Nonlinear Relationship between Mycophenolate Mofetil Dose and Mycophenolic Acid Exposure

Abstract

SummaryBackground and objectives Mycophenolate mofetil (MMF) is an immunosuppressive drug used in renal transplant patients. Upon oral administration it is hydrolyzed to the active agent mycophenolic acid (MPA). In renal transplant recipients, MMF therapy is optimal when the area under the curve of MPA is 30 to 60 mg⅐h/L. When MMF doses are adjusted, a linear relationship between dose and MPA exposure is assumed. In this study, the linearity of MMF pharmacokinetics was investigated.Design, setting, participants, & measurements MPA concentration-time profiles from renal transplant recipients cotreated with cyclosporine (n ϭ 140) or tacrolimus (n ϭ 101) were analyzed retrospectively using nonlinear mixed-effects modeling. The correlation between the MMF dose and the pharmacokinetics parameters was evaluated. ResultsIn the developed population pharmacokinetics model MPA clearance and the central volume of distribution were correlated with cyclosporine coadministration and time posttransplantation. The pharmacokinetics of MPA were not linear. Bioavailability decreased with increasing MMF doses. Compared with an MMF dose of 1000 mg (ϭ100%), relative bioavailability was 123%, 111%, 94%, and 90% in patients receiving MMF doses of 250, 500, 1500, and 2000 mg in combination with cyclosporine (P Ͻ 0.001); respective values in tacrolimus-cotreated patients were 176%, 133%, 85%, and 76% (P Ͻ 0.001). Because of the decreasing relative bioavailability, MPA exposure will increase less than proportionally with increasing MMF doses.Conclusions MMF exhibits nonlinear pharmacokinetics. This should be taken into account when performing therapeutic drug monitoring.

UGT1A9, UGT2B7, and MRP2 Genotypes Can Predict Mycophenolic Acid Pharmacokinetic Variability in Pediatric Kidney Transplant Recipients

“…In line with a recent observation in adult transplant patients [42], we observed a non-linear relationship between individual MPA exposure (AUC) and dose (Figure, Supplemental Digital Content 3, http://links.lww.com/TDM/A21). Based on recursive partitioning, we therefore stratified patients into high or low dosing groups based on BSA-normalized dose and subsequently explored the genetic effects on normalized pharmacokinetic parameter estimates.…”

Therapeutic Drug Monitoring of Mycophenolic Acid in Lupus Nephritis

“…It is supported by less than expected increase in MPA exposure with increasing MMF doses. 15 MPA is extensively bound to albumin (97%-99%) in patients with normal renal and liver function. However, the MPA binding can be decreased by several factors, including hypoalbuminemia, uremia, elevated concentrations of the MPA primary metabolite, 7-O-MPA-glucuronide, which competes for albuminbinding sites, and hyperbilirubinemia.…”

Nonlinear relationship between enteric-coated mycophenolate sodium dose and mycophenolic acid exposure in Han kidney transplantation recipients

“…In an early study, the authors compared MMF of 1000 mg with MMF of 1500 mg, both two times daily, in cyclosporine-treated patients, and found MPA AUC and MMF dose presented a linear relationship 18 . However, de Winter et al 6 reported that the bioavailability decreased with increasing MMF doses. The authors found the relative bioavailability was 176%, 133%, 85% and 76% in patients treated with MMF doses of 250, 500, 1500 and 2000 mg in combination with tacrolimus, compared with an MMF dose of 1000 mg (100%).…”