Pirfenidonea is a new investigational drug with unique therapeutic anti-inflammatory and antifibrotic properties. The compound is composed of a substituted pyridine (5 methyl-1-phenyl-2-[1H]-pyridone) and has a molecular weight of 185.2.1,2 It is marketed in an oral formulation in the United States and is approved for human and not veterinary use.
The drug has been investigated in humans for treatment of diverse conditions ranging from idiopathic pulmonary fibrosis to multiple sclerosis, rheumatoid arthritis, and neurofibromatosis.3–7 The oral formulation of the drug has had promising therapeutic benefits in human clinical trials and animal models for treatment of pulmonary, hepatic, cardiac, musculoskeletal, and renal fibrosis.6,8–11 The safety record for this medication in clinical trials and in a large number of animal models has been favorable.5,9,12–14 Unfortunately, the precise mechanism of action of pirfenidone is not well understood; however, it is known that the drug regulates key fibrotic growth factors and inhibits a number of proinflammatory cytokines.1,2,15–21 Pirfenidone also inhibits other cellular processes associated with tissue damage and inflammation,17,20 effectively scavenges reactive oxygen species,22,23 and increases concentrations of some anti-inflammatory cytokines, including interleukin-10.24,25
Most studies, including all of the human clinical trials5–7,9–11,26 as well as canine,13,27 rat,12,28–31 mouse,25,32 guinea pig,19 and hamster33 animal models, have used an oral route for drug administration. In those studies, administration intervals ranged from 1 to 3 times daily or the drug was provided continuously in feed or water, and the medication was generally administered for prolonged periods. However, IV,14,28,34 SC,20 and IP1,18,28 routes of administration have also been investigated. Limited pharmacokinetic data are available for oral administration in humans, rats, and dogs.13,26,31,35,36 and for IV administration in mice and sheep.14,34 Results of those studies indicate that the drug is rapidly distributed to peripheral tissues and metabolized in the liver and that its metabolites are eliminated primarily by the urinary tract.14,34 The principal metabolites identified include hydroxypirfenidone and carboxypirfenidone, identified in plasma and urine samples, as well as hydroxypirfenidone glucuronide and acetoxypirfenidone, identified in urine.14,31,34
There have been few publications addressing the potential benefits of this medication for use in horses, although 1 study37 did demonstrate the ability of pirfenidone to suppress bacterial lipopolysaccharide and interleukin-1–induced nitric oxide release in an in vitro equine chondrocyte model. We are not aware of any pharmacokinetic, safety, or efficacy data available for systemic administration of this drug in horses.
Considering the current wide-ranging application of this drug in human medical practice, pirfenidone should have therapeutic potential for treatment of a variety of inflammatory conditions in horses. In particular, the safety and efficacy of pirfenidone in animal models of endotoxemia1,25,38 and septic shock18 in addition to its documented ability to reduce serum concentration of tumor necrosis factor-α1,18,24,33 and other proinflammatory cytokines1,18,20 make it a promising compound for treatment of equine endotoxemia. Horses are exquisitely sensitive to endotoxin, with relatively low doses leading to severe physiologic derangements,39,40 and 10% to 40% of horses referred for treatment of acute abdominal disease have circulating endotoxins.41 Often these horses are unable to tolerate medications administered PO. Therefore, an IV route of administration was selected as the most appropriate for this pharmacokinetic study. Other conditions that may benefit from pirfenidone treatment in horses include intestinal ischemia reperfusion injury,28 chronic inflammatory airway disease,20,30 and joint disease.5,37,42
On the basis of clinical experience and research in other species, we hypothesized that pirfenidone could be safely administered IV to conscious, healthy adult horses with minimal adverse physiologic effects and would be rapidly metabolized and cleared. An initial pilot study was designed to determine the maximum dose of pirfenidone that could be rapidly infused IV without severe adverse effects. The objectives of the study reported here were to determine an appropriate dose, evaluate clinical physical examination variables associated with that dose, and determine the plasma pharmacokinetic disposition of pirfenidone and its major metabolites in horses after IV administration of a single dose.
Liquid chromatography–mass spectrometry
Deskar, Marnac Inc, Dallas, Tex.
Abbocath 14-gauge, 2.1 × 133 mm, Abbott Medical Health, Abbott Park, Ill.
5-methyl-1-phenyl-2-(1H)-pyridone, lot 06-95#1, Marnac Inc, Dallas, Tex.
Nalgene 90-mm filter unit-1,000 mL, Nalge Nunc Interantional Corp, Rochester, NY.
VitalMix 3,000 mL IV solution container with transfer set, Churchill Medical Systems Inc, Horsham, Pa.
MasterFlex pump drive L/S and Easy Load II pump head, ColeParmer Instrument Co, Vernon Hills, Ill.
MasterFlex precision tubing L/S25, silicone, 3.8 m, Cole-Parmer Instrument Co, Vernon Hills, Ill.
Equine Senior Horse Feed, Land O' Lakes Purina Mills, St Louis, Mo.
Kendall Monoject, Tyco Healthcare Group LP, Mansfield, Mass.
Kendall Monoject blood collection tubes 16 × 100mm, Tyco Healthcare Group LP, Mansfield, Mass.
Simport Cryovial with silicone washer seal, Phenix Research Products, Hayward, Calif.
Amicon Centricon, Microcon 3, Millipore Corp, Billerica, Mass.
Hypersil BDS-C18 Column, Agilent Technologies, Palo Alto, Calif.
LCQ Ion Trap mass spectrometer, Thermo Fischer Corp, San Jose, Calif.
Excel Solver tool, Microsoft Corp, Redmond, Wash.
BMDP Statistical Programs, Statistical Solutions, Saugus, Mass.
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