Population approach to assess the relationship of cyclosporin exposure and renal dysfunction in Japanese patients with rheumatoid arthritis
Tajima, Takeshi(1), Akihiro Yokoi (1), Peiming Ma (2), Ryosei Kawai (1)
(1) Novartis Pharma K.K., (2) Novartis Pharmaceuticals Corporation
Objectives: Cyclosporin, suppressing various T-lymphocytes functions, has been used to prevent allograft rejection and treat autoimmune diseases including rheumatoid arthritis. Because of large PK variability and narrow therapeutic window, the daily dose should be adjusted to maximize immunosuppressive effect and minimize adverse events. To optimize the adjustment, exposure/clinical event relationship has been studied, where exposure is measured by spot blood concentrations (C0 or C2) or PK parameters (AUC) on drug monitoring days. However, clinical events must be more closely related to trajectory of exposure from start of dosing to events, rather than such concentrations or PK parameters. In this study, relationship between trajectory of exposure and renal dysfunction (the major adverse event) was investigated. Population PK approach was used to identify source of PK variability and simulate exposure in each patient.
Methods: A Japanese clinical study was conducted to investigate the efficacy, safety and PK. A total of 527 blood concentrations obtained from 50 patients by sparse sampling were analyzed by NONMEM using a two-compartment model with first-order absorption. The effect of demographic factors on oral clearance was examined using likelihood ratio test (p<0.05). Correlation between incidence of renal dysfunction adverse event (AE) and exposure indices (total administered doses, average daily dose, total accumulated AUC, and mean blood concentration from start of dosing to the incidence in patients with AE or to the last available visit in patients without AE) was assessed by Cox proportional hazards model.
Results and Conclusion: Age and cholesterol were significant covariates for oral clearance. The population PK model fitted closely observed values. AE was reported in 9 of 50 patients. In patients with and without AE, total administered doses were 193 and 385 mg/kg (arithmetic mean); average daily dose were 2.67 and 2.58 mg/kg/day; total accumulated AUC were 512 and 676 ug.h/mL; mean concentration were 275 and 189 ng/mL, respectively. Mean concentration was significantly correlated with AE (p<0.01), suggesting renal dysfunction is related to mean drug concentration during cyclosporin treatment rather than total administered doses, average daily dose, or accumulated AUC.