Pharmacokinetic-pharmacodynamic analysis of the static allodynia response to pregabalin and sildenafil in a rat model of neuropathic pain

Gregor Bender, Jeffry A. Florian, Stephen Bramwell, Mark J. Field, Keith K.C. Tan, Scott Marshall, Joost DeJongh, Robert R. Bies, Meindert Danhof

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

The objective of this study was to develop a pharmacokinetic- pharmacodynamic (PK-PD) model of the static allodynia response to pregabalin with and without sildenafil in a chronic constriction injury model of neuropathic pain. Six treatment groups were evaluated every 30 min for 6 h. Rats were treated with either 1) a saline infusion; 2) a 2-h pregabalin infusion at 4 mg·kg-1·h-1; 3) a 2-h pregabalin infusion at 10 mg·kg-1·h-1; 4) a 2.2-mg loading dose + 12 mg·kg-1·min-1 infusion of sildenafil; 5) a 2-h pregabalin infusion at 1.6 mg·kg-1·h -1 with sildenafil; and 6) a 2-h infusion of pregabalin at 4 mg·kg-1·h with sildenafil. The static allodynia endpoint was modeled by using three population PD approaches: 1) the behavior of the injured paw using a three-category ordinal logistic regression model; 2) paw withdrawal threshold (PWT) (g) between the injured and uninjured paw using the Hill equation with a baseline function; and 3) the baseline normalized difference in PWT between the injured and uninjured paw. The categorical model showed a significant shift in the concentration-response relationship of pregabalin to lower concentrations with concomitant sildenafil. Likewise, the continuous PK-PD models demonstrated a reduction in the EC50 of pregabalin necessary for PD response in the presence of sildenafil. The difference-transformed PD model resulted in a 54.4% (42.3-66.9%) decrease in EC50, whereas the percentage-transformed PD model demonstrated a 53.5% (42.7-64.3%) shift. It is concluded from these studies that there is a synergistic PD interaction between pregabalin and sildenafil.

Original languageEnglish (US)
Pages (from-to)599-608
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume334
Issue number2
DOIs
StatePublished - Aug 1 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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