Abstract 15207: Predicting Tacrolimus Concentrations in Heart Transplant Recipients Using Population Pharmacokinetic Models
Background: Tacrolimus (TAC) promotes graft longevity in heart transplant recipients, yet is associated with large inter-patient variability that necessitates frequent drug monitoring. We hypothesized that a population pharmacokinetic (popPK) model could be used to generate accurate predictions of TAC concentrations in a population of pediatric heart transplant recipients.
Methods: Children receiving TAC during the first 6 weeks after heart transplant at Primary Children’s Hospital from 2007-2015 were studied. Demographics, dosing, and TAC concentrations were utilized to develop a one-compartment popPK model using NONMEM v7.3. Data from 1/2007-12/2013 were used for model development. Data from 1/2014-12/2015 were used for model validation.
Results: Thirty children with a median age of 5.7 yrs (range: 0.1-17.7) had 395 TAC troughs obtained (median: 12 per child). The median (range) observed TAC concentration was 12.7 (1.5-32.7) μg/L. Of the 275 samples collected at steady-state (>96 hours after 1st dose), 39% were within the target therapeutic range (12-16 μg/L), while 41% were <12 μg/L. The popPK model identified a positive correlation between age and volume of distribution (p<0.001). Individual parameter estimates were used to calculate a mean (%CV) half-life of 20.6 (63%) hours, consistent with prior PK studies in pediatric liver transplant recipients. Large inter-patient variability in the elimination rate (56%) was observed. Model validation revealed no evidence of bias (median prediction error (MPE): 0.36% [95% CI: -0.33, 1.21]) and high accuracy (median absolute prediction error (MAPE): 3.8% [95% CI: 3.2, 4.9]). Individual parameter estimates determined from ≥3 concentrations predicted future concentrations with a small positive bias (MPE: 13.8% [95% CI: 3.0, 23.7]) and acceptable accuracy (MAPE: 37.0% [95% CI: 31.7, 40.6]).
Conclusion: PopPK modeling is a valuable tool for generating reasonably unbiased and accurate predictions of TAC concentrations in pediatric heart transplant recipients. Prospective clinical validation is warranted to determine whether the use of a popPK model can effectively keep children within the target therapeutic range and reduce the need for frequent TAC monitoring.
Author Disclosures: K. Molina: None. J. Rower: None. C. Stockmann: None. C. Sherwin: None.
- © 2016 by American Heart Association, Inc.