Comparison of plasma and oral fluid concentrations of mycophenolic acid and its glucuronide metabolite by LC-MS in kidney transplant patients

Abstract

Purpose Mycophenolic acid is one of the most used immunosuppressive drugs in solid organ transplant treatments in the world. Developing a highly sensitive analytical method to analyse the drug and its metabolites in oral fluid and plasma is important to evaluate the possibility of using oral fluid as a biological matrix in therapeutic drug monitoring, instead of plasma. Method The liquid chromatography coupled to mass spectrometry (LC-MS) method was developed and validated for determining mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) in oral fluid and plasma, with both matrices presenting a detection limit of 1 ng/mL for MPA and 5 ng/mL for MPAG. Both analytes were analysed after a simple protein precipitation procedure. Transplanted-kidney samples of oral fluid and blood were collected from 13 patients that were hospitalised and kept at − 80 °C until analyses. Results The proposed method was linear in the concentration range of 5-500 ng/mL for MPA and 10-500 ng/mL for MPAG, with correlation coefficients (r) between 0.9925 and 0.9973. It was then applied to samples collected from kidney-transplanted patients and used for calculation of pharmacokinetics parameters. Conclusion After comparing plasma and oral fluid concentrations as well as performing a non-compartmental pharmacokinetic analysis of the average curves, it is possible to suggest that oral fluid concentration may be used as an alternative for MPA and MPAG monitoring in kidney transplant patients.

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

“…These issues taken collectively are likely responsible for the very conflicting results generated using oral fluid in the clinical setting. Some studies reported an acceptable correlation of total as well as fMPA concentrations between plasma and oral fluid concentrations, 266,267,351 whereas others found a poor correlation. 350 Therefore, the use of oral fluid for the purpose of MPA TDM cannot be recommended yet, and further studies are needed to identify the most appropriate sampling and sample pretreatment conditions.…”

High-performance liquid chromatography with fluorescence detection for mycophenolic acid determination in saliva samples

“…As the values of tMPA pharmacokinetics were shown to be higher in children with nephrotic syndrome [3][4][5], we analyzed the linearity of the method over a wide range and with a higher upper limit (5-2000 ng/mL) than in other literature studies. Our method meets the requirements for within-run and between-run accuracy and precision, with the sMPA LLOQ being 5 ng/mL, which is the same as in one study in the literature [22]. Generally, LC-MS/MS methods are more sensitive and show lower LLOQ, with values of 2.5 ng/mL [19], 2 ng/mL [16], 1.6 ng/mL [20], and 1 ng/mL [15].…”

“…However, more recently, two studies have reported contradictory results [15,21]. All studies on salivary MPA (sMPA) have employed liquid chromatography tandem mass spectrometry (LC-MS/ MS) for sMPA determination [8,15,16,19,20,22], but none have used high-performance liquid chromatography with fluorescence detection (HPLC-FLD). The HPLC-FLD method may have some advantages, such as lower analysis cost and greater availability of HPLC equipment than LC-MS/MS.…”

Utility of salivary mycophenolic acid concentration monitoring: Modeling and Monte Carlo validation approach

“… 16 , 22 Besides plasma, as the most used fluid for drug monitoring, saliva is assumed to be more suitable for the pharmacometric approach, regarding its non invasive, cost‐effective and friendly‐time consuming sampling and not requiring trained personnel, particularly for unbound drugs monitoring. 23 , 24 Therefore, question that has risen is how to mark a moment or patient when saliva becomes an optimal biological material. Still, this question is related with an effort for clarification of factors that might influence MPA plasma‐saliva relationship.…”

“…Consequently, therapeutic drug monitoring might be useful in reducing interindividual variability in MPA exposure, optimizing immunosuppressive therapy and avoiding graft rejection in routine clinical practice 16,22 . Besides plasma, as the most used fluid for drug monitoring, saliva is assumed to be more suitable for the pharmacometric approach, regarding its non invasive, cost‐effective and friendly‐time consuming sampling and not requiring trained personnel, particularly for unbound drugs monitoring 23,24 . Therefore, question that has risen is how to mark a moment or patient when saliva becomes an optimal biological material.…”