Mycophenolic acid in patients with immune‐mediated inflammatory diseases: From humans to dogs

Abstract

Mycophenolic acid (MPA), a noncompetitive, selective and reversible inhibitor of inosine 5′‐monophosphate dehydrogenase (IMPDH), is an immunosuppressive agent that has a long history in medicine. Mechanistically, the inhibition of IMPDH leads to the selective and eventual arrest of T‐ and B‐lymphocyte proliferation. Mycophenolate mofetil (MMF), the first MPA‐based product to receive marketing approval over two decades ago, was originally indicated for the prophylaxis of organ rejection in human transplant patients. Given its broad immunosuppressive properties and ability to selectively inhibit lymphocyte division and effector functions, the clinical utility of MPA was subsequently explored in a host of autoimmune diseases. Human clinical studies have shown MPA to be safe and effective and support its off‐label administration for immune‐mediated diseases such as lupus, myasthenia gravis and atopic dermatitis. MMF became generically available in the United States in 2008, and its clinical utility is increasingly being explored as a treatment option for dogs with immune‐mediated diseases. This review summarizes the available literature for MPA pharmacokinetics and pharmacodynamics, and the current status of MPA as a treatment for client‐owned dogs diagnosed with immune‐mediated diseases.

Pharmacokinetics of mycophenolate mofetil following single-dose intravenous and single- and multiple-dose oral administration and clinicopathologic effects of mycophenolate mofetil following long-term oral administration in healthy horses

“…Although MMF was originally developed to suppress organ rejection in hu- man transplant recipients, more recently it has been used as a treatment for immune-mediated diseases in people and (as the oral form) small animals. [11][12][13][14][15][16] Safety studies of cats [17][18][19] and pharmacokinetic and pharmacodynamic studies 20,21 of dogs have provided evidence of the safety (although not necessarily the efficacy) of MMF administered at a dose of 10 mg/kg twice daily in cats and a dose of 8 to 15 mg/kg twice daily in dogs. Adverse effects of MMF treatment generally involve the gastrointestinal tract (eg, vomiting and diarrhea).…”

Pharmacokinetics and Pharmacodynamics of Immediate- and Modified-Release Mycophenolic Acid Preparations in Healthy Beagle Dogs

“…The reported rates of GI intolerance have limited the clinical utility of MMF in dogs (4). The present study was not powered, nor was it of sufficient duration to measure the rates of GI side effects.…”

“…Decades of human clinical experience shows that MPA is highly effective (2,6), but its use is complicated by marked intra-and inter-patient PK variability (2,6,7,34). The use of MMF is increasingly being used to treat dogs with immune-mediated diseases (4,12), but its clinical utility in veterinary medicine may also be limited by PK variability. Various therapeutic drug monitoring (TDM) strategies are used in human medicine to achieve desired outcomes (7), but there is a notable absence of available TDM methods to aid in determining the dose required to treat dogs with immune-mediated diseases (27).…”

“…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). The immediaterelease (IR) MPA prodrug mycophenolate mofetil (MMF) is available as a generic drug and is the most common MPA preparation administered to dogs (4,5).…”

“…There is growing evidence that the immunomodulating properties of MPA are therapeutically beneficial for the treatment of immunemediated diseases in canine patients (3,4). The immediaterelease (IR) MPA prodrug mycophenolate mofetil (MMF) is available as a generic drug and is the most common MPA preparation administered to dogs (4,5). Despite common use in humans, target MPA plasma concentrations and dosing regimens are poorly defined in canines.…”