Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2011, 155(3):269-274 | DOI: 10.5507/bp.2011.020

SINGLE-DOSE AND STEADY STATE PHARMACOKINETICS OF CSA AND TWO MAIN PRIMARY METABOLITES, AM1 AND AM4N IN PATIENTS WITH RHEUMATIC/AUTOIMMUNE DISEASES

David Suchy^a, Miroslav Dostalek^b, Ilona Perinova^c, Hana Brozmanova^c, Milan Grundmann^c, Václav Vyskocil^d, Otto Mayer^a

^a Department of Clinical Pharmacology, Faculty Hospital Plzen, Czech Republic

^b Clinical Pharmacokinetic Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, 02881, RI, USA

^c Department of Clinical Pharmacology, Faculty Hospital Ostrava

^d Center for Metabolic Bone Disease, 2nd Department of Internal Medicine, Faculty Hospital Plzen

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.

Aim: 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.

Conclusion: 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.

Keywords: Cyclosporine, CsA, AM1, AM4N, Cyclosporine biotransformation, Rheumatic diseases

Received: October 30, 2010; Accepted: February 17, 2011; Published: September 1, 2011  Show citation