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

Danhof, Meindert; Alván, Gunnar; Dahl, Svein G.; Kuhlmann, J.; Paintaud, Gilles

doi:10.1007/s11095-005-5882-3

Cited by 151 publications

(80 citation statements)

References 36 publications

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“…However, to be an effective resource for treatment personalization, biomarkers must be identified that are sensitive to the disease state and progression, so that efficacy and toxicity of drugs can be better characterized in clinical practice. Undoubtedly, the availability of biomarkers would also represent an advancement for the diagnosis of disease, minimizing the need for a trial-and-error approach to pharmacotherapy [87][88][89][90]. In our expert opinion, we explore how the application of model-based algorithms may achieve these goals.…”

Section: Resultsmentioning

confidence: 99%

Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

Dijkman

Álvarez-Jiménez

Danhof

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Whereas ongoing efforts in epilepsy research focus on the underlying disease processes, the lack of a physiologically based rationale for drug and dose selection contributes to inadequate treatment response in children. In fact, limited information on the interindividual variation in pharmacokinetics and pharmacodynamics of anti-epileptic drugs (AEDs) in children drive prescription practice, which relies primarily on dose regimens according to a mg/kg basis. Such practice has evolved despite advancements in pediatric pharmacology showing that growth and maturation processes do not correlate linearly with changes in body size. Areas covered: In this review we aim to provide 1) a comprehensive overview of the sources of variability in the response to AEDs, 2) insight into novel methodologies to characterise such variation and 3) recommendations for treatment personalisation. Expert opinion: The use of pharmacokinetic-pharmacodynamic principles in clinical practice is hindered by the lack of biomarkers and by practical constraints in the evaluation of polytherapy. The identification of biomarkers and their validation as tools for drug development and therapeutics will require some time. Meanwhile, one should not miss the opportunity to integrate the available pharmacokinetic data with modeling and simulation concepts to prevent further delays in the development of personalised treatments for pediatric patients.

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Section: Resultsmentioning

confidence: 99%

Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

Dijkman

Álvarez-Jiménez

Danhof

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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“…Ultimately also the effects on and of disease processes and disease progression have to be considered. These can be characterized by biomarkers according to the biomarker classification system [71] (Table 1).…”

Section: Biomarkers Of Drug Effects and Diseasementioning

confidence: 99%

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics

Lange

Brink

Yamamoto

et al. 2017

Expert Opinion on Drug Discovery

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Introduction: CNS drug development has been hampered by inadequate consideration of CNS pharmacokinetic (PK), pharmacodynamics (PD) and disease complexity (reductionist approach). Improvement is required via integrative model-based approaches. Areas covered: The authors summarize factors that have played a role in the high attrition rate of CNS compounds. Recent advances in CNS research and drug discovery are presented, especially with regard to assessment of relevant neuro-PK parameters. Suggestions for further improvements are also discussed. Expert opinion: Understanding time-and condition dependent interrelationships between neuro-PK and neuro-PD processes is key to predictions in different conditions. As a first screen, it is suggested to use in silico/in vitro derived molecular properties of candidate compounds and predict concentrationtime profiles of compounds in multiple compartments of the human CNS, using time-course based physiology-based (PB) PK models. Then, for selected compounds, one can include in vitro drug-target binding kinetics to predict target occupancy (TO)-time profiles in humans. This will improve neuro-PD prediction. Furthermore, a pharmaco-omics approach is suggested, providing multilevel and paralleled data on systems processes from individuals in a systems-wide manner. Thus, clinical trials will be better informed, using fewer animals, while also, needing fewer individuals and samples per individual for proof of concept in humans. ARTICLE HISTORY

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“…According to the classification of biomarkers described by Danhof et al [7], thrombin generation is a biomarker of target activation or function (type 3 biomarker) and is useful to demonstrate the effect of a thrombin inhibitor [8]. Endogenous thrombin generation is measured ex vivo after initiation of the coagulation in plasma collected from the patient.…”

Section: Introductionmentioning

confidence: 99%

“…Thrombin accelerates its own formation by positive feedback activation of other coagulation factors and thrombin inhibition results in a decrease of thrombin generation. Fibrin D-dimer is a fibrin degradation product that has been used as a biomarker of thrombogenicity [9] and may be classified as a pathophysiological response (type 5 biomarker) [7]. Plasma fibrin D-dimer is an index of the degree of hypercoagulability and has been related to adverse thrombotic outcomes [10,11].…”

Section: Introductionmentioning

confidence: 99%

Exposure–response for biomarkers of anticoagulant effects by the oral direct thrombin inhibitor AZD0837 in patients with atrial fibrillation

Lip

Rasmussen

Olsson³

et al. 2015

Brit J Clinical Pharma

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AIMSAZD0837 is a novel oral anticoagulant investigated in clinical studies for stroke prevention in patients with atrial fibrillation (AF). It is bioconverted to its active form, AR-H067637, a potent, specific and reversible thrombin inhibitor. The effects on coagulation biomarkers were correlated with the pharmacokinetic (PK) exposure of AR-H067637 to guide selection of the effective dose regimen for a confirmatory efficacy study in AF patients. METHODSBlood samples were obtained from 601 AF patients randomized to one of four doses of AZD0837 (blinded treatment) or dose-adjusted vitamin K antagonists (VKA, open treatment) for 3-9 months. A pharmacodynamic model was developed to describe the time course of the AR-H067637 exposure dependent effects and the effect of VKA on fibrin D-dimer. The thrombin generation measured ex vivo in venous plasma was also investigated. RESULTSThe PK exposure of AR-H067637 was stable with an interindividual variability of 33% and no or minor influence of patient demographics or comedications. For AZD0837, D-dimer levels decreased with more rapid onset than for VKA. The decrease in D-dimer levels correlated with steady-state plasma concentrations (C ss ) of AR-H067637, with a maximum decrease of baseline D-dimer levels estimated to approximately 60% for both AZD0837 and VKA therapy. The effect on thrombin generation correlated closely with the plasma concentration of AR-H067637. CONCLUSIONSThe effects on thrombin generation and fibrin D-dimer levels correlated with the plasma concentration of its active form and provided comparable effects to well-controlled VKA therapy at an exposure at least corresponding to the 300 mg once daily dose of AZD0837. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• AZD0837 is a novel oral anticoagulant that after bioconversion to its active form is a potent and reversible thrombin inhibitor.• Effects of AZD0837 treatment on thrombin generation and fibrin D-dimer levels were investigated and compared with the effect of vitamin K antagonist (VKA) therapy (INR 2.0-3.0, in a phase II dose-guiding study.• Thrombin generation and fibrin D-dimer are biomarkers of target activation and thrombogenicity, respectively WHAT THIS STUDY ADDS• The PK of the active form of AZD0837 was stable with no or minor influence of patient demographic factors and comedications.• Following oral therapy with AZD0837, inhibitory effects on thrombin generation and fibrin D-dimer levels were correlated with the plasma concentration of its active form.• At an exposure at least corresponding to the 300 mg once daily dose, AZD0837 provided comparable effects to wellcontrolled VKA therapy.

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

Cited by 151 publications

References 36 publications

Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics

Exposure–response for biomarkers of anticoagulant effects by the oral direct thrombin inhibitor AZD0837 in patients with atrial fibrillation

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