title: Leveraging model-based study designs and serial micro-sampling techniques to understand the oral pharmacokinetics of the potent LTB4 inhibitor, CP-105696, for mouse pharmacology studies.
abstract: 1. Leukotriene B4 (LTB4) is a proinflammatory mediator important in the progression of a number of inflammatory diseases. Preclinical models can explore the role of LTB4 in pathophysiology using tool compounds, such as CP-105696, that modulate its activity. To support preclinical pharmacology studies, micro-sampling techniques and mathematical modeling were used to determine the pharmacokinetics of CP-105696 in mice within the context of systemic inflammation induced by a high-fat diet (HFD). 2. Following oral administration of doses > 35 mg/kg, CP-105696 kinetics can be described by a one-compartment model with first order absorption. The compound's half-life is 44-62 h with an apparent volume of distribution of 0.51-0.72 L/kg. Exposures in animals fed an HFD are within 2-fold of those fed a normal chow diet. Daily dosing at 100 mg/kg was not tolerated and resulted in a >20% weight loss in the mice. 3. CP-105696's long half-life has the potential to support a twice weekly dosing schedule. Given that most chronic inflammatory diseases will require long-term therapies, these results are useful in determining the optimal dosing schedules for preclinical studies using CP-105696.
authors.affiliation: a Pfizer Worldwide Research and Development, La Jolla Laboratories , San Diego , CA , USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Spilker
authors.affiliation: b Department of Medicine , University of California San Diego, La Jolla, CA , USA.
authors.forename: Heekyung
authors.initials: H
authors.lastname: Chung
authors.affiliation: a Pfizer Worldwide Research and Development, La Jolla Laboratories , San Diego , CA , USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Visswanathan
authors.affiliation: a Pfizer Worldwide Research and Development, La Jolla Laboratories , San Diego , CA , USA.
authors.forename: Shubha
authors.initials: S
authors.lastname: Bagrodia
authors.affiliation: c Pfizer Worldwide Research and Development , Groton , CT , USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Gernhardt
authors.affiliation: d ORIC Pharmaceuticals , South San Francisco , CA , USA , and.
authors.forename: Valeria R
authors.initials: VR
authors.lastname: Fantin
authors.affiliation: e Department of Pathology , University of California San Diego, La Jolla, CA , USA.
authors.forename: Lesley G
authors.initials: LG
authors.lastname: Ellies
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001578:Benzopyrans / Q000493:pharmacokinetics*; D002264:Carboxylic Acids / Q000493:pharmacokinetics*; D059305:Diet, High-Fat; D006207:Half-Life; D007249:Inflammation; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D051379:Mice; D008954:Models, Biological; D009504:Neutrophils
chemical_list: D001578:Benzopyrans; D002264:Carboxylic Acids; D007975:Leukotriene B4; C089698:CP 105696
keywords: BLT1 antagonist; high-fat diet; leukotriene B4; mathematical modeling; ovariectomized