastasios
A
Ortega
Ignacio
I
Suárez
Elena
E
D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D044382:Population Groups; D020123:Sirolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D020123:Sirolimus