title: Area-under-the-curve monitoring of prednisolone for dose optimization in a stable renal transplant population.
abstract: BACKGROUND
  Renal transplant recipients were noted to appear cushingoid while on low doses of steroid as part of a triple therapy immunosuppression of cyclosporin A (CsA), prednisolone, and azathioprine.
  
  
  METHODS
  The study group comprised adult renal transplant recipients with stable graft function who had received their renal allograft a minimum of 1 year previously (43 studies undertaken in 22 men and 20 women) with median daily prednisone dose of 7 mg (range 3-10). The control group was healthy nontransplant subjects [median dose 10 mg (10-30)]. Prednisolone bioavailability was measured using a limited 6-hour area under the curve (AUC), with prednisolone measured using specific HPLC assay.
  
  
  RESULTS
  The median prednisolone AUC/mg dose for all transplant recipients was significantly greater than the control group by approximately 50% (316 nmol x h/L/mg prednisolone versus 218). AUC was significantly higher in female recipients (median 415 versus 297 for men) and in recipients receiving cyclosporin (348 versus 285). The highest AUC was in women on estrogen supplements who were receiving cyclosporin (median 595). A significantly higher proportion of patients on triple therapy had steroid side effects compared with those on steroid and azathioprine (17/27 versus 4/15), more women than men had side effects (14/16 versus 7/22), and the AUC/mg prednisone was greater in those with side effects than without (median 377 versus 288 nmol x h/L/mg).
  
  
  CONCLUSIONS
  The results are consistent with the hypothesis that CsA increases the bioavailability of prednisolone, most likely through inhibition of P-glycoprotein. The increased exposure to steroid increased the side-effect profile of steroids in the majority of patients. Because the major contributor to AUC is the maximum postdose concentration, it may be possible to use single-point monitoring (2 hours postdose) for routine clinical studies.
authors.affiliation: Queensland Health Pathology Service, Prince Charles Hospital, Brisbane, Queensland, Australia. julia.potter@act.gov.au
authors.forename: Julia M
authors.initials: JM
authors.lastname: Potter
authors.forename: Brett C
authors.initials: BC
authors.lastname: McWhinney
authors.forename: Lee
authors.initials: L
authors.lastname: Sampson
authors.forename: Peter E
authors.initials: PE
authors.lastname: Hickman
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001379:Azathioprine / Q000627:therapeutic use; D001682:Biological Availability; D016572:Cyclosporine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011239:Prednisolone / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011239:Prednisolone; D001379:Azathioprine