PII-089 - POPULATION PHARMACOKINETICS OF ORAL MELTDOSE TACROLIMUS (LCPT) IN DE NOVO KIDNEY TRANSPLANT PATIENTS.

X. Huang¹, J. Jeon², J. Chae², J. Momper³; ¹UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, San Diego, CA, United States, ²College of Pharmacy, Chungnam National University, Daejeon, Chungcheongnam-do, Republic of Korea, ³University of California, San Diego, San Diego, CA, United States.

Background: Envarsus XR® (Veloxis Pharmaceuticals, Inc; LCPT) is a once-daily extended-release formulation of tacrolimus used for prophylaxis of organ rejection in kidney transplant patients. LCPT exhibits prolonged and variable absorption which may complicate early dose optimization. The goal of this study was to characterize the population pharmacokinetics (popPK) of LCPT in adult de novo kidney transplant patients.

Methods: Pharmacokinetic (PK) data were collected from an open-label phase II study in adult de novo kidney transplant patients, who received once daily LCPT with an initial dose of 0.17 mg/kg for African American (AA) or 0.14 mg/kg for non-AA patients within 48 hours after transplantation. Doses were titrated to attain target whole blood trough concentrations of 7-20 ng/mL, with intensive PK sampling performed on days 1, 7, and 14. A popPK model was developed using nonlinear-mixed effect modeling (NONMEM v. 7.5.1).

Results: Thirty-one patients (25 Caucasian, 5 AA, and 1 Asian) were included in the analysis with 1114 blood concentrations (331 day 1, 392 day 7, 391 day 14). Mean entry age was 49.1 years with a standard deviation (SD) of 12.2 years, and mean weight was 87.5kg (SD: 19). Median (interquartile range, IQR) daily doses of LCPT were 12 mg (10.25 – 14) on day 1, 10 mg (8 – 14) on day 7, and 10 mg (7 – 13.25) on day 14. Median (IQR) dose-normalized trough blood concentrations were 0.4 ng/mL/mg (0.3 – 0.6) on day 1, 0.9 ng/mL/mg (0.6 – 1.4) on day 7 and 1.1 ng/mL/mg (0.6 – 1.6) on day 14. LCPT concentrations were fit using a two-compartment model with prolonged absorption described by three transit compartments, each with a transit time of 1.05 hours (Figure 1). PopPK parameters included apparent oral clearance (21.5 L/h), apparent intercompartmental clearance (9.13 L/h), and apparent central and peripheral volume of distribution (1610 L and 2170 L, respectively). Race was an independent predictor of apparent central volume of distribution (Vd/F). The final popPK model parameter was: Vd/F (L) = 2275.58 × (1.45 if Race is AA)

Conclusion: The developed LCPT popPK model supports early steady-state prediction of tacrolimus exposure and may facilitate individualized dose optimization. Ongoing work includes Monte Carlo simulations to assess different dosing scenarios and the development of a web application for real-time decision support in clinical practice.