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.

Keywords:

• BLT1 antagonist
• high-fat diet
• leukotriene B4
• mathematical modeling
• ovariectomized

Acknowledgements

We thank Hang M. Ha for assistance with animal studies from UCSD and Yizhong Zhang, PhD for bioanalytical discussions from Pfizer Groton Labs.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

The study was supported by a grant from Pfizer (HC and LGE).