Study of Linearization of Hill Dose-Effect Curve with Metabolic Velocity Instead of Drug Concentration

Objective To explore the velocity-effect relationship in order to the establish linearization of effect on an equation with regard to the consistency of the Hill dose-effect expression with the metabolic kinetics of receptors.Methods The linear velocity-effect expression was obtained by solving multivariant differential equation groups,which were established to compare the coincidences and basic relations between the Hill dose-effect and metabolic kinetic Michaelis-Menten equation for receptors.The validation test was conducted with acetylcholine,adrenaline,and their mixture as model drugs.Results The linear velocity-effect modelling was represented in vivo or in vitro,for single and multidrug systems.Pharmacodynamic parameters,especially suitable for multicomponent CMM formulas,could be determined and calculated for single or multicomponent formulas at high saturating or low linear concentration for receptors.The validation test showed that the pharmacodynamic parameters of acetylcholine were:k,2.675×10^-3s^-1;ka,5.786×10^-9s^-1;km,2.500×10^-7s^-1;α,4.619×10^9张s·mg^-1;E0,13张(P<0.01)and those of adrenaline were:k,1.415×10^-3s^-1;ka,5.846×10^-9s^-1;km,2.300×10^-7s^-1;α,-1.627×10^9张s·m g^-1;E0,9.2张(P<0.01).For the mixture of the two components,the values were:α,1.375×1010张s·m g^-1;-6.150×10^9张s m g^-1for acetylcholine and adrenaline,respectively,and E0was7.08张in both,with the other parameters unchanged(P<0.01).Conclusion The velocity-effect equation can linearize the Hill dose-effect relationship,which can be applied to study the pharmacodynamics and availability of CMM formulations in vivo and in vitro.

Dosage individualization in children:integration of pharmacometrics in clinical practice

Background:Children are in a continuous and dynamically changing state of growth and development.A thorough understanding of developmental pharmacokinetics(PK)and pharmacodynamics(PD)is required to optimize drug therapy in children.Data sources:Based on recent publications and the experience of our group,we present an outline on integrating pharmacometrics in pediatric clinical practice to develop evidence-based personalized pharmacotherapy.Results:Antibiotics in septic neonates and immunosuppressants in pediatric transplant recipients are provided as proof-of-concept to demonstrate the utility of pharmacometrics in clinical practice.Dosage individualization based on developmental PK-PD model has potential benefits of improving the efficacy and safety of drug therapy in children.Conclusion:The pharmacometric technique should be better developed and used in clinical practice to personalize drug therapy in children in order to decrease variability of drug exposure and associated risks of overdose or underdose.

Pharmacometrics of nutraceutical sulforaphane and its implications in prostate cancer prevention

Sulforaphane(SFN), found in broccoli and other cruciferous vegetables, has a beneficial effect in chemoprevention of prostate cancer, whose incidence and associated mortality have gradually increased worldwide. There is great enthusiasm for bench-to-bedside development of SFN as a potent chemopreventive agent, possibly alone or as an adjunct to existing chemotherapy regimens, in the oncology care setting to reduce toxicity of chemotherapeutics and potentially enhance their cancer cell-kill efficacy. In this review, we appreciate existing knowledge on SFN using a pharmacometrics approach, which is fast becoming a gold standard in discovery research and validation of New Chemical Entities and New Biological Entities in pharmaceutical industry. We discuss the epistemology of SFN target engagement and quantitative systems pharmacology with due emphasis on mechanistic pharmacology, pharmacodynamics, pharmacogenomics and metabolism of SFN. In addition, we explore the quantitative freeway to SFN translational medicine by assessing the preclinical and clinical PK/metabolism aspects of SFN that form the cornerstone of SFN pharmacometric evaluation, as well as the promise of SFN in prostate cancer. Taken together, we share perspectives on the exciting developments in translational cancer chemoprevention, with emphasis on the pharmacometric aspects, of the nutraceutical SFN which is currently in clinical trials, and suggest that the pharmacometric approach holds great promise in the SFN translational pharmacology paradigm for prostate cancer.