A Pilot Study of Pharmacokinetics-Based Mycophenolate Mofetil Dosing for Acute Graft-Versus-Host-Disease Prophylaxis
Year: 2011
Type: article
Abstract: Mycophenolate mofetil (MMF) is an ester prodrug of mycophenolic acid (MPA) which has been used successfully in the prevention and treatment of acute graft-versus-host-disease (aGVHD). Previous pharmacokinetics (PK) studies have shown low MPA exposure in BMT recipients, especially in the period following conditioning therapy, which is associated with inferior transplant outcomes. Multiple strategies, including empiric fixed-dose-escalation or higher dose per kg body weight, have failed to achieve consistent target MPA exposure. Attempts at giving MMF as short-infusion doses have been unsuccessful in maintaining desired trough concentrations (Ctrough) of MPA, especially in pediatric BMT patients. We hypothesized that a PK-based dosing strategy using a novel continuous infusion of MMF will be able to achieve and maintain target MPA exposure. The primary aim of this pilot study is to evaluate the safety and feasibility of this approach. Continuous infusion MMF was evaluated in 5 pediatric patients undergoing unrelated donor myeloablative transplant between July, 2009 and June, 2010. Mean age was 8.5 y (2-17 y) (4 F, 1 M). Patient diagnoses were MDS (2), ALL in CR2, Kostmann syndrome, and congenital erythropoietic porphyria. Three patients received MMF for GVHD prophylaxis and two for treatment of severe aGVHD. In all cases, total MPA Ctrough levels remained < 1 mcg/mL with intermittent IV dosing (15 mg/kg/dose q8 hourly). PK measurements on this schedule were used to estimate MPA clearance in order to predict the rate of a continuous infusion to maintain total MPA steady-state concentrations (Css) between 2.5-5 mcg/mL. Rates of infusion used ranged from 38-96 mg/kg/day. Total MPA Css concentrations ranged between 1.1-3.9 mcg/mL (mean 2.17 ± 0.76 mcg/mL). Total MPA steady-state clearance (CLss) values ranged between 7.8-28.6 mL/min/kg. Therapeutic total MPA Css levels were maintained in these patients for a duration of 10-30 days. Patients tolerated the infusion well and no infusion-related reactions or other adverse events occurred. In conclusion, we show that continuous infusion of MMF is safe and feasible, and successfully achieves and maintains targeted steady-state concentrations of MPA. We have extended our pilot protocol in order to study the clinical impact and pharmacokinetics of a continuous infusion of MMF for GVHD prophylaxis on a larger and more diverse pediatric BMT population in our institution.
Institutions: Children's Hospital of Pittsburgh, University of Pittsburgh
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W1967104415