title: 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 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.
authors.affiliation: Leiden-Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
authors.forename: Gregor
authors.initials: G
authors.lastname: Bender
authors.forename: Jeffry A
authors.initials: JA
authors.lastname: Florian
authors.forename: Stephen
authors.initials: S
authors.lastname: Bramwell
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Field
authors.forename: Keith K C
authors.initials: KK
authors.lastname: Tan
authors.forename: Scott
authors.initials: S
authors.lastname: Marshall
authors.forename: Joost
authors.initials: J
authors.lastname: DeJongh
authors.forename: Robert R
authors.initials: RR
authors.lastname: Bies
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000700:Analgesics / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D002908:Chronic Disease; D004347:Drug Interactions; D006930:Hyperalgesia / Q000503:physiopathology*; D015640:Ion Channel Gating; D008024:Ligands; D008297:Male; D008954:Models, Biological; D010146:Pain / Q000503:physiopathology*; D017288:Pain Threshold / Q000187:drug effects; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D000069583:Pregabalin; D011687:Purines / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000493:pharmacokinetics / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000700:Analgesics; D015220:Calcium Channels; D008024:Ligands; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000068677:Sildenafil Citrate