title: Inosine monophosphate dehydrogenase (IMPDH) activity as a pharmacodynamic biomarker of mycophenolic acid effects in pediatric kidney transplant recipients.
abstract: Monitoring inosine monophosphate dehydrogenase (IMPDH) activity as a biomarker of mycophenolic acid (MPA)-induced immunosuppression may serve as a novel approach in pharmacokinetics (PK)/pharmacodynamics (PD)-guided therapy. The authors prospectively studied MPA pharmacokinetics and IMPDH inhibition in 28 pediatric de novo kidney transplant recipients. Pretransplant IMPDH activity and full PK/PD profiles were obtained at 3 different occasions: 1 to 3 days, 4 to 9 days, and approximately 6 months after transplant. Large intra- and interpatient variability was noted in MPA pharmacokinetics and exposure and IMPDH inhibition. MPA exposure (AUC(0-12 h)) was low early posttransplant and increased over time and stabilized at months 3 to 6. Mean pretransplant IMPDH activity (6.4 ± 4.6 nmol/h/mg protein) was lower than previously reported in adults. In most of the patients, IMPDH enzyme activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory E(max) model (EC(50) = 0.97 mg/L). This study suggests the importance of early PK/PD monitoring to improve drug exposure. Because IMPDH inhibition is well correlated to MPA concentration, pretransplant IMPDH activity may serve as an early marker to guide the initial level of MPA exposure required in a pediatric population.
authors.affiliation: Division of Clinical Pharmacology and Pediatric Pharmacology Research Unit, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukuda
authors.forename: Jens
authors.initials: J
authors.lastname: Goebel
authors.forename: Håvard
authors.initials: H
authors.lastname: Thøgersen
authors.forename: Denise
authors.initials: D
authors.lastname: Maseck
authors.forename: Shareen
authors.initials: S
authors.lastname: Cox
authors.forename: Barbara
authors.initials: B
authors.lastname: Logan
authors.forename: Joseph
authors.initials: J
authors.lastname: Sherbotie
authors.forename: Mouin
authors.initials: M
authors.lastname: Seikaly
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
mesh_terms: D000293:Adolescent; D015415:Biomarkers / Q000097:blood; D001711:Biotransformation; D002648:Child; D002675:Child, Preschool; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D020719:Glucuronides / Q000097:blood; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000097:blood*; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000009:adverse effects*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D057234:Preoperative Period; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D020719:Glucuronides; D007166:Immunosuppressive Agents; D011355:Prodrugs; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid