title: A pilot pharmacologic biomarker study in HLA-haploidentical hematopoietic cell transplant recipients.
abstract: OBJECTIVE
  Eleven patients diagnosed with various hematologic malignancies receiving an HLA-haploidentical hematopoietic cell transplant (HCT) participated in an ancillary biomarker trial. The goal of the trial was to evaluate potential pharmacologic biomarkers pertinent to the conditioning regimen [fludarabine monophosphate (fludarabine) and cyclophosphamide (CY)] or postgrafting immunosuppression [CY and mycophenolate mofetil (MMF)] in these patients.
  
  
  METHODS
  We characterized the interpatient variability of nine pharmacologic biomarkers. The biomarkers evaluated were relevant to fludarabine (i.e., area under the curve (AUC) of 2-fluoro-ara-A or F-ara-A), CY (i.e., AUCs of CY and four of its metabolites), and MMF (i.e., total mycophenolic acid (MPA) AUC, unbound MPA AUC, and inosine monophosphate dehydrogenase (IMPDH) activity).
  
  
  RESULTS
  Interpatient variability in the pharmacologic biomarkers was high. Among those related to HCT conditioning, the interpatient variability ranged from 1.5-fold (CY AUC) to 4.0-fold (AUC of carboxyethylphosphoramide mustard, a metabolite of CY). Among biomarkers evaluated as part of postgrafting immunosuppression, the interpatient variability ranged from 1.7-fold (CY AUC) to 4.9-fold (IMPDH area under the effect curve). There was a moderate correlation (R (2) = 0.441) of within-patient 4-hydroxycyclophosphamide formation clearance.
  
  
  CONCLUSIONS
  Considerable interpatient variability exists in the pharmacokinetic and drug-specific biomarkers potentially relevant to clinical outcomes in HLA-haploidentical HCT recipients. Pharmacodynamic studies are warranted to optimize the conditioning regimen and postgrafting immunosuppression administered to HLA-haploidentical HCT recipients.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Meagan J
authors.initials: MJ
authors.lastname: Bemer
authors.forename: Mohamed
authors.initials: M
authors.lastname: Sorror
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Sandmaier
authors.forename: Paul V
authors.initials: PV
authors.lastname: O'Donnell
authors.forename: Jeannine S
authors.initials: JS
authors.lastname: McCune
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006680:HLA Antigens / Q000276:immunology*; D019337:Hematologic Neoplasms / Q000473:pathology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D010865:Pilot Projects; D019172:Transplantation Conditioning / Q000379:methods*; D001084:Vidarabine Phosphate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D054316:Biomarkers, Pharmacological; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate; D003520:Cyclophosphamide; D009173:Mycophenolic Acid
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