Mycophenolic Acid Area under the Curve Monitoring via Limited Sampling Strategy in Pediatric Heart Transplant Recipients

Abstract

Purpose The study aim was to investigate exposure to mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), after pediatric orthotopic heart transplantation (pOHT). Previous studies in pediatric kidney recipients demonstrated a relationship between MPA concentration and risk of rejection or hematologic side effects. The quantification of MPA in pOHT is not well established, and the relationship between a single-time-point-correlate and area under the curve (AUC) is lacking. We sought to assess the clinical individualization of MPA dosing after initiation of MPA AUC measurements in our patients. Methods Between April 2017 and September 2018, 81 pOHT were performed, from which 22 AUCs in 14 patients were collected via a 3 point limited sampling strategy. Indication for MPA measurement, MMF dose, frequency of dosage adjustment, and time from transplant were examined via retrospective chart review. The first year post pOHT biopsies are for concern of rejection based on frequent echocardiograms, or per DSAs, monitored at transplant and months 3, 6, and 12 thereafter. Results Median MPA AUC was 37.5 mg*h/L (range 14-216) at 61 days post-pOHT (range 11-4426). Median patient age was 10 years (range 46 days-16 years). Of 22 MPA AUCs collected, 12 warranted dosage adjustments for optimization. Within those, 9 patients' AUCs were re-measured post adjustment with 8 attaining goal range 30-60 mg*h/L. Median MMF dose was 500 mg/m^2, or 18.8 mg/kg, both twice daily. Fifty percent of all AUCs were for-cause indications: high-risk Epstein-Barr Virus donor positive, recipient negative (n=4); high-risk Cytomegalovirus donor positive, recipient negative (n=2); recent infections requiring systemic antimicrobials (n=4); and diagnosis of post transplant lymphoproliferative disorder (n=1). All but one (90.9%) of the for-cause AUC analyses merited dose adjustments. Three patients had baseline nausea; one displayed a supratherapeutic AUC. One reported nausea abatement following MMF decrease whereas two spontaneously resolved. Five reports of leukopenia were found, three with AUCs above 60 mg*h/L. All leukocyte levels normalized following MMF dosage reduction. Conclusion Patient specific tailoring of MMF via therapeutic drug monitoring of MPA AUC in pOHT may increase tolerability and diminish short and long term side effects of therapy.