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

• Published in: The Journal of pharmacology and experimental therapeutics 2010-08, Vol.334 (2), p.599-608
• Main Authors: Bender, Gregor, Florian, Jr, Jeffry A, Bramwell, Stephen, Field, Mark J, Tan, Keith K C, Marshall, Scott, DeJongh, Joost, Bies, Robert R, Danhof, Meindert
• Format: Article
• Language: English
• Subjects: Analgesics - pharmacokinetics; Analgesics - pharmacology; Animals; Calcium Channels - metabolism; Chronic Disease; Drug Interactions; gamma-Aminobutyric Acid - analogs & derivatives; gamma-Aminobutyric Acid - pharmacokinetics; gamma-Aminobutyric Acid - pharmacology; Hyperalgesia - physiopathology; Ion Channel Gating; Ligands; Male; Models, Biological; Pain - physiopathology; Pain Threshold - drug effects; Phosphodiesterase 5 Inhibitors; Piperazines - pharmacokinetics; Piperazines - pharmacology; Pregabalin; Purines - pharmacokinetics; Purines - pharmacology; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones - pharmacokinetics; Sulfones - pharmacology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.110.166074

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 mgxkg(-1)xh(-1); 3) a 2-h pregabalin infusion at 10 mgxkg(-1)xh(-1); 4) a 2.2-mg loading dose + 12 mgxkg(-1)xmin(-1) infusion of sildenafil; 5) a 2-h pregabalin infusion at 1.6 mgxkg(-1)xh(-1) with sildenafil; and 6) a 2-h infusion of pregabalin at 4 mgxkg(-1)xh 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 EC(50) 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 EC(50), 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.