(329) Mycophenolic Acid Therapeutic Drug Monitoring Using Area Under the Curve in Pediatric Heart Transplant Recipients

• Published in: The Journal of heart and lung transplantation Vol. 42; no. 4; p. S156
• Main Authors: Newland, D.M., Pak, J.L., Ali, R., Nemeth, T.L., Tressel, W., Kronmal, R., Albers, E.L., Friedland-Little, J.M., Ahmed, H., Kemna, M.S., Hong, B.J., Spencer, K.L., Law, Y.M.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-04-2023
• ISSN: 1053-2498; 1557-3117
• DOI: 10.1016/j.healun.2023.02.1633

Pharmacokinetics (PK) of mycophenolic acid (MPA) display substantial interpatient variability, with up to 10-fold difference of exposure in individual patients under a fixed-dose regimen. MPA trough level (C0) monitoring is common in clinical practice but has not proven sufficiently informative in predicting MPA exposure or patient outcomes, especially in children. No limited sampling strategies (LSSs) have been generated from pediatric heart transplant (HTx) recipients to estimate MPA area under the curve (AUC).
Single-center, observational analysis of 135 de novo pediatric HTx recipients ≤ 21 yo who underwent MPA AUC during index HTx hospitalization between 2011 and 2021. Mycophenolate mofetil (MMF) doses were titrated to target 100 or 70 mg/kg/day in divided doses for those < 5 or ≥ 5 yo, respectively (max 2000 mg/day). Steady state serum concentrations of MPA were drawn serially at 20 (C1), 60 (C2), 90 (C3), 180 (C4), and 360 (C5) minutes after MMF dose followed by C0 before next dose. Trapezoidal MPA AUCs were calculated and standardized to a 24-hour interval. Pearson correlation coefficients (r) were used to measure linear association between fixed MMF doses and individual MPA levels and MPA AUC0-24h. LSS models for estimating MPA AUC0-24h were created for each combination of 2 through 6 of C1, C2, C3, C4, C5, and C0.
Median age was 4 years (IQR 0.6 - 12.1). Median time from HTx to MPA AUC was 15 days (IQR 11 - 19). Regimens included tacrolimus (64%) or cyclosporine (34%). MMF doses (mg or mg/day) had no correlation (r = -0.005 and -0.002, respectively) while doses adjusted for weight or body surface area correlated poorly with MPA AUC0-24h (r = 0.3 and 0.383, respectively). MPA C0 correlated poorly (r = 0.451) with MPA AUC0-24h. 64% had MPA C0 levels < 2 mcg/mL. Of n=111 with MPA AUC within or above goal, 60% had C0 < 2 mcg/mL. MMF doses were increased in 33% and decreased in 30% per AUC. LSS with two PK sampling time points at 90 (C3) and 360 (C5) minutes (estimated MPA AUC0-24h = 32.82 + 4.12 × C3 + 11.53 × C5; target = 60-120 mg·h/L) showed very good correlation with trapezoidal MPA AUC0-24h (r = 0.87).
MMF at adjusted or fixed doses, as well as MPA trough levels, correlate poorly with MPA AUC0-24h. We developed novel LSSs to estimate trapezoidal MPA AUC from a large cohort of pediatric HTx recipients. Validation of our LSSs will be performed in a future cohort.