Pharmacokinetics and pharmacodynamics profiles of enteric‐coated mycophenolate sodium in female patients with difficult‐to‐treat lupus nephritis

Abstract

Relapsed or resistant lupus nephritis (LN) is considered a difficult-to-treat type of LN, and enteric-coated mycophenolate sodium (EC-MPS) has been used in this condition. Therapeutic drug monitoring using the area under the plasma mycophenolic acid concentration from 0 to 12 h postdose (MPA-AUC 0-12h ) ≥45 μg.h/ml is a useful approach to achieve the highest efficiency. This study assessed EC-MPS's pharmacokinetic (PK) and pharmacodynamic (PD) profiles and investigated an optimal level of the single time point of plasma MPA concentration.Nineteen biopsy-proven patients with class III/IV LN received 1440 mg/day of EC-MPS for 24 weeks. PK (maximum plasma MPA concentration [C max ], time to C max , and MPA-AUC 0-12h ) and PD (activity of inosine-5′-monophosphate dehydrogenase [IMPDH]) parameters were measured at weeks 2, 8, 16, and 24. We found that IMPDH activity decreased from baseline by 31-42% within 2-4 h after dosing, coinciding with the increased plasma MPA concentration. MPA-AUC 0-12h ≥45 μg.h/ml was best predicted by a single time point MPA concentration at C0.5, C2, C3, C4, and C8 (r 2 = 0.516, 0.514, 0.540, 0.611, and 0.719, respectively), independent of dose, albumin, urine protein/creatinine ratio, and urinalysis. The MPA-C0.5 cutoff of 2.03 g/ml yielded the highest overall sensitivity of 85% and specificity of 88.2% in predicting MPA-AUC 0-12h ≥45 μg.h/ml. A single timepoint of plasma MPA-C0.5 ≥2.03 μg/ml may help guide EC-MPS adjustment to achieve adequate drug exposure. Further study of EC-MPS used to validate this cutoff is warranted. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Therapeutic drug monitoring (TDM) is crucial in lupus nephritis (LN) treated with mycophenolic acid (MPA), especially mycophenolate mofetil. The area under the plasma concentration-time curve of MPA from time 0 to 12 h

Therapeutic drug monitoring of mycophenolic acid and clinical outcomes of lupus nephritis: a systematic review and meta-analysis

“…MPA was administered to patients during both the induction and maintenance phases. The majority of the studies examined the PK parameter of MMF, while Chariyavilaskul et al 29 used EC-MPS and Lertdumrongluk et al 21 investigated both MMF and EC-MPS. Concurrent immunosuppressive drugs were calcineurin inhibitors (ciclosporin and tacrolimus), 24 25 belimumab, 30 mizoribine 25 and cyclophosphamide.…”

“…Due to the limited evidence regarding the association between MPA C 0 and clinical response in the existing studies (total five studies reported mean C 0 and response rate), a meta-regression analysis for MPA C 0 was not performed. Nevertheless, various studies have reported divergent target MPA concentrations, with C 0 of 2.0–2.4 mg/L, 27 C 0.5 ≥2.03 mg/L 29 and C 1 ≥13 mg/L 22 being associated with a more favourable treatment response. In the context of our meta-analysis, patients demonstrating a renal response displayed an average C 0 of 2.5±1.7 mg/L, contrasting with 1.5±1.3 mg/L among non-responders.…”

Population Pharmacokinetics of Enteric-Coated Mycophenolate Sodium in Children after Renal Transplantation and Initial Dosage Recommendation Based on Body Surface Area

“…The minor part of MPA is later metabolized to acyl-glucuronide (AcMPAG) [ 9 ]. MPA selectively and reversibly inhibits an enzyme called inosine monophosphate dehydrogenase (IMPDH), which plays a key role in the de novo purine biosynthesis [ 7 , 10 ]. By blocking the pathway above, MPA inhibits T and B lymphocytes from proliferating, thus causing immunosuppression to prevent graft rejection [ 7 ].…”