Mycophenolic Acid AUC estimation in patients with lupus nephritis using an algorithm validated in an heart transplanted population

Mycophenolic Acid AUC estimation in patients with lupus nephritis using an algorithm validated in an heart transplanted population P.G. Cojutti1, L. Franceschi1, V. Tursi2, U. Livi2, A. Zabotti3, S. Sacco3, L. Quartuccio3, S. De Vita3, M. Baraldo1 1 Institute of Clinical Pharmacology and Toxicology, Azienda Ospedaliero Universitaria Santa Maria della Misericordia, Dept. of Experimental and Clinical Pathology and Medicine, Medical School, University of Udine, Udine 2 Dept. of Cardio-Thoracic Surgery, Azienda Ospedaliero Universitaria Santa Maria della Misericordia, Udine 3 Clinic ofRheumatology, Department ofMedical and Biological Sciences, Medical School, University of Udine, Udine The standard of care for lupus nephritis is represented by cyclophosphamide and steroids, but the occurrence of serious drug-related adverse events is commonplace. Mycophenolic acid (MPA) showed a similar efficacy and a less toxic profile than cyclophosphamide and consequently has recently replaced this latter drug as the first-line treatment for proliferative lupus nephritis. However, the pharmacokinetic of MPA is characterized by a wide intra- and inter-individual variability, and therapeutic drug monitoring (TDM) has been advocated as a useful tool in optimizing MPA dosing regimen. TDM of MPA has been initially adopted for preventing organ rejection following transplantation: in this setting, MPA area under the curve (MPA-AUC0-12h) has demonstrated to be a better predictor of rejection in both renal and cardiac transplantation with respect to trough concentration (C0), with a therapeutic range between 30 and 60 mg*h/L. From a clinical point of view, MPA-AUC0-12h determination is an important burden both for the patients and for the medical staff; consequently, different limited sampling strategies (LSSs) for MPA-AUC0-12h estimation have been studied and validated in renal, liver and heart transplanted patients. Two of these LSSs are currently used at our University- Hospital for routine MPA-AUC0-12h calculation in heart transplanted patients: AUC = 5.568 + 0.902*C1.25 + 2.022*C2 + 4.594*C6 or, the preferred formula, AUC = 3.800 + 1.015*C1.25 + 1.819*C2 + 1.566*C4 + 3.479*C6. Considering that some authors have recently hypothesized that an AUC0-12h > 45 mg * h /L allows a better response even in lupus nephritis, the aim of this study is to verify whether the LSSs for MPA-AUC0-12h estimation, validated in heart transplanted patients, might be suitable for MPA-AUC0-12h estimation in rheumatological patients affected by lupus nephritis. In 5 rheumatological patients (mean age 34.2±10.3 yrs) with lupus nephritis, receiving concomitant steroid therapy and whose clinical conditions were deemed stable, 31 MPA full AUC0-12h profiles have been collected. The mean MPA dose was 2.2±0.8 g/die. Blood samples were collected in EDTA tubes at 0 (pre-dose), 0.5, 1.25, 2, 4, 6, 8 and 12 hour post-dose, after the morning dose. Plasma MPA concentrations have been measured by a validated high performance liquid chromatography (HPLC) method. Full MPA-AUC0-12h values were calculated using Winnonlin version 1.1. These full MPA-AUC0-12 profiles were compared to those obtained using the two LSS algorithms at the analysis of variance. The mean ± standard deviation of MPA-AUC0-12h calculated with the standard sampling strategy and using the two proposed formula were 77.5±26.5, 58.9±18.5 and 60.9±19.5 mg*h /L respectively. A statistically significant difference between the three method emerged (p = 0.011). This study demonstrates that the MPA-AUC0-12h estimation in rheumatological patients cannot be carried out using LSSs validated in heart transplanted