Abstract
Background: Mycophenolic acid (MPA) is a broad-acting immunomodulating agent that may be therapeutically beneficial for the treatment of immune-mediated diseases in canine patients.Objectives: To determine the suppressive effects of MPA on T-cell proliferation, and to assess the feasibility of a canine-specific q24 h modified-release MPA formulation (OKV-1001b).Animals: Fifteen healthy purpose-bred male beagle dogs.Methods: Two nearly identical open-label fifteen-day studies were conducted in which dogs were randomized to receive mycophenolate mofetil (MMF; 10 mg/kg q12h), or two doses of OKV-1001b (270 mg and 180 mg; q24h). Serial pharmacokinetic (PK) and pharmacodynamic (PD) samples were collected on Days 1, 8, and 15. MPA plasma concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), while an ex vivo T-cell proliferation assay assessed PD effects. Dogs were continuously monitored for evidence of side effects and gastrointestinal tolerability.Results: MPA induced inhibition of T-cell proliferation was observed following administration of all MPA preparations in a clear concentration-dependent manner. The PK/PD relationship was maintained across all days and time-points. Data generated herein suggest that MPA plasma concentrations above 600 ng/mL achieve at least 50% inhibition of T-cell proliferation.Conclusions and Clinical Importance: MPA holds therapeutic potential for treating dogs with immune-mediated disease, but clinical trials will be necessary to determine its safety and efficacy in naturally occurring disease. Likewise, q24h oral modified release MPA preparations that maintain MPA plasma concentrations between 600 and 1,000 ng/mL are warranted for further studies in client-owned dogs.
Highlights
Mycophenolic acid (MPA), a broad-acting immunomodulating agent, is commonly used in human medicine to treat patients with immune-mediated inflammatory diseases [1, 2]
The 180 mg and 270 mg doses of OKV-1001b corresponded to an MPA dose of 11.9–17.1 mg/kg and 18.0–28.8 mg/kg, respectively
Following administration of mycophenolate mofetil (MMF), mean MPA concentrations increased rapidly with high plasma concentrations observed at the 45-min timepoint (Supplementary Table 2)
Summary
Mycophenolic acid (MPA), a broad-acting immunomodulating agent, is commonly used in human medicine to treat patients with immune-mediated inflammatory diseases [1, 2]. There is growing evidence that the immunomodulating properties of MPA are therapeutically beneficial for the treatment of immunemediated diseases in canine patients [3, 4]. Target MPA exposure is not always achieved with standardized dosing. Reliance on human MPA dosing protocols can be misleading because factors such breed-specific differences (e.g., size) and other properties of canine physiology can uniquely impact the pharmacokinetics and absorption characteristics of orally administered drugs [9, 10]. Mycophenolic acid (MPA) is a broad-acting immunomodulating agent that may be therapeutically beneficial for the treatment of immune-mediated diseases in canine patients
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