Mechanism‐Based Enterohepatic Circulation Model of Mycophenolic Acid and Its Glucuronide Metabolite: Assessment of Impact of Cyclosporine Dose in Asian Renal Transplant Patients

Abstract

Mycophenolic acid (MPA) is mainly metabolized to MPA-glucuronide (MPAG), which may be reconverted to MPA following enterohepatic circulation (EHC). A physiologically realistic EHC model was proposed to estimate and assess the impact of cyclosporine (CsA) dose on the extent of EHC of MPA and MPAG. After the first oral dose of mycophenolate mofetil (MMF), the MPA and MPAG plasma concentration-time data of 14 adult renal transplant patients (12 receiving concomitant CsA and prednisolone and 2 receiving only concomitant prednisolone without CsA) were analyzed by individual pharmacokinetic modeling using a proposed 5-compartment drug and metabolite EHC model with a time-varying gallbladder emptying process. Simulations were performed to assess the influence of the time of bile release after dosing (T(bile)) and the gallbladder emptying interval (tau(gall)) on the EHC process. The extent of EHC for both MPA and MPAG tended to be lower in the group receiving CsA coadministration and decreased with increasing total body weight-adjusted CsA dose. Simulations revealed that T(bile) and tau(gall) influenced the time of occurrence and maximum concentration of the second peak, as well as the extent of EHC, for MPA and MPAG.

The Evolution of Population Pharmacokinetic Models to Describe the Enterohepatic Recycling of Mycophenolic Acid in Solid Organ Transplantation and Autoimmune Disease

“…However, this was probably related to the exclusion of subjects with functional SNPs such as UGT1A9− 275 and −331/−440 [96] from the study analysis. WinNonLin® was used by Yau et al [69] to produce a five-compartment parent drug and metabolite EHC model (tables I and II, figure 2e). Simulations were used to investigate the influence of the time of bile release after dosing and the gallbladder emptying interval on enterohepatic recycling of MPA and MPAG.…”

“…Only one study included children [68] and one study used Win-NonLin. [69] Two studies[ 87] used MMF® software, with one of those studies investigating MPA pharmacokinetics in SLE patients. [90] In total, only three published papers involved non-transplant patients.…”

“…[70,89] In the renal-transplant studies, time post-transplant ranged from 1 to 1538 days. Five studies [26,42,69,70,91] simultaneously modelled MPA and MPAG, with one study undertaken in healthy subjects. [26] One study included AcMPAG [70] and one modelled total and unbound MPA and MPAG.…”

“…The EHC peak was typically observed in the post-absorption phase (6–12 hours post-dosing). Eight of the studies [26,42,67,69–71,91,92] included an EHC function in the final model, although most papers considered the inclusion of an EHC model during model development (tables I and II). …”

“…The estimated MPA apparent total oral clearance (CL/F) in adults post-renal transplant receiving MMF concomitant therapy with ciclosporin without corticosteroid therapy was 14.1–34.9 L/h [42,83–85] and with corticosteroid co-therapy was 15–42.85 L/h. [69,86–88] In those receiving tacrolimus the mean CL/F estimates ranged from 11.9 to 25.4 L/h without corticosteroid co-therapy. [42,85] In healthy subjects, MPA CL/F was reported to be 10.2 L/h [26] and in patients with SLE receiving corticosteroid co-therapy was 40.3 L/h.…”