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

Autor:	Klotsman M; Okava Pharmaceuticals, San Francisco, CA, United States., Coquery S; WORK-FLOW, Elmsford, NY, United States., Sathyan G; Okava Pharmaceuticals, San Francisco, CA, United States., Naageshwaran V; Absorption Systems LP, Exton, PA, United States., Shivanand P; Okava Pharmaceuticals, San Francisco, CA, United States., Fairchild AJ; Department of Psychology, University of South Carolina, Columbia, SC, United States., Garden OA; Clinical Sciences and Advanced Medicine, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, United States., Anderson WH; Okava Pharmaceuticals, San Francisco, CA, United States.; Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in veterinary science [Front Vet Sci] 2021 Jan 28; Vol. 7, pp. 611404. Date of Electronic Publication: 2021 Jan 28 (Print Publication: 2020).
DOI:	10.3389/fvets.2020.611404
Abstrakt:	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. Competing Interests: MK, GS, WA, and PS are Okava Pharmaceuticals shareholders. OG, AJF, and SC are consultants to Okava. VN was employed by Absorption Systems LP. (Copyright © 2021 Klotsman, Coquery, Sathyan, Naageshwaran, Shivanand, Fairchild, Garden and Anderson.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu