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Blood, 15 December 2005, Vol. 106, No. 13, pp. 4381-4388.
Prepublished online as a Blood First Edition Paper on September 6, 2005; DOI 10.1182/blood-2005-06-2217.
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Submitted June 2, 2005
Accepted August 12, 2005
Pharmacodynamics of mycophenolate mofetil after nonmyeloablative conditioning and unrelated donor hematopoietic cell transplantation
Luisa Giaccone, Jeannine S McCune, Michael B Maris, Theodore A Gooley, Brenda M Sandmaier, John T Slattery, Scott Cole, Richard A Nash, Rainer F Storb, and George E Georges*
Fred Hutchinson Cancer Research Center, Seattle, WA, USA; University of Turin, Turin, Italy
Fred Hutchinson Cancer Research Center, Seattle, WA, USA; University of Washington, Seattle, WA, USA
Fred Hutchinson Cancer Research Center, Seattle, WA, USA
* Corresponding author; email: ggeorges{at}fhcrc.org;blarson@fhcrc.org.
The immunosuppressive drug mycophenolate mofetil (MMF) is used after nonmyeloablative hematopoietic cell transplantation (HCT); however, limited pharmacodynamic data are available. We evaluated plasma concentrations of mycophenolic acid (MPA), the active metabolite of MMF, and outcomes in 85 patients with hematologic malignancies conditioned with fludarabine and 2 Gy total body irradiation, followed by HLA-matched unrelated-donor HCT, and post-grafting cyclosporine and MMF. The first 38 patients received MMF 15 mg/kg twice daily (BID); the next 47 patients received MMF three times daily (TID). MPA pharmacokinetics was determined on days 7 and 21. Comparing the BID and TID MMF groups, the mean total MPA concentration steady state (Css) was 1.9 and 3.1 µg/mL; the unbound Css was 18 and 36 ng/mL, respectively (P<0.0001). Sixteen patients with a total MPA Css <3 µg/mL had low (<50%) donor T-cell chimerism (P=0.03), and 6 patients with MPA Css <2.5 µg/mL had graft rejection. An elevated unbound Css was associated with cytomegalovirus reactivation (P=0.03). There were no significant associations between MPA pharmacokinetics and acute GVHD or relapse. We conclude that increased MPA Css predicted higher degrees of donor T-cell chimerism after unrelated donor nonmyeloablative HCT and suggest that targeting MPA Css >2.5 µg/mL could prevent graft rejection.
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