title: Pharmacokinetic and pharmacodynamic analysis of inosine monophosphate dehydrogenase activity in hematopoietic cell transplantation recipients treated with mycophenolate mofetil.
abstract: A novel approach to personalizing postgrafting immunosuppression in hematopoietic cell transplantation (HCT) recipients is evaluating inosine monophosphate dehydrogenase (IMPDH) activity as a drug-specific biomarker of mycophenolic acid (MPA)-induced immunosuppression. This prospective study evaluated total MPA, unbound MPA, and total MPA glucuronide plasma concentrations and IMPDH activity in peripheral blood mononuclear cells (PMNCs) at 5 time points after the morning dose of oral mycophenolate mofetil (MMF) on day +21 in 56 nonmyeloablative HCT recipients. Substantial interpatient variability in pharmacokinetics and pharmacodynamics was observed and accurately characterized by the population pharmacokinetic-dynamic model. IMPDH activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration in most patients. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory maximum effect model with an IC50 of 3.23 mg/L total MPA and 57.3 ng/mL unbound MPA. The day +21 IMPDH area under the effect curve (AUEC) was associated with cytomegalovirus reactivation, nonrelapse mortality, and overall mortality. In conclusion, a pharmacokinetic-dynamic model was developed that relates plasma MPA concentrations with PMNC IMPDH activity after an MMF dose in HCT recipients. Future studies should validate this model and confirm that day +21 IMPDH AUEC is a predictive biomarker.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Schools of Medicine, University of Washington, Seattle, Washington.
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Sandmaier
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Barry E
authors.initials: BE
authors.lastname: Storer
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Schools of Medicine, University of Washington, Seattle, Washington.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Boeckh
authors.affiliation: School of Pharmacy, University of Washington, Seattle, Washington.
authors.forename: Meagan J
authors.initials: MJ
authors.lastname: Bemer
authors.affiliation: School of Pharmacy, University of Washington, Seattle, Washington.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Phillips
authors.affiliation: School of Pharmacy, University of Washington, Seattle, Washington.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Risler
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; School of Pharmacy, University of Washington, Seattle, Washington. Electronic address: jmccune@fhcrc.org.
authors.forename: Jeannine S
authors.initials: JS
authors.lastname: McCune
mesh_terms: D000328:Adult; D000368:Aged; D016903:Drug Monitoring; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007291:Inosine Monophosphate / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011446:Prospective Studies; D019172:Transplantation Conditioning / Q000379:methods*
chemical_list: D007291:Inosine Monophosphate; D009173:Mycophenolic Acid
keywords: Albumin; Covariates; Cyclosporine; Hematopoietic cell transplantation; Limited sampling schedule; Mycophenolic acid; Population pharmacokinetics; Therapeutic drug monitoring
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