Population Pharmacokinetics of Tacrolimus in Pediatric Hematopoietic Stem Cell Transplant Recipients: New Initial Dosage Suggestions and a Model-Based Dosage Adjustment Tool

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Abstract
The population pharmacokinetics of tacrolimus was described in 22 pediatric hematopoietic stem cell transplant recipients, and a model-based dosage adjustment tool that may assist with therapy in new patients was developed. Patients received tacrolimus by continuous intravenous (IV) infusion (0.03 mg.kg(-1).d(-1)) starting. 2 days before transplantation, with conversion to oral therapy 2-3 weeks after transplant. Population pharmacokinetic analysis was performed using NONMEM. A Bayesian dosage adjustment tool that searches for individual parameter estimates to describe concentration measurements, counterbalanced by the final population model, was created in Excel. Typical clearance was 106 mL.h(-1).kg(-0.75), typical distribution volume was 3.71 L/kg, and typical bioavailability was 15.7%. Tacrolimus clearance decreased with increasing serum creatinine, and bioavailability decreased with postoperative day. A Bayesian dosage adjustment tool capable of suggesting an initial infusion rate based on patient covariate values and devising a further individualized dosage regimen as drug concentration measures become available was developed. Predictions from the model showed that current IV dose recommendations of 0.03 mg.kg(-1).d(-1) may potentially produce toxic drug concentrations in this patient population, whereas current oral conversion of 4 times the adjusted IV dose may lead to subtherapeutic concentrations. A more suitable infusion rate to obtain a steady state concentration of 12 ng/mL was predicted to be 0.035 mg.kg(-0.75).d(-1). An additional loading dose of 0.07 mg.kg(-1).d(-1) (total dose: 0.07 mg.kg(-1).d(-1) + 0.035 mg.kg(-0.75).d(-1)) during the first 24 hours of therapy should allow rapid achievement of steady state concentrations. A conversion factor of 6 from TV to enteric therapy may be more suitable. Such dosage recommendations may be site specific. The appropriateness of targets was not investigated in this Study. The Bayesian dosing adjustment tool and suggested dose recommendations need to be evaluated in a prospective Study before they can be applied in the clinical setting.