title: Monitoring mycophenolate in liver transplant recipients: toward a therapeutic range.
abstract: Predose plasma mycophenolic acid (MPA) concentrations measured with a semi-automated enzyme-multiplied immunoassay were related to adverse events (e.g., rejection, leukopenia, infection), drug dose, and clinical status in 147 adult and 63 pediatric liver allograft recipients receiving adjunctive immunosuppression with mycophenolate mofetil (MMF). In 12 of 13 acute rejection episodes, predose MPA levels were below the 1 mg/L cut-off defined using receiver operating characteristic (ROC) curve analysis. The relative risk of developing infection or leukopenia increased more than 3-fold above predose MPA levels of 3 to 4 mg/L. Plasma MPA levels correlated weakly (r2 = 0.081) with MMF dose and the dose / level relationship was variably influenced by age, the indication for MMF, concentrations of serum albumin and creatinine, and comedication with tacrolimus or cyclosporine. The median mycophenolate dose required per unit mycophenolate level was 50% lower in children than in adults. Comparable drug requirements were also decreased by renal dysfunction (by 40 and 43% in adults and children, respectively), and in patients prescribed MMF alone rather than with tacrolimus or cyclosporine. However, in patients with serum albumin less than 35 g/L, MMF dose requirements were higher than in those with normal albumin levels (by 2.1- and 2.6-fold in adults and children, respectively). In adults, 44.7% achieved clinically acceptable therapeutic MPA concentrations at a dose less than 1 g MMF twice daily and only 6.3% required 1.5 g twice daily as suggested by the manufacturer. The immunoassay was a rapid, reliable, and acceptably precise technique in which only 10.8% of measurements were unproductive. In conclusion, our data suggests that MPA predose level monitoring is both clinically- and cost-effective and that a therapeutic range of 1 to 3.5mg/L (by immunoassay) is applicable in liver allograft recipients given adjunctive MMF.
authors.affiliation: Institute of Liver Studies, King's College Hospital and Guy's, King's and St. Thomas' School of Medicine, London UK. michael.tredger@kcl.ac.uk
authors.forename: John Michael
authors.initials: JM
authors.lastname: Tredger
authors.forename: Nigel William
authors.initials: NW
authors.lastname: Brown
authors.forename: Jemimah
authors.initials: J
authors.lastname: Adams
authors.forename: Chris Elton
authors.initials: CE
authors.lastname: Gonde
authors.forename: Anil
authors.initials: A
authors.lastname: Dhawan
authors.forename: Mohamed
authors.initials: M
authors.lastname: Rela
authors.forename: Nigel
authors.initials: N
authors.lastname: Heaton
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D003362:Cost-Benefit Analysis; D016572:Cyclosporine / Q000097:blood / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000191:economics / Q000379:methods*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques / Q000191:economics / Q000379:methods*; D007166:Immunosuppressive Agents / Q000097:blood / Q000627:therapeutic use; D007223:Infant; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood* / Q000627:therapeutic use; D016559:Tacrolimus / Q000097:blood / Q000627:therapeutic use; D014180:Transplantation
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D016559:Tacrolimus