Pharmacokinetic–Pharmacodynamic Analysis of the Static Allodynia Response to Pregabalin and Sildenafil in a Rat Model of Neuropathic Pain

Abstract

The objective of this study was to develop a pharmacokineticpharmacodynamic (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 mg⅐kg Ϫ1 ⅐h Ϫ1 ; 3) a 2-h pregabalin infusion at 10 mg⅐kg Ϫ1 ⅐h Ϫ1 ; 4) a 2.2-mg loading dose ϩ 12 mg⅐kg Ϫ1 ⅐min Ϫ1 infusion of sildenafil; 5) a 2-h pregabalin infusion at 1.6 mg⅐kg Ϫ1 ⅐h Ϫ1 with sildenafil; and 6) a 2-h infusion of pregabalin at 4 mg⅐kg Ϫ1 ⅐h 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.Neuropathic pain represents an area of largely unmet medical need with significant impact on health-related quality of life (Jensen et al., 2007). At present, neuropathic pain is treated by using a variety of different medications (e.g., antidepressants, gabapentin, pregabalin, opioids) with mechanisms of action that include inhibiting serotonin and norepinephrine uptake, altering ion channel transport, and occupying N-methyl-D-aspartate receptors (Nurmikko and Haanpä ä , 2005;Chong and Brandner, 2006;Francis et al., 2006;Gilron et al., 2006;Jackson 2006;Stillman, 2006). The current treatments for neuropathic pain achieve some relief; however, there remains significant room for improvement (Harden and Cohen, 2003). An intriguing question is whether increased relief can be obtained by using rational combinations of drugs (Gilron and Max, 2005;Backonja et al., 2006). The optimization of a rational drug combination represents a major challenge, because it involves not only the selection of the appropriate combination of drugs, each with a different mechanism of action, but also the optimal doses for using those drugs. The overall goal of this project was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model describing the interaction between pregabalin and sildenafil in rats.Pregabalin is a ligand to the ␣ 2 ␦ subunit of the voltagegated calcium channel. Avid binding at this site reduces calcium influx at...

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