Michael Klotsman1, Sebastien Coquery2, Gayatri Sathyan1, Vatsala Naageshwaran3, Paddy Shivanand1, Amanda J Fairchild4, Oliver A Garden5, Wayne H Anderson1,6. 1. Okava Pharmaceuticals, San Francisco, CA, United States. 2. WORK-FLOW, Elmsford, NY, United States. 3. Absorption Systems LP, Exton, PA, United States. 4. Department of Psychology, University of South Carolina, Columbia, SC, United States. 5. Clinical Sciences and Advanced Medicine, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, United States. 6. Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
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.
Background: Mycophenolic acid (MPA) is a broad-acting immunomodulating agent that may be therapeutically beneficial for the treatment of immune-mediated diseases in caninepatients. 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 allMPA 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.
Authors: Yannick Le Meur; Richard Borrows; Mark D Pescovitz; Klemens Budde; Josep Grinyo; Roy Bloom; Robert Gaston; Rowan G Walker; Dirk Kuypers; Teun van Gelder; Bryce Kiberd Journal: Transplant Rev (Orlando) Date: 2011-03-30 Impact factor: 3.943
Authors: M Grobman; D M Boothe; H Rindt; B G Williamson; M L Katz; J R Coates; C R Reinero Journal: J Vet Pharmacol Ther Date: 2017-06-25 Impact factor: 1.786
Authors: Alissa K Orvis; Stanton K Wesson; Thomas S Breza; Ann A Church; Christina L Mitchell; Shannon W Watkins Journal: J Am Acad Dermatol Date: 2009-02 Impact factor: 11.527
Authors: James W Swann; Oliver A Garden; Claire L Fellman; Barbara Glanemann; Robert Goggs; Dana N LeVine; Andrew J Mackin; Nathaniel T Whitley Journal: J Vet Intern Med Date: 2019-03-07 Impact factor: 3.333