The pharmacokinetics of oclacitinib maleate, a Janus kinase inhibitor, in the dog
The pharmacokinetics of oclacitinib maleate was evaluated in four separate studies. The absolute bioavailability study used a crossover design with 10 dogs. The effect of food on bioavailability was investigated in a crossover study with 18 dogs. The breed effect on pharmacokinetics was assessed in a crossover study in beagles and mongrels dogs. Dose proportionality and multiple dose pharmacokinetics were evaluated in a parallel design study with eight dogs per group. In all four studies, serial blood samples for plasma were collected. Oclacitinib maleate was rapidly and well absorbed following oral administration, with a time to peak plasma concentration of <1 h and an absolute bioavailability of 89%. The prandial state of dogs did not significantly affect the rate or extent of absorption of oclacitinib maleate when dosed orally, as demonstrated by the lack of significant differences in pharmacokinetic parameters between the oral fasted and oral fed treatment groups. The pharmacokinetics of oclacitinib in laboratory populations of beagles and mixed breed dogs also appeared similar. Following oral administration, the exposure of oclacitinib maleate increased dose proportionally from 0.6 to 3.0 mg/kg. Additionally, across the pharmacokinetic studies, there were no apparent differences in oclacitinib pharmacokinetics attributable to sex.
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Available from: Tomoki Fukuyama
- "The JAK inhibitors (tofacitinib or oclacitinib) were administered orally or topically 30 minutes before and 4 hours after TDI challenge because the absorption of tofacitinib and oclacitinib was rapid, with plasma concentrations for both tofacitinib and oclacitinib peaking at around 1 hour after oral or intravenous administration. Tofacitinib and oclacitinib both have a short half-life of 2 and 4 hours after administration, respectively (Collard et al., 2014; Dowty et al., 2014). Each drug was diluted in a 0.5% methylcellulose/0.25% "
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ABSTRACT: The prevalence of allergic skin disorders has increased rapidly and development of therapeutic agents to alleviate the symptoms are still needed. In this study, we orally or topically administered the Janus kinase (JAK)-inhibitors, tofacitinib and oclacitinib in a mouse model of dermatitis, and compared the efficacy to reduce the itch and inflammatory response. In vitro effects of JAK-inhibitors on bone marrow derived dendritic cells (BMDCs) were analyzed. For the allergic dermatitis model, female BALB/c mice were sensitized and challenged with toluene-2,4-diisocyanate (TDI). Each JAK-inhibitor was orally or topically applied 30 min before and 4 h after TDI challenge. After scratching bouts and ear thickness were measured, cytokines were determined in challenged skin and cells of the draining lymph node were analysed by means of flow cytometry. In vitro, both JAK-inhibitors significantly inhibited cytokine production, migration and maturation of BMDC. Mice treated orally with JAK-inhibitors showed a significant decrease in scratching behavior; however, ear thickness was not significantly reduced. By contrast, both scratching behavior and ear thickness in the topical treatment group were significantly reduced compared to vehicle treatment group. Cytokine production, however, was differentially regulated by the JAK-inhibitors with some cytokines significantly decreased and some significantly increased. In conclusion, oral treatment with JAK-inhibitors reduced itch behavior dramatically but had only little effect on the inflammatory response, whereas topical treatment improved both itch and inflammatory response. Although the JAK-inhibitory profile differs between both JAK-inhibitors in vitro as well as in vivo, effects have been comparable.
The American Society for Pharmacology and Experimental Therapeutics.
Journal of Pharmacology and Experimental Therapeutics 07/2015; 354(3). DOI:10.1124/jpet.115.223784 · 3.97 Impact Factor
Available from: Tomoki Fukuyama
- "The allergic reaction was challenged 7 days later by application of 30 μl of 0.5% TDI in acetone onto the shaved dorsal region (day 32). JAK-inhibitors tofacitinib or oclacitinib were administered orally 30 min before TDI challenge, because the absorption of tofacitinib and oclacitinib is rapid, with plasma concentrations for both tofacitinib and oclacitinib peaking at around 1 h after oral administration (Collard et al., 2014; Dowty et al., 2014). For each drug, vehicle-only control group (oral administration with 0.5% methylcellulose/0.25% "
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ABSTRACT: Janus kinase (JAK) inhibitors have recently been developed for allergic diseases. We focused on the 2 different JAK inhibitors, tofacitinib (selective for JAK3) and oclacitinib (selective for JAK1 and 2), to clarify the mechanism of anti-inflammatory and anti-itching potency of these drugs. In the process of detecting anti-itching potency, we observed that tofacitinib treated mice showed aggression behaviour. The objective of the study reported here was to investigate the aggressive behaviour induced by tofacitinib by using a mouse model of allergic dermatitis and the resident-intruder test. For the allergic dermatitis model, female BALB/c mice were sensitized and challenged topically with toluene-2,4-diisocyanate (TDI). Vehicle, tofacitinib or oclacitinib, was administered orally 30min before TDI challenge. Scratching, aggression and standing behaviours were monitored in the 60min period immediately following challenge of TDI. Another group of male BALB/c mice treated with vehicle, tofacitinib or oclacitinib was evaluated in the resident-intruder test and brains were obtained to determine blood brain barrier penetration. In the allergic dermatitis model, a significant increase in aggression and standing behaviour was only obvious in the tofacitinib treatment group. There was no effect in non-sensitized mice, but similar aggression was also induced by tofacitinib in male resident-intruder test. Penetration of blood-brain barrier was observed both in tofacitinib and oclacitinib treated mice. These results suggest that aggression was induced by tofacitinib under some kind of stressful environment. This study indicates a possible role of the JAK-STAT pathway in modulation of aggression behaviour.
Copyright © 2015. Published by Elsevier B.V.
European journal of pharmacology 07/2015; 764. DOI:10.1016/j.ejphar.2015.06.060 · 2.53 Impact Factor
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