The pharmacokinetics of oclacitinib maleate, a Janus kinase inhibitor, in the dog.
ABSTRACT 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.
- SourceAvailable from: Alain Bousquet-Melou
Article: Plasma clearance.[Show abstract] [Hide abstract]
ABSTRACT: Plasma (total, systemic...) clearance is determined by all the individual metabolizing/eliminating organ clearances and involves mainly liver and kidney clearances. Plasma clearance (a volume per time, i.e. a flow) expresses the overall ability of the body to eliminate a drug by scaling the drug elimination rate (amount per time) by the corresponding plasma concentration level. The interpretation of plasma clearance and inter-species comparisons are made easier by computing the overall body extraction ratio (from 0 to 1), which is the ratio of the body clearance divided by cardiac output. Plasma clearance is the most important pharmacokinetic parameter because it is the only one which controls the overall drug exposure (for a given bioavailability) and it is the parameter which allows computation of the dosage required to maintain an average steady-state plasma concentration.Journal of Veterinary Pharmacology and Therapeutics 01/2005; 27(6):415-25. · 1.35 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Atopic dermatitis is a chronic inflammatory skin disease that causes significant morbidity in affected individuals. It is characterized by dysregulated immune responses that consist of an increased systemic Th2 response and a combination of Th2 and Th1 responses in the skin lesions. In this article, we review factors that contribute to these abnormal responses, including key effector cells of the immune system, chemokines, defective skin barrier, genetic predisposition, and environmental triggers. Understanding these pathomechanisms may improve our current therapies for atopic dermatitis.Current Allergy and Asthma Reports 10/2006; 6(5):384-9. · 2.75 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: This article reviews currently used approaches for establishing dose proportionality in Phase I dose escalation studies. A review of relevant literature between 2002 and 2006 found that the power model was the preferred choice for assessing dose proportionality in about one-third of the articles. This article promotes the use of the power model and a conceptually appealing extension, i.e. a criterion based on comparing the 90% confidence interval for the ratio of predicted mean values from the extremes of the dose range (R(dnm)) to pre-defined equivalence criterion (theta(L),theta(U)). The choice of bioequivalence default values of theta(L)=0.8 and theta(U)=1.25 seems reasonable for dose levels only a doubling apart but are impractically strict when applied over the complete dose range. Power calculations are used to show that this prescribed criterion lacks power to conclude dose proportionality in typical Phase I dose-escalation studies. A more lenient criterion with values theta(L)=0.5 and theta(U)=2 is proposed for exploratory dose proportionality assessments across the complete dose range.Pharmaceutical Statistics 05/2008; 8(1):38-49. · 0.99 Impact Factor