Evaluation and Extrapolation of a Tacrolimus Population Pharmacokinetic Model in Adult Recipients of Allogeneic Hematopoietic Cell Transplantation Receiving Post‐Transplant Cyclophosphamide

Abstract Allogeneic hematopoietic cell transplant (allo‐HCT) is potentially curative for many hematologic diseases but complicated by acute graft‐versus‐host disease (aGVHD). While tacrolimus remains the cornerstone of aGVHD prophylaxis, regimens are increasingly including post‐transplant cyclophosphamide (PTCy). This single‐center study evaluated a previously published tacrolimus population pharmacokinetic (popPK) model developed from allo‐HCT recipients administered standard (tacrolimus plus methotrexate) aGVHD prophylaxis for generalizability to PTCy recipients. Adult allo‐HCT recipients treated with PTCy for aGVHD prophylaxis were included. Applicability of the established popPK model to the PTCy population was based on an evaluation of simulated to observed concentration ratios, and the distribution was interpreted with respect to a clinical equivalence range (0.8 to 1.25). The model was refit using data from both the standard and PTCy cohorts to describe the PK and support extrapolation to the PTCy population. Individual PK parameters from PTCy recipients were used to simulate steady‐state concentrations (C trough, ss ) using the current institutional weight‐based dosing strategy and the proposed model‐informed precision dosing (MIPD) algorithm. The proportion of patients predicted to experience a subtherapeutic C trough, ss (<5 ng/mL) was compared between dosing strategies. Five hundred and ninety‐three tacrolimus C trough, ss values from 95 allo‐HCT recipients who received PTCy were included. The previous model did not successfully predict tacrolimus C trough, ss values among PTCy patients, but highlighted similarities between clearance in PTCy and standard aGVHD prophylaxis patients who received reduced‐intensity conditioning. Dosing simulations suggested a decreased proportion of PTCy patients would experience subtherapeutic tacrolimus C trough, ss with MIPD (3%) compared to conventional weight‐based dosing (23%).