Higher Mycophenolate Dose Requirements in Children Undergoing Hematopoietic Cell Transplant (HCT).

Abstract

Mycophenolate mofetil (MMF), a pro-drug of mycophenolic acid (MPA), is commonly used as part of the immunosuppressive regimen after hematopoietic cell transplantation (HCT). Although MMF is widely used in HCT transplant recipients, systemic exposure has not been thoroughly studied in pediatric HCT recipients. Hence, the dosing strategies used in children undergoing kidney transplantation have been adopted or the adult dose has been extended to HCT children. Therefore, we studied mycophenolate pharmacokinetics in 19 children with median age of 17 (3–140) months with nonmalignant diseases undergoing myeloablative HCT who received mycophenolate in combination with cyclosporine for graft-versus-host disease prophylaxis. All subjects, except two, received 15 mg/kg mycophenolate intravenously every 8 hours. Pharmacokinetics were studied once between days 3–7 and again between days 10–14 post-transplant. The median [range] MPA total area under the curve (AUC)0-8 was 12.6 mcg hr/ml [4.9–49.2] and unbound AUC0-8 was 0.274 mcg hr/ml [0.037–1.4]. Unbound MPA fraction was 1.7% [0.76–5.1]. The median total mycophenolic acid glucuronide (MPAG) AUC0-8 was 269.1 mcg hr/mL [127.6–957.0]. Total and unbound MPA trough concentrations were 0.24 [0.03–2.9] and 0.005 [0–0.034] mcg/mL, respectively, with 8 hour dosing. MPA troughs were not good surrogates for overall exposure (AUC)0-8,[r2≤0.55]. MPA exposures did not change significantly between weeks 1 and 2 (p≤0.51), although several patients had an increase or decrease in AUC by 50% or more. SCr, CrCl, bilirubin, age, weight and albumin were poorly correlated with MPA AUC0-8 (all r2<0.40). Twenty % of the AUC's achieved a total MPA target previously associated with better donor chimerism and 54% met the unbound MPA targets associated with reduced acute GVHD risk in adults undergoing nonmyeloablative transplant. These data suggest that 15 mg/kg every 8 hours may be too low. However, whether these targets are relevant in the pediatric myeloablative setting is not known. MMF given 15 mg/kg every 8 hours intravenously in our patients achieved an exposure similar to that previously observed in adult nonmyeloablative HCT recipients receiving 1gm every 12 hours intravenously. MPA exposure in pediatric HCT recipients is lower than pediatric organ transplant recipients despite receiving a 33% higher dose. Children undergoing HCT should receive an MMF dose of at least 15 mg/kg intravenously every 8 hours to achieve systemic concentrations near those proposed to be therapeutic in the adult HCT population. The optimal MPA exposure target, particularly the upper limit of safety, in children undergoing myeloablative HCT has yet to be determined.