103: Investigating Tacrolimus Population Pharmacokinetics in Adult Hispanic Renal Transplant Recipients

Statement of Purpose: Tacrolimus trough levels must be monitored and maintained to prevent rejection and minimize toxicity following kidney transplantation. However, the narrow therapeutic window and significant fluctuation of tacrolimus levels in the early phase after transplantation can make it challenging to achieve optimal exposure. It is still unclear whether tacrolimus exposure during the early stages of transplantation differs among Hispanic subjects and other populations. Therefore, we aimed to (i) develop a population pharmacokinetic model for tacrolimus that can adequately describe the Hispanic population and (ii) evaluate the impact of intrinsic and extrinsic factors during the early phase following kidney transplantation.

Description of Methods & Materials: Retrospective data were collected from the electronic medical records at St Joseph Transplant Clinic. Self-identified Hispanic subjects that had a renal transplant and received a regimen consisting of tacrolimus, mycophenolate mofetil, thymoglobulin, and solumedrol were included in the pharmacokinetic analysis. Blood samples were collected before the morning dose (trough) for the first 30 days after renal transplant and tacrolimus dose was adjusted accordingly with a target trough concentration of 10-12 ng/ml. Rich data from a bioequivalence study in renal transplant subjects were used to obtain the structural model parameters. Central volume (Vc) 180 L, peripheral volume (Vp) 533 L, inter-compartmental clearance (Q) 63.7 L/hr, and transfer rate (Ktr) 4.28 hr-1 were fixed, apparent clearance was estimated, and potential covariates were identified. The final population model was evaluated using standard diagnostics and quantitative predictive check analysis. The population pharmacokinetic analysis was performed using Pumas software v2.3 and JuliaPro v1.7.2.

Data & Results: A total of 121 renal transplant subjects with 2,248 trough tacrolimus concentrations were used for pharmacokinetic modeling. A two-compartment model with transit absorption process and additive residual error best described tacrolimus concentration-time data. Allometrically scaled body weight and time-varying hematocrit were significant covariates on apparent clearance. The estimated apparent clearance was 13.7 L/h for a typical patient of 70 kg and 30% Hematocrit.

Interpretation, Conclusion or Significance: A pharmacokinetic model for tacrolimus was developed for Hispanic renal transplant subjects that showed, an estimated 1.4-fold decrease of apparent clearance in the typical patient compared to other populations with similar characteristics (mean clearance value 23.5 L/hr with a range [20.5-28]). Similar findings of lower apparent clearance have been reported in Native American and Mexican populations. Such ethnic differences in clearance might have potential implications on tacrolimus dose titrations. The study showcased a correlation between hematocrit levels and tacrolimus clearance due to the drug’s high binding affinity to erythrocytes. Hematocrit levels decrease post-transplantation but return to baseline within a few weeks, leading to increased binding of tacrolimus to erythrocytes over time, potentially accounting for early post-transplantation variability in clearance. The study provides valuable insights into the understudied tacrolimus pharmacokinetics in the Hispanic population and may inform the development of optimized dosing strategies for Hispanic patients receiving tacrolimus.

Disclosures: