1ABSTRACT OF A ZOETIS POSTER PRESENTATION JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS

THE ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION OF OCLACITINIB MALEATE, A NOVEL JANUS KINASE INHIBITOR, IN THE DOG

T. COLLARD, A. FIELDER, J. ZAYA1 & M. R. STEGEMANN Zoetis, Kalamazoo, MI, USA;

Zoetis, Zaventem, Belgium

REFERENCE: Journal of Veterinary Pharmacology and Therapeutics 35 (Suppl. 3), 137178

INTRODUCTION

Oclacitinib maleate is a novel selective Janus Kinase (JAK) inhibitor which preferentially inhibits JAK1

over other family members and has been shown to inhibit the activity of proinflammatory cytokines such

as IL-2, pro-allergic cytokines such as IL-4, and pruritogenic cytokines such as IL-31.

OBJECTIVE

The ADME (absorption, distribution, metabolism, and elimination) of oclacitinib maleate was evaluated

in vitro and in laboratory beagle dogs.

MATERIALS AND METHODS

The extent and route of elimination and metabolism of oclacitinib were investigated following

administration of a single 0.4 mg kg)1 (40 lCi kg)1) 14C-oclacitinib dose to 12 dogs. Blood, urine, feces,

various tissues, and body fluids samples were collected up to 72 h post dose. Samples were analyzed by

combustion and liquid scintillation counting to quantify total 14C-oclacitinib related residues. Extracts

of plasma and urine were also analyzed by radio-chromatography and LC/MS/MS for identification of

parent oclacitinib and profiling of oclacitinib metabolites. Plasma protein binding of oclacitinib was

determined in canine plasma by equilibrium dialysis using the Thermo Scientific RED (rapid equilibrium

dialysis) device inserts. Canine plasma was fortified with oclacitinib to concentrations of 10, 100, 1000

ng ml)1 and allowed to equilibrate for 4 h. The potential of oclacitinib to inhibit canine cytochrome

P450 mediated metabolism was evaluated in pooled beagle liver microsomes. The canine P450 probe

substrates for the major canine drug metabolizing P450 enzymes (1A1/1A2, 2B11, 2C21/2C42, 2D15, and

3A12/24) were used.

RESULTS

In dogs, the radioactivity was widely distributed to the tissues up to 24 h post dose of 14C-oclacitinib.

The highest concentrations of total radioactivity were measured in the liver and along the

gastrointestinal tract. The main route of excretion of total radioactivity was via the urine (51% of the

2ABSTRACT OF A ZOETIS POSTER PRESENTATION: JOURNAL OF VETERINARY PHARMACOLOGY

administered dose), with a significant amount also excreted via the feces (38% of the administered dose).

In plasma parent oclacitinib accounted for 85% and 64% of the total chromatographic radioactivity at

1 and 6 h post dose, respectively. Parent oclacitinib accounted for a small percentage of the residues in

the urine with approximately 3.6% of residues in the 024 h sample. Oclacitinib was metabolized in the

dog to multiple metabolites, with one major oxidative metabolite identified in plasma and urine. Overall

the major clearance route is metabolism with minor contributions from renal and biliary elimination.

Oclacitinib protein binding was low with 66.369.7% bound in fortified canine plasma at nominal

concentrations ranging from 10 to 1000 ng ml)1. Inhibition of canine cytochrome P450s by oclacitinib is

minimal with IC50s 50-fold greater than the observed mean Cmax at the proposed use dose.

CONCLUSIONS

Therefore, the risk of metabolic drug-drug interactions due to oclacitinib inhibition is very low.