TY - JOUR
T1 - An integrated sampling strategy for therapeutic mycophenolic acid monitoring in lung transplant recipients
AU - Tague, Laneshia K.
AU - Anthony, Hephzibah
AU - Salama, Noha N.
AU - Hachem, Ramsey R.
AU - Gage, Brian F.
AU - Gelman, Andrew E.
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2025/1
Y1 - 2025/1
N2 - Background: Mycophenolic Acid (MPA) is the most used anti-proliferative in lung transplantation, but its pharmacokinetic (PK) variability has precluded therapeutic drug monitoring. Both genetic and clinical factors have been implicated in MPA variability. This study aimed to integrate genetic and clinical factors with PK measurements to quantify MPA exposure. Methods: We performed 12-hour pharmacokinetic analysis on 60 adult lung transplant recipients maintained on MPA for immunosuppression. We genotyped a SLCO1B3 polymorphisms previously associated MPA metabolism and collected relevant clinical data. We calculated area under the curve (AUC0–12) and performed univariate linear regression analysis to evaluate its association with genetic, clinical, and pharmacokinetic variables. We performed lasso regression analysis to create final AUC estimation tools. Results: PK-only measurements obtained 2, 3, and 8 hours after MPA administration (C2, C3, and C8) were strongly associated with MPA AUC0–12 (R2 67%, 67% and 68% respectively). Clinical and genetic factors associated with MPA AUC0–12 included the MPA dose (p = 0.001), transplant diagnosis (p = 0.015), SLCO1B3 genotype (p = 0.049), and body surface area (p = 0.050). The best integrated single-sampling strategy included C2 and achieved an R2 value of 80%. The best integrated limited-sampling strategy included C0, C0.25, and C2 and achieved an R2 value of 90%. Conclusions: An integrated limited sampling strategy (LSS) for MPA allows increased accuracy in prediction of MPA AUC0–12 compared to PK-only modeling. Validation of this model will allow for clinically feasible MPA therapeutic drug monitoring and help advance precision management of MPA.
AB - Background: Mycophenolic Acid (MPA) is the most used anti-proliferative in lung transplantation, but its pharmacokinetic (PK) variability has precluded therapeutic drug monitoring. Both genetic and clinical factors have been implicated in MPA variability. This study aimed to integrate genetic and clinical factors with PK measurements to quantify MPA exposure. Methods: We performed 12-hour pharmacokinetic analysis on 60 adult lung transplant recipients maintained on MPA for immunosuppression. We genotyped a SLCO1B3 polymorphisms previously associated MPA metabolism and collected relevant clinical data. We calculated area under the curve (AUC0–12) and performed univariate linear regression analysis to evaluate its association with genetic, clinical, and pharmacokinetic variables. We performed lasso regression analysis to create final AUC estimation tools. Results: PK-only measurements obtained 2, 3, and 8 hours after MPA administration (C2, C3, and C8) were strongly associated with MPA AUC0–12 (R2 67%, 67% and 68% respectively). Clinical and genetic factors associated with MPA AUC0–12 included the MPA dose (p = 0.001), transplant diagnosis (p = 0.015), SLCO1B3 genotype (p = 0.049), and body surface area (p = 0.050). The best integrated single-sampling strategy included C2 and achieved an R2 value of 80%. The best integrated limited-sampling strategy included C0, C0.25, and C2 and achieved an R2 value of 90%. Conclusions: An integrated limited sampling strategy (LSS) for MPA allows increased accuracy in prediction of MPA AUC0–12 compared to PK-only modeling. Validation of this model will allow for clinically feasible MPA therapeutic drug monitoring and help advance precision management of MPA.
KW - limited sampling strategy
KW - lung transplantation
KW - mycophenolic acid
KW - pharmacogenetics
KW - therapeutic drug monitoring
UR - http://www.scopus.com/inward/record.url?scp=85205267857&partnerID=8YFLogxK
U2 - 10.1016/j.healun.2024.09.007
DO - 10.1016/j.healun.2024.09.007
M3 - Article
C2 - 39293551
AN - SCOPUS:85205267857
SN - 1053-2498
VL - 44
SP - 46
EP - 56
JO - Journal of Heart and Lung Transplantation
JF - Journal of Heart and Lung Transplantation
IS - 1
ER -