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Pharmacokinetics Of Mycophenolate Mofetil (MMF) In Combination With Tacrolimus In Pediatric Allogeneic Stem Cell Transplant (AlloSCT) Recipients ≤ 12 Years Of Age

Year: 2010

Type: article

Abstract: The optimal dosing of MMF in pediatric AlloSCT recipients is unknown. To determine MMF PK in pediatric AlloSCT recipients<12 years of age. GVHD prophylaxis included tacrolimus Day –1 (5-20 ng/mL) and MMF 900 mg/m2 IV Q6H starting on Day +1, then converted to PO (same dose) after Day +14. MPA serum samples were drawn on Days +1, +7, +14 (IV phase) and twice between Day +45-+100 (PO phase) at hour 0, 0.5, 1, 2, 3, 4, 6 post-dose. MPA plasma concentrations were determined by reverse-phase HPLC and LC/MS/MS. Non-compartmental PK analysis of total MPA was performed. PK was completed in 25 pts: mean age 5 yrs; M:F 12:13; 14 pts<6 yrs & 11 pts 6-12 yrs; 11 pts non-malignant & 14 with malignant disease; 14 pts received unrelated AlloSCT. Patients with non-malignant disease received reduced-intensity conditioning. Median time to myeloid and platelet engraftment was 21 and 33 days, respectively. KM probability of Grade II-IV acute GVHD (aGVHD) and limited + extensive chronic GVHD was 52% and 39.8%, respectively. Probability of 1 year OS was 78.8% (CI95: 62%-95%). There was a significant inter- and intrapatient variability in AUC0-6 and MPA trough (C0) (Table 1). There was no significant difference in MMF PK between pts<6 vs 6-12 yrs of age following IV or PO MMF administration. Univariate analyses did not find a correlation between AUC, C0 or Css on Days 7 or 14 and risk of aGVHD. There was a significant ↑ in MPA trough on day 7 vs 1 (P=0.009), ↑AUC on day 14 vs 7 (P=0.049) and ↓ Vss day 14 vs day 1 & 7 (P=0.001). There was also a significant ↑ T1/2 on day 45 vs day 1 and 7 (P=0.043 and P=0.042, respectively) as well as ↑ CLss and Vss on day 45 vs day 14 (P=0.01 for CLss and P=0.006 for Vss). This change in PK parameters with time could be due to improved mucosal healing following conditioning that leads to improved drug absorption and enterohepatic recirculation. Based on these results, we recommend reducing MMF dose to 600-900 mg/m2 q8 h in the early post-transplant period in children <12 yrs of age to target Css=2.5-5 mg/L (Nash et al, BBMT 2005).Table 1IV MMF AdministrationMMF PO 1st sampleMMF PO 2nd sampleMean pK values (±SD)Day +1 (N=18)Day +7 (N=23)Day +14 (N=23)Day +45-100 (N=13)Day +45-100 (N=7)Cmaxmg/L)15.7±23.612.1±5.417.8±15.213.4±12.813.5±8.4Tmax (h)1.97±0.441.98±0.571.87±0.341.65±1.051.36±0.85C0 (mg/L)0.31±0.330.68±0.610.68±0.641.39±1.441.66±1.48Css (mg/L)5.57±7.744.84±2.166.35±3.115.00±3.467.22±3.70AUC0-6 (mg•h/L)32.8±46.427.4±11.936.6±18.626.4±20.627.45±16.0CLss (L/h•kg)1.80±1.101.48±0.651.30±0.632.32±1.421.61±1.02Vss (L/kg)3.60±2.043.60±1.633.00±1.0210.43±8.9921.22±38.25T1/2 (h)0.94±0.641.38±1.161.25±1.022.98±2.3812.78±20.58 Open table in a new tab

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2009.12.123