Population Pharmacokinetics of Mycophenolic Acid: An Update

Abstract

The most recent comprehensive reviews on the population pharmacokinetics of mycophenolic acid (MPA) were published in 2014. Since then, several population pharmacokinetic studies on MPA have been published. The majority of literature is still focused on the kidney transplant population, although studies have also been conducted in liver and lung transplantation, autoimmune diseases, and hematopoietic stem cell transplant. While the majority of the model building is still based on parametric non-linear mixed-effects modeling, recent studies suggest the suitability of other methodologies. Additionally, instead of just focusing on pharmacokinetic modeling, a trend toward describing the relationships between pharmacokinetic and pharmacodynamic parameters is observed. Given the importance of enterohepatic recirculation (EHR) in the pharmacokinetics of MPA, more authors have attempted to characterize this process in their models. Overall, the recent models have become more sophisticated and incorporate EHR, pharmacodynamic relationships, and metabolites while maintaining many of the population values and covariates identified previously. However, the number of MPA population pharmacokinetic models describing the enteric-coated formulation of MPA (EC-MPA) is still limited. Given the increasing use of EC-MPA, more studies are needed to fill this literature gap. In addition, few studies are yet available characterizing free MPA concentration or MPA metabolites. Given the extensive protein binding, low to intermediate extraction, and intrinsic clearance characteristics of MPA in humans, including these variables would improve the population structural models.

Prospective study of the changes in pharmacokinetics of immunosuppressive medications after laparoscopic sleeve gastrectomy

“…The pharmacokinetic (PK) analysis of gastric bypass patients suggested that higher doses of tacrolimus, sirolimus, and mycophenolate mofetil (MMF) were required in order to provide a similar exposure to the healthy, nonbypass control. 15 Clinical visits after bariatric surgery were scheduled at 1 month, then every 3 months. Neither formulation affected the bioavailability of MMF.…”

“…MPA-glucuronides (MPAG) bind extensively to albumin and undergo enterohepatic recirculation by means of the transporter, multidrug-resistant protein-2, and is eliminated in the urine. 15,16…”

Systematic external evaluation of published population pharmacokinetic models of mycophenolate mofetil in adult kidney transplant recipients co‐administered with tacrolimus

“…Although various popPK models have been developed to quantitatively describe the PK characteristics of MPA over the past decades, whether they can be appropriately extrapolated to other centres remains unclear . Assessing the model transferability may also facilitate the identification of potential centre‐based factors influencing model predictability.…”

The development of a population physiologically based pharmacokinetic model for mycophenolic mofetil and mycophenolic acid in humans using data from plasma, saliva, and kidney tissue

“…Many studies have shown that hepatic UGT1A9 shows a high variability (5–15 fold) in mRNA levels, relative protein content, and in vitro activity (Aueviriyavit, Furihata, Morimoto, Kobayashi, & Chiba, ; Court, ; Girard et al, ) which can cause high variability in MPA PK in transplant patients (Bernard & Guillemette, ). Previous studies showed MPA shows high intersubject variability of tMPA of 2–3 orders of magnitude along the whole concentration–time profile (de Winter et al, ; Kiang & Ensom, ) that can be attributed to variability in UGT1A9 activity (Baldelli et al, ). Other studies showed that no single variable (UGT1A9, UGT2B7, or MRP‐2 activity) alone explained the observed high variability in the exposure of the pharmacologically active fMPA in plasma (Frymoyer, Verotta, Jacobson, & Long‐Boyle, ).…”

“…Previous studies showed MPA shows high intersubject variability of tMPA of 2-3 orders of magnitude along the whole concentrationtime profile (de Winter et al, 2008;Kiang & Ensom, 2018) that can be attributed to variability in UGT1A9 activity (Baldelli et al, 2007).…”