title: Exposure-effect relationship of mycophenolic acid and prednisolone in adult patients with lupus nephritis.
abstract: OBJECTIVE
  The aim was to examine relationships between total and unbound mycophenolic acid (MPA) and prednisolone exposure and clinical outcomes in patients with lupus nephritis.
  
  
  METHODS
  Six blood samples were drawn pre- and at 1, 2, 4, 6 and 8 h post-dose and total and unbound MPA and prednisolone pre-dose (C0 ), maximum concentration (Cmax ) and area under the concentration-time curve (AUC) were determined using non-compartmental analysis in 25 patients. The analyses evaluated drug exposures in relation to treatment response since starting MPA and drug-related adverse events.
  
  
  RESULTS
  Dose-normalized AUC varied 10-, 8-, 7- and 19-fold for total MPA, unbound MPA, total prednisolone and unbound prednisolone, respectively. Median values (95% CI) of total MPA AUC(0,8 h) (21.5 [15.0, 42.0] vs. 11.2 [4.8, 30.0] mg l(-1) h, P= 0.048) and Cmax (11.9 [6.7, 26.3] vs. 6.1 [1.6, 9.2] mg l(-1) , P = 0.016) were significantly higher in responders than non-responders. Anaemia was significantly associated with higher total (37.8 [14.1, 77.5] vs. 18.5 [11.7, 32.7] mg l(-1) h, P = 0.038) and unbound MPA AUC(0,12 h) (751 [214, 830] vs. 227 [151, 389] mg l(-1) h, P = 0.004). Unbound prednisolone AUC(0,24 h) was significantly higher in patients with Cushingoid appearance (unbound: 1372 [1242, 1774] vs. 846 [528, 1049] nmol l(-1) h, P = 0.019) than in those without. Poorer treatment response was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared with patients with middle and higher tertile exposure (17% vs. 74%, P = 0.023).
  
  
  CONCLUSIONS
  This study suggests a potential role for therapeutic drug monitoring in individualizing immunosuppressant therapy in patients with lupus nephritis.
authors.affiliation: School of Pharmacy, University of Queensland, Brisbane, Queensland, Australia.|School of Pharmacy, International Islamic University of Malaysia, Kuantan, Pahang, Malaysia.
authors.forename: Azrin N
authors.initials: AN
authors.lastname: Abd Rahman
authors.affiliation: School of Pharmacy, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Tett
authors.affiliation: Nephrology Unit, Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia.
authors.forename: Halim A
authors.initials: HA
authors.lastname: Abdul Gafor
authors.affiliation: Department of Chemical Pathology, Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Brett C
authors.initials: BC
authors.lastname: McWhinney
authors.affiliation: School of Pharmacy, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Staatz
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008181:Lupus Nephritis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011239:Prednisolone / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D011239:Prednisolone; D009173:Mycophenolic Acid
keywords: lupus nephritis; mycophenolic acid; pharmacodynamics; pharmacokinetics; prednisolone; treatment outcome