Kinetics of pharmacologic response

Holford, Nicholas H.G.; Sheiner, Lewis B.

doi:10.1016/0163-7258(82)90051-1

Cited by 420 publications

(196 citation statements)

References 54 publications

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“…The pharmacokinetic (PK) and pharmacodynamic (PD) properties of a drug are determinants of its efficacy and the duration of its clinical action [1]. PK and PD have long been considered to be separate disciplines, and the time course of the pharmacological effect of a drug has essentially been considered in terms of the temporal fluctuation of its free concentration [2].…”

Section: Introductionmentioning

confidence: 99%

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Vauquelin

2016

Brit J Clinical Pharma

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The time course of the beneficial pharmacological effect of a drug has long been considered to depend merely on the temporal fluctuation of its free concentration. Only in the last decade has it become widely accepted that target-binding kinetics can also affect in vivo pharmacological activity. Although current reviews still essentially focus on genuine dissociation rates, evidence is accumulating that additional micro-pharmacokinetic (PK) and -pharmacodynamic (PD) mechanisms, in which the cell membrane plays a central role, may also increase the residence time of a drug on its target. The present review provides a compilation of otherwise widely dispersed information on this topic. The cell membrane can intervene in drug binding via the following three major mechanisms: (i) by acting as a sink/repository for the drug; (ii) by modulating the conformation of the drug and even by participating in the binding process; and (iii) by facilitating the approach (and rebinding) of the drug to the target. To highlight these mechanisms, we focus on drugs that are currently used in clinical therapy, such as the antihypertensive angiotensin II type 1 receptor antagonist candesartan, the atypical antipsychotic agent clozapine and the bronchodilator salmeterol. Although the role of cell membranes in PK-PD modelling is gaining increasing interest, many issues remain unresolved. It is likely that novel biophysical and computational approaches will provide improved insights in the near future. IntroductionThe pharmacokinetic (PK) and pharmacodynamic (PD) properties of a drug are determinants of its efficacy and the duration of its clinical action [1]. PK and PD have long been considered to be separate disciplines, and the time course of the pharmacological effect of a drug has essentially been considered in terms of the temporal fluctuation of its free concentration [2]. In accordance with this principle, the frequently observed time lag between the concentration of a drug in the systemic circulation and its effect was initially attributed to slow equilibration between the plasma and a hypothetical target-surrounding 'effect compartment' [3]. By contrast, preclinical screening studies traditionally aim to optimize drug candidates in terms of only their efficacy and potency (i.e. PD properties). Inherent to this practice is the proposal that drug-target interactions are adequately described by equilibrium equations and, hence, that association and dissociation rates play only subordinate roles. In addition to a few noteworthy exceptions [4,5], it is only in the last decade that it has become fashionable to include binding kinetics as an additional criterion for clinical efficacy. This insight was largely sparked by the seminal articles by Swinney [6] and Copeland et al. [7]. The numerous review articles that have been published subsequently have focused mainly on long residence times. This property is now recognized to play a key role with respect to the clinical British Journal of Clinical Pharmacology Br J Clin Pharmacol (2016...

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Section: Introductionmentioning

confidence: 99%

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Vauquelin

2016

Brit J Clinical Pharma

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“…Similar to small-molecule drugs, the relationship between the antibody dose or concentration(s) and the observed pharmacological response(s) can be characterized by linear and log-linear, sigmoid E max , biophase distribution, or indirect response models (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). The relationships between the drug dose or concentrations and the observed pharmacological effect can be characterized by linear or loglinear PD models in the form of E ¼ E 0 þ m C (or ln C), where E and E 0 denote the observed and baseline (no-drug) effects, respectively, and m is the slope of the concentrationeffect relationship.…”

Section: Introductionmentioning

confidence: 99%

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

Tabrizi

Funelas

Suria

2010

AAPS J

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Abstract. The advancement of therapeutic monoclonal antibodies during various stages of the drug development process can be effectively streamlined when appropriate translational strategies are applied. Design of successful translational strategies for development of monoclonal antibodies should allow for understanding of the dose-and concentration-response relationships with respect to both beneficial and toxic effects from early phases of drug development. Evaluation of relevant biomarkers during early stages of drug development should facilitate the successful design of safe and effective dosing strategies. Moreover, application of quantitative pharmacology is critical for translation of exposure-response relationships early on.

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“…(21) where c(t) is the EPO concentration and N is the autonomic transduction function that commonly is of a nonlinear form. The hysteresis approach [3] attempts to estimate the transduction function, N, by minimizing the size of the hysteresis loop obtained by plotting the activation rate versus the EPO concentration from 100 equally spaced points using time as the independent variable.…”

Section: Hysteresis Minimization and Epo Transduction Functionmentioning

confidence: 99%

“…Several models have been investigated and proposed to establish the nature of the PD relationship [21,22]. A number of different methodologies have also been developed from the traditional structured modeling approaches [23,24] to the nonparametric developments using hysteresis minimization principles [3,[25][26][27].…”

Section: The New Analysis Paradigmmentioning

confidence: 99%

“…In the traditional methodology, specific parametric PD models are utilized [21] and the 'topdown' approach is employed where the model complexity is increased as extra details are integrated into the existing model or the model is developed to better agree with observed data. Alternatively, system analysis approaches to PD modeling [2,28] are more objective and make fewer assumptions about the kinetic relationships.…”

Section: The New Analysis Paradigmmentioning

confidence: 99%

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A ‘bottom‐up’ approach for endo‐PK/PD analysis

Neelakantan

Widness

Schmidt

et al. 2006

Biopharm & Drug Disp

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A 'bottom-up' PK/PD analysis approach employing system analysis principles of convolution/ deconvolution and special nonparametric estimation procedures is presented to resolve the complex 'endo-PK/PD' of the endogenous form of recombinant drugs using erythropoietin (EPO) as an example. A novel cellular deconvolution algorithm is presented that facilitates the identification of the functional relationship between the variables involved in EPO's complex PK/PD. Five sheep each underwent two phlebotomies spaced 4-6 weeks apart when their hemoglobin levels were reduced from 12 g/dl to 3-4 g/dl. EPO levels and reticulocyte counts were frequently sampled. The data were analysed using end-constrained cubic splines. The rate of reticulocyte production was determined using the novel deconvolution methodology. The erythroid progenitor cells activation rate by EPO was estimated from the reticulocyte production rate using a lag-time parameter which determines the delay in the reticulocyte appearance in the blood relative to the activation of erythroid progenitors. Hysteresis minimization combined with cellular deconvolution was employed to determine the population PK/PD transduction function relating the progenitor activation rate to EPO concentrations in a nonparametric manner without assuming a specific structure. The proposed approach provides a rational informative starting point for developing parametric PK/PD models to resolve the complex endo-PK/PD of recombinant drugs.

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Kinetics of pharmacologic response

Cited by 420 publications

References 54 publications

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

A ‘bottom‐up’ approach for endo‐PK/PD analysis

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