Population Pharmacokinetics of Tacrolimus in Healhty Korean Subjects:role of CYP3A5 genotype and metabolite
Boram Ohk, Joomi Lee, PhD, Mi-Ri Gwon, PhD, Bo Kyung Kim, Hae Won Lee, MD, PhD, Hyun-Ju Kim, PhD, Sook-Jin Seong, MD, PhD, Woo Youl Kang, MD, and Young-Ran Yoon MD, PhD
Department of Biomedical Science, BK21 Plus KNU Bio-Medical Convergence Program for Creative Talent, and Clinical Trial Center, Kyungpook National University Graduate School and Hospital, Daegu, Korea
Objectives: Tacrolimus, an immunosuppressive agent that has been commonly used to prevent rejection after organ transplantation, is known to have substantial inter-individual pharmacokinetic (PK) variability and narrow therapeutic range. The aim of this study was to develop a population PK model of Tacrolimus in healthy Korean subjects.
Methods: This study was conducted in 29 healthy Korean subjects. All subjects received a single 0.075mg/kg oral dose of tacrolimus. Blood samples were drawn at 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours after dosing. Plasma tacrolimus concentrations were analyzed using liquid chromatography mass spectrometry (LC/MS). A population PK analysis was conducted using NONMEM (Ver. 7.2).
Results: A 2-compartment model with first-order absorption provided the best fit from healthy subjects. Estimates of the population PK parameter were as follows; CL, 12.5 L/h; Vc, 19.6 L; Ka, 0.545 h-1; ALAG, 0.363 h-1; Vp, 359 L/h; Q, 26.4 L/h. The visual predictive check (VPC) was performed and the result exhibited the acceptable predictive performance of the final model.
Conclusions: A population PK model was successfully developed and reasonable parameters in agreement with previously published datawere obtained. Further study will be required to find out covariates affecting the PK parameters.