Pharmacokinetics of Enteric-Coated Mycophenolate Sodium in Lupus Nephritis (POEMSLUN).

BACKGROUND: Mycophenolate mofetil or enteric-coated mycophenolate sodium (EC-MPS) and steroids are used for induction and maintenance therapy in severe lupus nephritis. Blood concentrations of mycophenolic acid (MPA), the active metabolite of these drugs, vary among patients with lupus nephritis. The objective of this study was to examine whether concentration-controlled (CC) dosing (through therapeutic drug monitoring) of EC-MPS results in a higher proportion of participants achieving target exposure of MPA compared with fixed-dosing (FD). An additional aim of the study was to evaluate the influence of CC dosing on clinical outcomes. METHODS: Nineteen participants were randomly assigned either to the FD or CC group. All the participants were eligible to have free and total measurements of MPA over a period of 8-12 hours on 3 different occasions. Area under the concentration-time curve between 0 and 12 hours (AUC0-12) was calculated using noncompartmental methods. Dose of EC-MPS was titrated according to AUC0-12 in the CC group. RESULTS: Thirty-two AUC0-12 measurements were obtained from 9 FD and 9 CC participants. Large inter-patient variability was observed in both groups but was more pronounced in the FD group. There were no significant differences between FD and CC participants in any pharmacokinetic parameters across the study visits, except for total C0 (FD 2.0 ± 0.3 mg/L versus CC 1.1 ± 0.3; P = 0.01) and dose-normalized C0 (FD 2.9 ± 0.2 mg/L/g versus CC 2.1 ± 0.7 mg/L/g; P = 0.04) at the second visit and total AUC0-12 (FD 66.6 ± 6.0 mg·h/L versus CC 35.2 ± 11.4 mg·h/L; P = 0.03) at the third visit. At the first study visit, 33.3% of the FD and 11.1% of the CC participants achieved the target area under the concentration-time curve (P = 0.58). From the second visit, none of the FD participants, compared with all the CC participants, achieved target AUC0-12 (P = 0.01). More CC participants achieved remission compared with FD participants (absolute difference of -22.2, 95% confidence interval (Equation is included in full-text article.)0.19 to 0.55; P = 0.62). The mean free MPA AUC0-12 was significantly lower in those who had complete remission. CONCLUSIONS: CC participants reached target AUC0-12 quicker. Larger studies are required to test clinical efficacy.

A Protocol for the Pharmacokinetics of Enteric Coated Mycophenolate Sodium in Lupus Nephritis (POEMSLUN): an open-label, randomised controlled trial.

INTRODUCTION: Mycophenolate sodium, an enteric-coated tablet (EC-MPS), is as effective and safe as mycophenolate mofetil (MMF) in preventing transplant rejection. EC-MPS and MMF improve the outcome of severe lupus nephritis (LN) and have fewer side effects than pulsed intravenous cyclophosphamide. Blood concentrations of mycophenolic acid (MPA), the active metabolite of EC-MPS, vary between participants despite fixed dosing. Interpatient variability has been studied in transplantation, but not well documented in LN. The relationship between MPA concentration and its clinical effect on LN has not been described. METHODS AND ANALYSIS: This is a prospective, open-label, randomised controlled trial. -32 participants with LN who meet the inclusion and exclusion criteria will be randomised into two groups: one receiving a fixed dose of EC-MPS and the second, a dosing regimen that is titrated with therapeutic drug monitoring. Included participants will have blood sampled over a period of 8-12 h on three different occasions. Pharmacokinetic parameters will be calculated using non-compartmental methods. ETHICS AND DISSEMINATION: The Human Research and Ethics Committee of the Royal Brisbane Women's Hospital have approved this study. The study is registered with Australian and New Zealand Clinical Trials Registry-ACTRN12611000798965 We planned to present the de-identified information at conferences and publish the results in medical journals. TRIAL REGISTRATION: ACTRN12611000798965.