Nano Express

Nanoscale Research Letters

, Volume 2, Issue 6, pp 291-296

Open Access This content is freely available online to anyone, anywhere at any time.

Pharmacokinetic evaluation of a 1,3-dicyclohexylurea nanosuspension formulation to support early efficacy assessment

  • Jan L. WahlstromAffiliated withPharmacokinetics, Dynamics and Metabolism, Pfizer Global Research & Development, St. Louis Laboratories, Pfizer Inc. Email author 
  • , Po-Chang ChiangAffiliated withPharmaceutical Sciences, Pfizer Global Research & Development, St. Louis Laboratories, Pfizer Inc.
  • , Sarbani GhoshAffiliated withMolecular Pharmacology, Pfizer Global Research & Development, St. Louis Laboratories, Pfizer Inc.
  • , Chad J. WarrenAffiliated withPharmacokinetics, Dynamics and Metabolism, Pfizer Global Research & Development, St. Louis Laboratories, Pfizer Inc.
  • , Steve P. WeneAffiliated withPharmacokinetics, Dynamics and Metabolism, Pfizer Global Research & Development, St. Louis Laboratories, Pfizer Inc.
  • , Lesley A. AlbinAffiliated withPharmacokinetics, Dynamics and Metabolism, Pfizer Global Research & Development, St. Louis Laboratories, Pfizer Inc.
  • , Mark E. SmithAffiliated withPharmacokinetics, Dynamics and Metabolism, Pfizer Global Research & Development, St. Louis Laboratories, Pfizer Inc.
  • , Steven L. RoberdsAffiliated withMolecular Pharmacology, Pfizer Global Research & Development, St. Louis Laboratories, Pfizer Inc.

Abstract

Time and resource constraints necessitate increasingly early decisions to advance or halt pre-clinical drug discovery programs. Early discovery or “tool” compounds may be potent inhibitors of new targets, but all too often they exhibit poor pharmaceutical and pharmacokinetic properties that make early assessment of in vivo efficacy difficult. 1,3-Dicyclohexylurea, a potent and selective inhibitor of soluble epoxide hydrolase (sEH), reduces blood pressure in hypertensive preclinical animal models when administered intraperitoneally using DMSO/corn oil as a delivery vehicle. However, the poor aqueous solubility of DCU poses a challenge for in vivo dosing in a multiple dose situation. Therefore, we developed a nanosuspension formulation of DCU to support oral, intravenous bolus and intravenous infusion dosing. Use of the nanosuspension formulation maintained DCU free plasma levels above the sEH IC50 and demonstrated that the application of formulation technology can accelerate in vivo evaluation of new targets by enabling pharmacodynamic studies of poorly soluble compounds.

Keywords

Nanosuspension Formulation Pharmacokinetics Efficacy Tool compounds