Population pharmacokinetics of mycophenolic acid in Mexican patients with lupus nephritis

Abstract

Background Mycophenolic acid (MPA) is an effective oral immunosuppressive drug used to treat lupus nephritis (LN), which exhibits large pharmacokinetic variability. This study aimed to characterize MPA pharmacokinetic behaviour in Mexican LN patients and to develop a population pharmacokinetic model which identified factors that influence MPA pharmacokinetic variability. Methods Blood samples from LN patients treated with mycophenolate mofetil (MMF) were collected pre dose and up to six hours post dose. MPA concentrations were determined by a validated ultra-performance liquid chromatography tandem mass spectrometry technique. Patients were genotyped for polymorphisms in enzymes (UGT1A8, 1A9 and 2B7) and transporters (ABCC2 and SLCO1B3). The anthropometric, clinical, genetic and co-medication characteristics of each patient were considered as potential covariates to explain the variability. Results A total of 294 MPA concentrations from 40 LN patients were included in the development of the model. The data were analysed using NONMEM software and were best described by a two-compartment linear model. MPA CL, Vc, Vp, Ka and Q were 15.4 L/h, 22.86 L, 768 L, 1.28 h−1 and 20.3 L/h, respectively. Creatinine clearance and prednisone co-administration proved to have influence on clearance, while body weight influenced Vc. The model was internally validated, proving to be stable. MMF dosing guidelines were obtained through stochastic simulations performed with the final model. Conclusions This is the first MPA population pharmacokinetic model to have found that co-administration of prednisone results in a considerable increase on clearance. Therefore, this and the other covariates should be taken into account when prescribing MMF in order to optimize the immunosuppressant therapy in patients with LN.

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology

“…Less data are available regarding the association of other UGT1A9 variants and MPA PK. 15,355,373,374 Genetic variants in UGT1A7, 171,[375][376][377][378] UGT1A8, 364,368-370,378-384 UGT1A10, 369,383 and UGT2B7 171,358,364,[367][368][369][370][376][377][378][379][380][382][383][384][385][386][387][388] have yielded conflicting results.…”

“…Similarly, one population pharmacokinetic study in 65 KTR reported ABCC2 variants to affect MPA absorption and clearance, 392 whereas others found no associations between ABCC2 variants and MPA PK. [368][369][370]377,383,384,[393][394][395][396] Of note, the interpretation of associative studies on ABCC2 variants and MPA PK may be complicated in patients receiving concomitant immunosuppressive therapy with cyclosporine A, which is not uncommon in the population receiving MPA. Cyclosporine A exhibits extensive inhibition of ABCC2, which likely masks any impact of ABCC2 variants on MPA PK.…”

“…382,390 One population pharmacokinetic study reported an increased distribution volume of MPAG for SLCO1B3 c.334T.G (rs4149117) carriers, whereas 4 other studies found no effect of SLCO1B3 on MPA PK. 370,377,383,384,396…”

Cystatin C and myeloperoxidase based mycophenolic acid dosage optimization in pediatric anti-neutrophilic cytoplasmic antibody-associated nephritis

“…Our study revealed that glucocorticoids had a dose-dependent effect on absorption, but were not included in final model (Supplemental Figure 1). A significant increase on MPA CL has been reported in renal transplant and lupus nephritis patients with concomitant use of corticosteroids compared to those with a corticosteroid free (17)(18)(19).…”

Population pharmacokinetics and limited sampling strategy for therapeutic drug monitoring of mycophenolate mofetil in Japanese patients with lupus nephritis

“…For Asian LN patients treated with MMF, however, the pharmacokinetic properties of MPA remain largely unexplored and few, if any, population pharmacokinetic (PPK) models, which may help in the development of LSS, appear to have been built. PPK models have been reported for transplant patients with various backgrounds [ 24 – 26 ], and a few have been described for autoimmune patients of different ethnicities [ 10 , 27 ]; but these may not be applicable to Asian LN patients because of potential differences in MPA pharmacokinetics. While previous studies have reported that a range of 30–45 μg∙h/mL in AUC 0-12 is associated with good clinical outcomes [ 28 ], an LSS appears less likely to be available for Asian LN patients.…”