Pharmacokinetic and Pharmacodynamic Analysis of Inosine Monophosphate Dehydrogenase Activity in Hematopoietic Cell Transplantation Recipients Treated.

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Presentation transcript:

Pharmacokinetic and Pharmacodynamic Analysis of Inosine Monophosphate Dehydrogenase Activity in Hematopoietic Cell Transplantation Recipients Treated with Mycophenolate Mofetil Hong Li, Donald E. Mager, Brenda M. Sandmaier, Barry E. Storer, Michael J. Boeckh, Meagan J. Bemer, Brian R. Phillips, Linda J. Risler, Jeannine S. McCune Biology of Blood and Marrow Transplantation Volume 20, Issue 8, Pages 1121-1129 (August 2014) DOI: 10.1016/j.bbmt.2014.03.032 Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Final pharmacokinetic model characterizing total MPA, unbound MPA, and total MPAG concentrations following oral MMF administration. tlag, lag time; GI, gastrointestinal tract; ka, first-order absorption rate constant; fu, fraction unbound of MPA; Vc, volume of central compartment of total MPA; Q, intercompartment clearance of total MPA; Vp, volume of peripheral compartment of total MPA; CLMPA, clearance of total MPA; CLMPAG, clearance of total MPAG; Vm, volume of central compartment of total MPAG; k41, first-order rate constant of EHC. Biology of Blood and Marrow Transplantation 2014 20, 1121-1129DOI: (10.1016/j.bbmt.2014.03.032) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Interpatient variability in IMPDH activity in PMNCs on day +21. Concentration-response of IMPDH activity by total MPA (A) and unbound MPA (B) plasma concentrations. Time course of IMPDH activity and total MPA concentration (mean ± SD) (C). Percentage of IMPDH activity (mean ± SD) vs. total MPA corrected for baseline (ie, predose) values (D). Biology of Blood and Marrow Transplantation 2014 20, 1121-1129DOI: (10.1016/j.bbmt.2014.03.032) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Association of IMPDH AUEC (pmol × 106 cells) with acute GVHD (A), CMV reactivation (B), nonrelapse mortality (C), and overall mortality (D) in 45 patients receiving an unrelated donor graft. Only events on or after day +26 are included. Biology of Blood and Marrow Transplantation 2014 20, 1121-1129DOI: (10.1016/j.bbmt.2014.03.032) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Visual representation of IMPDH AUEC (gray area, in units of pmol × 106 cells) after a single dose of MMF at steady state (A) and distribution of IMPDH AUEC in all patients (B). Biology of Blood and Marrow Transplantation 2014 20, 1121-1129DOI: (10.1016/j.bbmt.2014.03.032) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions