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

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.