A model eliciting transient responses

Ekblad, Eva; Ličko, Vojtech

doi:10.1152/ajpregu.1984.246.1.r114

Cited by 19 publications

(11 citation statements)

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“…The baseline threshold was established before starting the infusion and was defined as three equal effect measurements. During the pretreatment period, the ANE was measured in conjunction with each blood collection time, while during the morphine administration the response was evaluated at 5,15,30,45,60,90,120,135,150,165,180,195,210,225,240,270,300,330, and 360 min. ANE is represented by the measured value in the fitting of the pharmacodynamic model.…”

Section: Methodsmentioning

confidence: 99%

Morphine-3-Glucuronide Has a Minor Effect on Morphine Antinociception. Pharmacodynamic Modeling

Gårdmark

Karlsson

Jönsson

et al. 1998

Journal of Pharmaceutical Sciences

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The objective of this study was to quantify the influence of morphine-3-glucuronide (M3G) on the morphine antinociceptive effect (ANE) and respiratory effects in the rat. Three groups of rats were pretreated with either saline or M3G at two different rates. Morphine infusion of 10 mg/h/kg (group A) or 20 mg/h/kg (group B) was administered to each pretreatment group for 3 h. The ANE was measured by the electrical stimulation vocalization method, and blood gas parameters (pCO2, pO2, and pH) were assessed. Independent of pretreatment all groups displayed a concurrent increase in the ANE. The maximal effect diverged between pretreatments. Acute tolerance was observed, but no rebound effect was detected. To characterize the ANE, an effect compartment model and an indirect response model were selected, both capable of describing the observed features. In both models incorporation of M3G led to a better explanation of the data. On the basis of the parameters obtained in the fits, naturally occurring M3G would reduce the antinociceptive effect during a morphine infusion (plasma concentration 15 microM) by 15-20%. The exposure of M3G did not significantly change the respiratory response following the morphine treatment.

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Section: Methodsmentioning

confidence: 99%

Morphine-3-Glucuronide Has a Minor Effect on Morphine Antinociception. Pharmacodynamic Modeling

Gårdmark

Karlsson

Jönsson

et al. 1998

Journal of Pharmaceutical Sciences

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“…These models are in part based on the work by Ekblad and Licko (22). An example is the model proposed by Bauer et al to characterize tolerance to the hemodynamic effects of nitroglycerin in experimental heart failure (23).…”

Section: Homeostatic Feedbackmentioning

confidence: 99%

Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling—A New Classification of Biomarkers

et al. 2005

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In recent years, pharmacokinetic/pharmacodynamic (PK/PD) modeling has developed from an empirical descriptive discipline into a mechanistic science that can be applied at all stages of drug development. Mechanism-based PK/PD models differ from empirical descriptive models in that they contain specific expressions to characterize processes on the causal path between drug administration and effect. Mechanism-based PK/PD models have much improved properties for extrapolation and prediction. As such, they constitute a scientific basis for rational drug discovery and development. In this report, a novel classification of biomarkers is proposed. Within the context of mechanism-based PK/PD modeling, a biomarker is defined as a measure that characterizes, in a strictly quantitative manner, a process, which is on the causal path between drug administration and effect. The new classification system distinguishes seven types of biomarkers: type 0, genotype/phenotype determining drug response; type 1, concentration of drug or drug metabolite; type 2, molecular target occupancy; type 3, molecular target activation; type 4, physiological measures; type 5, pathophysiological measures; and type 6, clinical ratings. In this paper, the use of the new biomarker classification is discussed in the context of the application of mechanism-based PK/PD analysis in drug discovery and development.

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“…The action of the drug takes place through the drug mechanism function H(C), where C = C(t) is the plasma concentration of the drug as a function of time (the drug function) (3,4). This action may take place either via the gain term k in , in which case Eq.…”

Section: Turnover Modelsmentioning

confidence: 99%

A Dynamical Systems Analysis of the Indirect Response Model with Special Emphasis on Time to Peak Response

Peletier

Gabrielsson

Haag³

2005

J Pharmacokinet Pharmacodyn

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In this paper we present a mathematical analysis of the four classical indirect response models. We focus on characteristics such as the evolution of the response R(t) with time t, the time of maximal/minimal response T max and the area between the response and the baseline AU C R , and the way these quantities depend on the drug dose, the dynamic parameters such as E max and EC 50 and the ratio of the fractional turnover rate k out to the elimination rate constant k of drug in plasma. We find that depending on the model and on the drug mechanism function, T max may increase, decrease, decrease and then increase, or stay the same, as the drug dose is increased. This has important implications for using the shift in T max as a diagnostic tool in the selection of an appropriate model.

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A model eliciting transient responses

Cited by 19 publications

References 0 publications

Morphine-3-Glucuronide Has a Minor Effect on Morphine Antinociception. Pharmacodynamic Modeling

Morphine-3-Glucuronide Has a Minor Effect on Morphine Antinociception. Pharmacodynamic Modeling

Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling—A New Classification of Biomarkers

A Dynamical Systems Analysis of the Indirect Response Model with Special Emphasis on Time to Peak Response

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