Andy R Eugene1. 1. Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Gonda 19, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA, Tel.: +1-507-284-2790.
Abstract
INTRODUCTION: Numerous studies have emerged over the course of several decades describing the properties of drugs eliciting vasodilatory or vasoconstrictor responses in the human vasculature. During drug development, decisions to move forward with testing with a new chemical entity are very costly. To fund or not to fund development, go or no-go, decisions are often limited by efficacy comparisons with the current products on the market. The primary aim of this paper is to use dose-response modeling and simulations to quantify differences in blood flow to Acetylcholine, Albuterol, ATP, Bradykinin, 17β-Estradiol, Glyceryl Trinitrate, L-NMMA, Nevibolol, Norepinephrine, Sodium Nitroprusside, Substance P, and Verapamil. METHODS: Five studies were identified in the literature that included a total of 12 compounds. Infusion doses were normalized to nmol/min and forearm blood flow values were normalized and scaled to the percent increase or decrease in forearm blood flow from baseline resting values. The original published studies were mathematically modeled using the Emax model or Sigmoid Emax model equation parameters. Lastly, dose-response simulations of higher doses using a virtual population were produced to account for population variability. RESULTS: The gender difference between the Emax estimates, interpreted as the %Change from Baseline resting forearm blood flow, were found to be: Albuterol 253%, Acetylcholine 231%, Substance P 159%, Verapamil 145%, Bradykinin 42%, Sodium Nitroprusside 41%, and Glyceryl Trinitrate 26%. Contrastingly, Norepinephrine and L-NMMA Emax gender difference resulted in a 6% and 7% difference, respectively. CONCLUSION: These results provide insight into the differences in men and women seen in anti-hypertensive patient management. Further, the modeling estimates provide pharmacometricians evaluating new compounds with mathematical parameters for comparative efficacy studies through the various phases of drug development.
INTRODUCTION: Numerous studies have emerged over the course of several decades describing the properties of drugs eliciting vasodilatory or vasoconstrictor responses in the human vasculature. During drug development, decisions to move forward with testing with a new chemical entity are very costly. To fund or not to fund development, go or no-go, decisions are often limited by efficacy comparisons with the current products on the market. The primary aim of this paper is to use dose-response modeling and simulations to quantify differences in blood flow to Acetylcholine, Albuterol, ATP, Bradykinin, 17β-Estradiol, Glyceryl Trinitrate, L-NMMA, Nevibolol, Norepinephrine, Sodium Nitroprusside, Substance P, and Verapamil. METHODS: Five studies were identified in the literature that included a total of 12 compounds. Infusion doses were normalized to nmol/min and forearm blood flow values were normalized and scaled to the percent increase or decrease in forearm blood flow from baseline resting values. The original published studies were mathematically modeled using the Emax model or Sigmoid Emax model equation parameters. Lastly, dose-response simulations of higher doses using a virtual population were produced to account for population variability. RESULTS: The gender difference between the Emax estimates, interpreted as the %Change from Baseline resting forearm blood flow, were found to be: Albuterol 253%, Acetylcholine 231%, Substance P 159%, Verapamil 145%, Bradykinin 42%, Sodium Nitroprusside 41%, and Glyceryl Trinitrate 26%. Contrastingly, Norepinephrine and L-NMMA Emax gender difference resulted in a 6% and 7% difference, respectively. CONCLUSION: These results provide insight into the differences in men and women seen in anti-hypertensivepatient management. Further, the modeling estimates provide pharmacometricians evaluating new compounds with mathematical parameters for comparative efficacy studies through the various phases of drug development.
Authors: J R Cockcroft; P J Chowienczyk; S E Brett; C P Chen; A G Dupont; L Van Nueten; S J Wooding; J M Ritter Journal: J Pharmacol Exp Ther Date: 1995-09 Impact factor: 4.030