Noncompartmental pharmacokinetics of three intravenous mycophenolate mofetil concentrations in healthy Standardbred mares

Abstract

Background: Mycophenolate mofetil (MMF) is the prodrug of mycophenolic acid (MPA) which acts as an immunosuppressive agent. During the biotransformation of MMF to MPA, additional metabolites including MPA phenol glucuronide (MPAG), MPA acyl glucuronide (AcMPAG) and MPA phenol glucoside (MPG) are formed. Objective: To define the noncompartmental pharmacokinetic (PK) parameters of three single doses of intravenous (i.v.) MMF and its downstream metabolites in healthy horses. Animals: Six healthy Standardbred mares. Materials and Methods: Generic MMF (Par Pharmaceuticals; Chestnut Ridge, NY, USA) was reconstituted and administered as a single i.v. bolus at 1.0 mg/kg, 5.0 mg/kg and 10.0 mg/kg with an eight day washout between treatments. Blood samples were collected immediately before MMF administration and over 24 h. A liquid chromatography-tandem mass spectrometry assay was developed following FDA guidance to determine plasma MMF, MPA, MPAG, AcMPAG and MPG concentrations. Plasma concentrations were analysed independently, followed by calculation of geometric mean and coefficient of variation. Results: Noncompartmental PK parameters were determined for MMF and all metabolites at all doses. MMF was rapidly converted to MPA in all horses. Each incremental dose of MMF resulted in increases in C max and AUC inf _ obs for MPA and the three additional metabolites. Within the 10-fold dose range, the increase in C max and AUC inf _obs for MMF and its metabolites was nonlinear. Conclusions and clinical relevance: Horses biotransform MMF into MPA, MPAG, AcMPAG and MPG via the glucuronidation and glucosidation clearance pathways. Equine reference PK profiles for MPA and the metabolites, MPAG, AcMPAG and MPG were established.

Pharmacokinetics and tolerability of multiple‐day oral dosing of mycophenolate mofetil in healthy horses

“…In a previous study, escalating IV doses of 1, 5, and 10 mg/kg yielded MPA AUCs lower than reported therapeutic plasma concentrations in humans, with the 10 mg/kg dose achieving the highest plasma MPA AUC concentration. All doses were tolerated well by every horse 11 . With limited information on drug metabolism, accumulation, and tolerability in horses, we avoided doses higher than 10 mg/kg for this multiple‐dose study with the aim of preventing drug toxicity.…”

“…Lower limits of quantification for MMF, MPA, MPAG, AcMPAG, and MPG were 0.043, 0.32, 0.993, 0.993, and 0.483 ng/mL, respectively. The bioanalytical LC‐MS/MS assay was fully validated according to the Food and Drug Administration (FDA) Bioanalytical Method Validation Guidance as described previously 11 …”

“…Calculations for all 6 horses were combined and descriptive statistics (geometric mean with SE and 95% confidence interval) were used to report the results of continuous variables. The estimated sample size was based on practical considerations as well as the justification and results from our previous MMF study 11 . Paired t ‐tests using the model assumption that the differences between the 2 time point measurements for each horse had a normal (Gaussian) distribution, and 2‐tailed P values were used.…”

“…Several additional metabolites are formed during MMF metabolism, including mycophenolic acid glucuronide (MPAG), mycophenolic acid acyl glucuronide (AcMPAG), and mycophenolic acid phenol glucoside (MPG) 2,9,10 . A recent study documented the formation of downstream MMF metabolites, indicating that horses successfully transform MMF into MPA, MPAG, AcMPAG, and MPG 11 . Currently, the biological activity of these metabolites in horses is unknown.…”

“…2,9,10 A recent study documented the formation of downstream MMF metabolites, indicating that horses successfully transform MMF into MPA, MPAG, AcMPAG, and MPG. 11 Currently, the biological activity of these metabolites in horses is unknown.…”