Concentrations of CCI-779 and sirolimus were adequately described with a population model incorporating factors for dose, attenuated exposure of multiple doses, body surface area, and hematocrit. Correlations with adverse event severity and duration profiles were provided to aid in the detection of treatment-emergent effects. Pharmacogenomic profiling of PBMCs identified altered ribonucleic acid transcript expression levels that correlate with exposure. These transcripts represent potential biomarkers of CCI-779 exposure in peripheral blood.
Purpose. Preliminary evidence has suggested a synergistic interaction between pregabalin and sildenafil for the treatment of neuropathic pain. The focus of this study was to determine the influence of sildenafil on the pharmacokinetics (PK) of pregabalin with the objective of informing the design of a quantitative pharmacodynamic (PD) study. Methods. The pharmacokinetics were determined in rats following 2-hr intravenous infusions of pregabalin at doses of 4 mg/kg/hr and 10 mg/kg/hr with and without a sildenafil bolus (2.2 mg) and steady state infusion (12 mg/kg/hr for 6 h). This PK model was utilized in a preclinical trial simulation with the aim of selecting the optimal sampling strategy to characterize the PK-PD profile in a future study. Eight logistically feasible PK sampling strategies were simulated in NONMEM and examined through trial simulation techniques. Results. A two-compartment population PK model best described pregabalin pharmacokinetics. Significant model covariates included either a binary effect of sildenafil administration (30.2% decrease in clearance) or a concentration-dependent effect due to sildenafil's active metabolite. Conclusions. Analysis of simulations indicated that three post-PD samples had the best cost/benefit ratio by providing a significant increase in the precision (and minor improvement in bias) of both PK and PD parameters compared with no PK sampling.
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...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.