title: Single-dose and steady state pharmacokinetics of CSA and two main primary metabolites, AM1 and AM4n in patients with rheumatic/autoimmune diseases.
abstract: BACKGROUND
  Cyclosporine A (CsA) is an immunomodulatory agent used in standard immunosuppressive regimens in solid organ transplantations as well as in the treatment of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus and psoriasis. Its immunosuppressive activity is primarily due to parent drug. However, following oral administration, absorption is incomplete and varies between individuals. Further, there is a dearth of pharmacokinetic data for CsA in autoimmune patients compared to transplant recipients.
  
  
  OBJECTIVE
  The goal of this study was to investigate the single-dose and steady state pharmacokinetics of CsA and two main primary metabolites, AM1 and AM4N, in patients with rheumatic/autoimmune diseases.
  
  
  METHODS
  Thirty-eight subjects, average age (years± SD) 46.8 (±11.6) years with rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, ankylosing spondylitis and undifferentiated SpA were included in an observational open study. The single dose pharmacokinetics (area under the concentration-time curve of CsA and its metabolites (AUC) and other PK parameters) were determined over a 24 h period following oral administration of 1.3 mg/kg oral CsA. Two CsA formulations-Neoral and the Czech generic substitute Consupren®, were used. Pharmacokinetic analysis was performed on all 38 patients after administration of a single dose of CsA (1.34 mg/ kg/day). In 12 patients only, a second series of blood samples was taken to calculate monitored PK parameters under steady state conditions.
  
  
  RESULTS
  Pharmacokinetic assessment showed AUC(0-24) 3009.66 ± 1449.78 ng/ml.h and C(max) 827.84 ± 425.84 after administration of a single dose of CSA, AUC(0-24) 3698.50 ± 2147 ng/ml.h and C(max) 741 ± 493 ng/ml after repeated dose. The proportion of the AM1 metabolite (AUC(0-24)) after a single dose of CsA corresponded to 40% of the parent compound and to approximately 35% of the parent compound in steady state conditions. The proportion of AM4N metabolite was low in both conditions and represented only 3 and 4.5% after a single dose and at steady state, respectively.
  
  
  CONCLUSIONS
  The pharmacokinetic data (AUC(CsA), C(max)) for the whole 24 h interval were similar to the published findings, mainly under steady state conditions. The AM1 (AUC(0-24)) after a single dose of CsA and in steady state conditions represented about 40% of the parent drug. The ratio of AM4N metabolite was low in both conditions.
authors.affiliation: Department of Clinical Pharmacology, Czech Republic. suchyd@fnplzen.cz
authors.forename: David
authors.initials: D
authors.lastname: Suchy
authors.forename: Miroslav
authors.initials: M
authors.lastname: Dostalek
authors.forename: Ilona
authors.initials: I
authors.lastname: Perinova
authors.forename: Hana
authors.initials: H
authors.lastname: Brozmanova
authors.forename: Milan
authors.initials: M
authors.lastname: Grundmann
authors.forename: Vaclav
authors.initials: V
authors.lastname: Vyskocil
authors.forename: Otto
authors.initials: O
authors.lastname: Mayer
mesh_terms: D019540:Area Under Curve; D001327:Autoimmune Diseases / Q000378:metabolism*; D016572:Cyclosporine / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D012216:Rheumatic Diseases / Q000378:metabolism*
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine