TY - JOUR T1 - Pharmacokinetic–Pharmacodynamic Analysis of the Static Allodynia Response to Pregabalin and Sildenafil in a Rat Model of Neuropathic Pain JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 599 LP - 608 DO - 10.1124/jpet.110.166074 VL - 334 IS - 2 AU - Gregor Bender AU - Jeffry A. Florian, Jr. AU - Stephen Bramwell AU - Mark J. Field AU - Keith K. C. Tan AU - Scott Marshall AU - Joost DeJongh AU - Robert. R. Bies AU - Meindert Danhof Y1 - 2010/08/01 UR - http://jpet.aspetjournals.org/content/334/2/599.abstract N2 - 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. ER -