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.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.

Therapeutic drug monitoring of cyclosporine and area under the curve prediction using a single time point strategy: appraisal using peak concentration data

“…Table provides the tabulation of the reported C max and AUC values from the various patient studies and healthy subject clinical pharmacology studies reported in the literature . The prediction of AUC values for cyclosporine was performed using the regression equation: and the appropriate fold differences were computed (Table ).…”

Pharmacokinetic modeling of therapies for systemic lupus erythematosus

“…Neoral ® is a new microemulsion formulation of CsA. It has greater and more balanced gastrointestinal absorption, improved bioavailability and smaller inter-patient variability in PK profiles than conventional oil-based formulations, indicating more consistent and more predictable absorption of CsA from microemulsion formulations [94,95]. Higher C max and AUC were achieved during the steady state in patients who received Neoral.…”