Abstract
BackgroundTacrolimus therapy is standard of care for immunosuppression after lung transplantation. However, tacrolimus exposure variability during the early postoperative period may contribute to poor outcomes in this population. Few studies have examined tacrolimus pharmacokinetics (PK) during this high-risk period. MethodsWe conducted a retrospective pharmacokinetic study in lung transplant recipients at the University of Pennsylvania who were enrolled in the Lung Transplant Outcomes Group (LTOG) cohort. We used using non-linear mixed-effects regression to derive a population PK model in 270 patients and examined validity in a separate cohort of 114 patients. Covariates were examined with univariate analysis and a multivariable model was developed using forward and backward stepwise selection. Performance of the final model in the validation cohort was examined with calculation of prediction error (PE). ResultsWe developed a one-compartment base model with a fixed rate absorption constant. Covariates improving model fit were postoperative day, hematocrit, transplant type, CYP3A5 genotype, weight, exposure to CYP inhibitor drugs. The strongest predictor of tacrolimus clearance was postoperative day, with median predicted clearance increasing more than threefold over the 14 day study period. In the validation cohort, the final model showed a mean PE of 36.4% (95%CI 30.8%-41.9%) and a median PE of 7.2% (IQR -29.3%-70.53%). ConclusionTacrolimus clearance is highly dynamic during the early post-lung transplant period. Population-PK models that include lung-transplant specific covariates may enable precision dosing algorithms that account for this highly dynamic clearance. Future multicenters studies including a broader set of covariates are warranted.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Similar Papers
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.