Pharmacokinetics (PK) of Mycophenolate Mofetil (MMF) in Pediatric Allogeneic Stem Cell Transplant (AlloSCT) Recipients Are Associated with Significantly Higher Clearance.
Authors: Militano Olga , Roache Kate , Shaw Leslie M. , Figurski Michael , Satwani Prakash , Ayello Janet , Wolownik Karen , Foley Sandra , Hawkes Ria , Del Toro Gustavo , Bradley M. Brigid , George Diane , Garvin James , Bhatia Monica , Roman Liz , Cairo Mitchell S. 
Published: April 2020

We have previously reported altered PK requiring significantly higher doses of MMF in pediatric AlloSCT recipients (Osunkwo et al, BBMT 2004). The objective of this study is to further evaluate effects of age and type of conditioning regimen (ablative vs reduced intensity on the PK of MMF in pediatric AlloSCT recipients. From Jan ’04 through April ’05 we have enrolled 21 pediatric AlloSCT recipients in an IRB approved protocol. Mean age 6.2 yrs (0.33–15); weight 28.6 kg (5.7–129.3); M:F = 11:10; NBL PR (n=3), SCD (n=2), AML (CR1 [n=2], CR2 [n=1], CR3 [n=1], relapsed [n=1], induction failure [n=1]), SAA (n=2), CML CP (n=1), ALL (CR1 [n=1], CR2 [n=1], CR3 [n=1]), WAS (n=1), HD CR2 (n=1), ALCL refractory (n=1), SCID (n=1); donor sources included MFD (6/6 PBSC [n=5], 6/6 BM [n=1], 5/6 PBSC [n=2]), 6/6 related CB (n=1), UCB (6/6 [n=2], 5/6 [n=2], 4/6 [n=7]), and 8/10 MUD PBSC (n=1). Cohort 1 (&lt; 6 yrs) (n=10); 2 (6–12 yrs of age) (n=6); 3 (12–16 yrs) (n=5). GVHD prophylaxis included tacrolimus and MMF (+ methotrexate for MUD). Tacrolimus was initiated on Day −1 or 1st day of conditioning (protocol dependent) at 0.03 mg/kg/d CI or 0.12 mg/kg/d PO Q8–12H to maintain concentrations 5–20 ng/mL. MMF was initiated on Day +1 at 900 mg/m2/dose IV Q6H and then converted to PO (same dose) on Day +14 or later. MMF PK was performed on Day +1, +7, and +14 (while on IV MMF) at hour 0, 0.5, 1, 2, 3, 4, and 6 post-dose. MPA plasma concentrations were determined by reverse-phase HPLC. MMF dose was adjusted to maintain MPA trough 1–3.5 mcg/mL. The mean CD34+ cell dose/kg = 23 x 105, nucleated cell dose/kg = 45 x 107. Time to neutrophil engraftment (ANC ≥ 500/mm3 x 2 d) was 22 d and platelet engraftment (untransfused count ≥ 20K x 7 d) was 28 d. The mean f/u was 241 d. Mean MPA PK on Day +14 demonstrated Cmax=12.4 mg/L, total MPA trough =0.9 mg/L, AUC0–12=32.7 mcg•hr/mL, Css=2.7 mg/L, T1/2=1.5 h, Vss=1.8 L/kg, and CL=1.4 L/kg/h at a mean MMF dose of 1080 mg/m2 IV Q6H. The breakdown of age cohorts is shown in Table 1. Gastrointestinal adverse events attributable to MMF occurred in 50% of patients (grade 2–3 nausea (n=9), grade 2–3 vomiting (n=4), abdominal pain (n=2), pneumatosis intestinalis (n=1), colitis (n=1)). Kaplan-Meier probability of grade II–IV aGVHD (18 evaluable pts) was 71.1% (CI: 46.9–95.4) and cGVHD (15 evaluable pts) was 37.7% (CI: 8.2–67.1). In comparison to MMF PK in adult AlloSCT pts receiving cyclosporine/MMF (Nash et al, BBMT 2005), pediatric pts appear to have significantly higher MMF clearance rates (1.4 vs 0.54 L/kg/h). MMF doses &gt; 3-fold higher than those used in pediatric SOT recipients were required to achieve AUC0–12=30–60 mcg•h/mL. Short half-life (1.5 hrs) and rapid clearance of MMF in pediatric AlloSCT recipients in part appear related to a lack of enterohepatic recycling and enhanced UDP-glucuronosyltransferase activity.

Table 1. Age-Based MMF PK in Pediatric AlloSCT Recipients on Day +14 Age Group &lt; 6 y.o. (n=6) 6–12 y.o. (n=5) 12–16 y.o. (n=2) Cmax(mg/L) 12.2 11.8 14.4 Total MPA trough (mg/L) 1.0 0.4 1.4 Free MPA trough (ng/mL) 18.7 14.8 17.9 Mean AUC0–12 (mcg•h/mL) 34 29.5 39.9 Mean total Css (mg/L) 2.8 2.5 3.3 T1/2 (h) 1.8 1.1 1.5 Vss(L/kg) 2.1 1.8 0.5 CL (L/kg/h) 1.6 1.4 0.6