Model-Informed Estimation of Acutely Decreased Tacrolimus Clearance and Subsequent Dose Individualization in a Pediatric Renal Transplant Patient With Posterior Reversible Encephalopathy Syndrome

Abstract

Background: Considerable interpatient and interoccasion variability has been reported in tacrolimus pharmacokinetics (PK) in the pediatric renal transplant population. This study investigated tacrolimus PK in a 2-year-old post–renal transplant patient and a known CYP3A5 expresser who developed posterior reversible encephalopathy syndrome (PRES) and had significantly elevated tacrolimus blood concentrations during tacrolimus treatment. A model-informed PK assessment was performed to assist with precision dosing. Tacrolimus clearance was evaluated both before and after the development of PRES on post-transplant day (PTD) 26. Methods: A retrospective chart review was conducted to gather dosing data and tacrolimus concentrations, as part of a clinical pharmacology consultation service. Individual PK parameters were estimated by Bayesian estimation using a published pediatric PK model. Oral clearance (CL/F) was estimated for 3 distinct periods—before CNS symptoms (PTD 25), during the PRES event (PTD 27–30), and after oral tacrolimus was restarted (PTD 93). Results: Bayesian estimation showed an estimated CL/F of 15.0 L/h in the days preceding the PRES event, compared with a population mean of 16.3 L/h (95% confidence interval 14.9–17.7 L/h) for CYP3A5 expressers of the same age and weight. Samples collected on PTD 27–30 yielded an estimated CL/F of 3.6 L/h, a reduction of 76%, coinciding with clinical confirmation of PRES and therapy discontinuation. On PTD 93, an additional assessment showed a stable CL/F value of 14.5 L/h 1 month after reinitiating tacrolimus and was used to recommend a continued maintenance dose. Conclusions: This is the first report to demonstrate acutely decreased tacrolimus clearance in PRES, likely caused by the downregulation of metabolizing enzymes in response to inflammatory cytokines. The results suggest the ability of model-informed Bayesian estimation to characterize an acute decline in oral tacrolimus clearance after the development of PRES and the role that PK estimation may play in supporting dose selection and individualization.