General clinical and methodological considerations on the extrapolation of pharmacokinetics and optimization of study protocols for small molecules and monoclonal antibodies in children
British Journal of Clinical Pharmacology, vol. 88, pp. 4985–4996
Abstract
Pharmacometric modelling plays a key role in both the design and analysis of regulatory trials in paediatric drug development. Studies in adults provide a rich source of data to inform the paediatric investigation plans, including knowledge on drug pharmacokinetics (PK), safety and efficacy. In children, drug disposition differs widely from birth to adolescence but extrapolating adult to paediatric PK, safety and efficacy either with pharmacometric or physiologically based approaches can help design or in some cases reduce the need for clinical studies. Aspects to consider when extrapolating PK include the maturation of drug metabolizing enzyme expression, glomerular filtration, drug excretory systems, and the expression and activity of specific transporters in conjunction with other drug properties such as fraction unbound. Knowledge of these can be used to develop extrapolation tools such as allometric scaling plus maturation functions or physiologically based PK. PK/pharmacodynamic approaches and well-designed clinical trials in children are of key importance in paediatric drug development. In this white paper, state-of-the-art of current methods used for paediatric extrapolation will be discussed. This paper is part of a conect4children implementation of innovative methodologies including pharmacometric and physiologically based PK modelling in clinical trial design/paediatric drug development through dissemination of expertise and expert advice. The suggestions arising from this white paper should define a minimum set of standards in paediatric modelling and contribute to the regulatory science.
Authors 15
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Naïm Bouazza corresponding
Inserm · Université Paris Cité · Assistance Publique – Hôpitaux de Paris · Pharmacologie et évaluation thérapeutiques chez l'enfant et la femme enceinte · Centre d'Investigation Clinique Mère-Enfant Necker Cochin Paris Centre
Affiliation as printed
CIC‐1419 Inserm, Cochin‐Necker Paris France
Pediatric and Perinatal Drug Evaluation and Pharmacology Université Paris Cité Paris France
Unité de Recherche Clinique Université Paris Cité Necker‐Cochin, AP‐HP Paris France
Pediatric and Perinatal Drug Evaluation and Pharmacology Université Paris Cité Paris France
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National and Kapodistrian University of Athens
Affiliation as printed
Department of Pharmacy National and Kapodistrian University of Athens Athens Greece
Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
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Catherijne A. J. Knibbe Aachen Division of Systems Biomedicine and Pharmacology Leiden Academic Centre for Drug Research
Leiden University · St. Antonius Ziekenhuis
Affiliation as printed
Department of Clinical Pharmacy St. Antonius Hospital Nieuwegein The Netherlands
Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research Leiden University Leiden The Netherlands
Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands
Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
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Radboud University Nijmegen · Radboud University Medical Center · Erasmus MC - Sophia Children’s Hospital · Radboud Institute for Health Sciences
Affiliation as printed
Department of Intensive Care and Paediatric Surgery Erasmus MC‐Sophia Children's Hospital Rotterdam The Netherlands
Department of Pharmacology and Toxicology, Radboud Institute for Health Sciences Radboud University Medical Center Nijmegen The Netherlands
Department of Intensive Care and Paediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
Department of Pharmacology and Toxicology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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GlaxoSmithKline (United Kingdom)
Affiliation as printed
Clinical Pharmacology Modelling and Simulation GlaxoSmithKline plc London UK
Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline plc, London, UK
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Ghent University Hospital · Ghent University
Affiliation as printed
Department of Basic and Applied Medical Sciences Ghent University Ghent Belgium
Department of Pediatric Intensive Care Ghent University Hospital Ghent Belgium
Department of Pharmacy Ghent University Hospital Ghent Belgium
Department of Basic and Applied Medical Sciences, Ghent University, Ghent, Belgium
Department of Pediatric Intensive Care, Ghent University Hospital, Ghent, Belgium
Department of Pharmacy, Ghent University Hospital, Ghent, Belgium
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Affiliation as printed
Department of Bioanalysis, Faculty of Pharmaceutical Sciences University of Ghent Ghent Belgium
Department of Bioanalysis, Faculty of Pharmaceutical Sciences, University of Ghent, Ghent, Belgium
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Inserm · Université Paris Cité · Assistance Publique – Hôpitaux de Paris · Pharmacologie et évaluation thérapeutiques chez l'enfant et la femme enceinte · Centre d'Investigation Clinique Mère-Enfant Necker Cochin Paris Centre
Affiliation as printed
CIC‐1419 Inserm, Cochin‐Necker Paris France
Pediatric and Perinatal Drug Evaluation and Pharmacology Université Paris Cité Paris France
Unité de Recherche Clinique Université Paris Cité Necker‐Cochin, AP‐HP Paris France
Pediatric and Perinatal Drug Evaluation and Pharmacology Université Paris Cité Paris France
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Inserm · Université Paris Cité · Assistance Publique – Hôpitaux de Paris · Pharmacologie et évaluation thérapeutiques chez l'enfant et la femme enceinte · Centre d'Investigation Clinique Mère-Enfant Necker Cochin Paris Centre
Affiliation as printed
CIC‐1419 Inserm, Cochin‐Necker Paris France
Pediatric and Perinatal Drug Evaluation and Pharmacology Université Paris Cité Paris France
Unité de Recherche Clinique Université Paris Cité Necker‐Cochin, AP‐HP Paris France
Pediatric and Perinatal Drug Evaluation and Pharmacology Université Paris Cité Paris France
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Affiliation as printed
Department of Clinical Pharmacology Uppsala University Hospital Uppsala Sweden
Department of Clinical Pharmacology, Uppsala University Hospital, Uppsala, Sweden
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Affiliation as printed
Clinical Pharmacology and Pharmacometrics Janssen Research & Development Beerse Belgium
Clinical Pharmacology and Pharmacometrics Janssen Research & Development Beerse Belgium
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Shandong University · Shandong Provincial QianFoShan Hospital · Shandong First Medical University
Affiliation as printed
Clinical Research Centre The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital Jinan China
Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine Shandong University Jinan China
Department of Pharmacy The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital Jinan China
Clinical Research Centre, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
Department of Pharmacy, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China
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Affiliation as printed
Department of Bioanalysis, Faculty of Pharmaceutical Sciences University of Ghent Ghent Belgium
Department of Bioanalysis, Faculty of Pharmaceutical Sciences, University of Ghent, Ghent, Belgium
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Great Ormond Street Hospital · University College London
Affiliation as printed
Department of Pharmacy Great Ormond Street Hospital for Children London UK
Infection, Inflammation and Immunology UCL Great Ormond Street Institute of Child Health London UK
Department of Pharmacy, Great Ormond Street Hospital for Children, London, UK
Infection, Inflammation and Immunology, UCL Great Ormond Street Institute of Child Health, London, UK
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Inserm · Université Paris Cité · Assistance Publique – Hôpitaux de Paris · Pharmacologie et évaluation thérapeutiques chez l'enfant et la femme enceinte · Centre d'Investigation Clinique Mère-Enfant Necker Cochin Paris Centre
Affiliation as printed
CIC‐1419 Inserm, Cochin‐Necker Paris France
Pediatric and Perinatal Drug Evaluation and Pharmacology Université Paris Cité Paris France
Unité de Recherche Clinique Université Paris Cité Necker‐Cochin, AP‐HP Paris France
Pediatric and Perinatal Drug Evaluation and Pharmacology Université Paris Cité Paris France
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