title: Formulation modifications of PD 0313052, a direct Factor Xa Inhibitor, alter pharmacokinetics and pharma-codynamics following subcutaneous administration to rabbits.
abstract: OBJECTIVE
  PD 0313052 is a potent, direct factor Xa (FXa) inhibitor (Ki = 0.33 nM) and its antithrombotic effect has been previously demonstrated in several animal models, via intravenous (IV) administration. In the present study, we evaluated four different subcutaneous (SC) formulations to test the feasibility of developing PD 0313052 as a subcutaneous agent.
  
  
  METHODS
  PD 0313052 was formulated in saline, methylcellulose (MC, 0.5% methylcellulose solution containing 1% Tween-80), sesame oil, and F127 (25% aqueous solution). Each formulation was injected subcutaneously into rabbits and the relative plasma exposure and the duration of action of PD 0313052 were assessed. Plasma concentration, FXa activity, and coagulation parameters were used to monitor the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of PD 0313052.
  
  
  RESULTS
  Regardless of formulation, there was a significant (p < 0.05) correlation between PD 0313052 plasma concentration and FXa activity (R2 = 0.90), prothrombin time (PT) (R2 = 0.86), and Heptest (R2 = 0.93). The saline and MC formulations had similar effects on FXa activity, coagulation parameters, and Heptest, peaking at 30 to 120 minutes after administration and decreasing rapidly thereafter. In contrast, formulations of F127 and sesame oil yielded lower maximal effects on PD markers but produced sustained PD effects over time.
  
  
  CONCLUSIONS
  The data indicate that PD 0313052 is bioavailable after SC administration to rabbits and that there is a strong correlation between the PD parameters and plasma concentrations of PD 0313052. Modifications in the formulation of PD 0313052 produce marked differences in the PK and PD profiles of this agent after SC administration to rabbits. These results suggest that SC formulations can be optimized to improve the PK and PD profiles of PD 0313052, and that PD 0313052 is a viable candidate for development as a SC antithrombotic agent.
authors.affiliation: Cardiovascular Biology, Pharmacokinetics Dynamics and Metabolism, Biostatistics, Antibacterial Biology, Pfizer Global R&D, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
authors.forename: Yun-Wen
authors.initials: YW
authors.lastname: Peng
authors.forename: Liguo
authors.initials: L
authors.lastname: Chi
authors.forename: Glenn
authors.initials: G
authors.lastname: Gibson
authors.forename: Nancy
authors.initials: N
authors.lastname: Janiczek
authors.forename: Paul
authors.initials: P
authors.lastname: Juneau
authors.forename: Daniel
authors.initials: D
authors.lastname: Ross
authors.forename: Lisa
authors.initials: L
authors.lastname: A Perrin
authors.forename: Robert
authors.initials: R
authors.lastname: Leadley
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D007279:Injections, Subcutaneous; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011817:Rabbits
chemical_list: D005343:Fibrinolytic Agents; C503110:PD0313052; D010880:Piperidines; D000990:Antithrombin III