Advanced population pharmacokinetic modelling to quantify selected characteristics of drugs [Elektronische Ressource] / vorgelegt von Khaled Mohammed Abdulwahab Abduljalil

Khaled Mohammed Abdulwahab Abduljalil

Sujets

• Gesundheit

Informations

• Publié par: rheinische_friedrich-wilhelms-universitat_bonn
• Publié le: 01 janvier 2010
• Nombre de lectures: 31
• Langue: Deutsch
• Poids de l'ouvrage: 1 Mo

Extrait

ADVANCED POPULATION PHARMACOKINETIC MODELLING TO QUANTIFY
SELECTED CHARACTERISTICS OF DRUGS




Dissertation
zur
Erlangung des Doktorgrades (Dr. rer. nat.)
der
Mathematisch-Naturwissenschaftlichen Fakultät
der
Rheinischen Friedrich-Wilhelms-Universität Bonn



vorgelegt von

Khaled Mohammed Abdulwahab Abduljalil
aus
Taiz-Jemen


Bonn, Februar 2010


















Angefertigt mit Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät
der Rheinischen Friedrich-Wilhelms-Universität Bonn
Am Pharmakologichem Institut der Universität zu Köln




1. Gutachter
Prof. Dr. Richard Süverkrüp
Pharmazeutisches Institut der Universitat Bonn,
Pharmazeutische Technologie,
Gerhard-Domagk-Straße
53121 Bonn,
Germany

2. Gutachter
Prof. med. Dr. Uwe Fuhr
Klinikum der Universität zu Köln,
Institut für Pharmakologie, Klinische Pharmakologie
Gleueler Straße 24,
50931 Köln
Germany



Tag der Promotion: 26.07.2010
Erscheinungsjahr: 2010





IN DER DISSERTATION EINGEBUNDEN:
Zusammenfassung
Lebenslauf



ii

























For obtaining the doctorate degree in pharmacy
Pharmaceutical Technology Section
Department of Pharmacy,
Faculty of Mathematics and Natural Science
University of Bonn
Germany



Doctoral Thesis 2010
Department of Pharmacology
University of Cologne
Germany








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To my parents






iv

Publications
This thesis is based on the following papers:

 Abduljalil K, Diestelhorst M, Doroshyenko O, Lux A, Steinfeld A, Dinslage S, Süverkrüp R,
Fuhr U.Modelling ocular pharmacokinetics of fluorescein administered as lyophilisate or
conventional eye drops. Eur J Clin Pharmacol. 2008 May;64(5):521-9.

 Abduljalil K, Kinzig M, Bulitta J, Horkovics-Kovats S, Sörgel F, Rodamer M, Fuhr U.
Modeling the autoinhibition of clarithromycin metabolism during repeated oral
administration. Antimicrob Agents Chemother. 2009 Jul;53(7):2892-901.

 Abduljalil K, Frank D, Gaedigk A, Klaasse T, Tomalik-Scharte D, Jetter A, Jaehde U,
Kirchheiner J, Fuhr U. Activity assessment for individual CYP2D6 alleles by population
pharmacokinetics of dextromethorphan. To be submitted to Clin Pharmacol Ther

 Abduljalil K, Stehle S, Zadoyan G, Schwab M, Lazar A, Tomalik-Scharte D, Kirchheiner J,
Gleiter C, Harenberg J, Wu W, Fuhr U. Prospective evaluation of the pharmacogenetics
component in pharmacokinetics and pharmacodynamics of steady state
phenprocoumon. To be submitted to Clin Pharmacol Ther
v
CONTENTS
1 INTRODUCTION ....................................................................................................................................... 1
1.1 GENERAL INTRODUCTION ........................... 1
1.2 AIM OF THE THESIS .. 3
1.3 OVERVIEW OF POPULATION APPROACHES ...................................................................................................... 4
1.3.1 Definitions.................................. 4
1.3.2 Theory of Population Approach .. 5
1.3.3 Software .... 6
1.3.4 Types of Models ......................................................................................................................... 6
1.3.5 Model Development and Evaluation Strategies ........... 7
1.3.6 Properties of the Final Model ...................................... 8
1.4 POTENTIAL EXAMPLES OF MODELLING PHARMACOKINETIC-PHARMACODYNAMIC PROCESSES ..... 8
1.4.1 Absorption ................................................................................................. 8
1.4.2 Distribution .............................. 10
1.4.3 Clearance ................................. 10
1.4.3.1 Variability in renal clearance .......... 10
1.4.3.2 Variability in hepatic clearance ...................................................................... 11
1.4.4 Metabolites.............................................................. 12
1.4.5 Modelling Drug Response ......................................................................... 13
1.5 CHARACTERISTICS OF PROBE DRUGS ........................................... 15
1.5.1 Chemical Structures.................. 16
1.5.2 Bioavailability of Fluorescein for Ocular Administration ............................................................ 17
1.5.3 Clarithromycin and Autoinhibition of Metabolism ..................................... 19
1.5.4 The Use of Dextromethorphan as a CYP2D Phenotyping Drug ................... 22
1.5.5 Understanding Variability in Phenprocoumon Response 25
2 MATERIALS AND METHODS .................................................................................................................. 29
2.1 FLUORESCEIN DATA ................................ 30
2.1.1 Clinical Studies and Ethical Conduct .......................... 30
2.1.2 Measurements and Variables ................................................................... 30
2.2 CLARITHROMYCIN DATA ................................ 31
2.2.1 Clinical Studies and Ethical Conduct .......................... 31
2.2.2 Measurements and Variables ................................... 32
2.3 DEXTROMETHORPHAN DATA .................................................................................... 33
2.3.1 Clinical Studies and Ethical Conduct .......................... 33
2.3.2 Measurements and Variables ................................................................... 33
2.4 PHENPROCOUMON DATA ........................................................ 35
2.4.1 Clinical Studies and Ethical Conduct .......................... 35
2.4.2 Measurements and Variables ................................... 35
2.5 DATA ANALYSIS ..................................................................................................... 37
2.5.1 Software .. 37
2.5.2 Model Justifications.................................................................................. 38
2.5.3 Covariate Analyses ................................................... 39
2.5.4 Statistical Models ..................... 39
2.5.5 Fluorescein Data Analysis ......................................................................... 40
2.5.6 Clarithromycin Data Analysis .................................... 41
2.5.7 Dextromethorphan Data Analysis ............................. 43
2.5.8 Phenprocoumon Data Analysis . 44
3 RESULTS ................................................................................................................................................ 47
3.1 FLUORESCEIN ........ 48
3.2 CLARITHROMYCIN .................................................................................................................................. 59
3.3 DEXTROMETHORPHAN ............................ 75
3.4 PHENPROCOUMON 90
4 DISCUSSION ........................................................................................................................................ 103
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4.1 FLUORESCEIN ...................................................................................................................................... 104
4.2 CLARITHROMYCIN 106
4.3 DEXTROMETHORPHAN .......................... 109
4.4 PHENPROCOUMON .............................................................................................................................. 111
5 CONCLUSIONS ..................................... 115
5.1 FLUORESCEIN ...... 116
5.2 CLARITHROMYCIN ................................................................................................ 116
5.3 DEXTROMETHORPHAN .......................... 117
5.4 PHENPROCOUMON .............................. 117
6 SUMMARY .......................................................................................................................................... 118
7 REFERENCES: ....... 120
8 ACKNOWLEDGMENTS ......................................................................................................................... 141
9 CURRICULUM VITAE ............................ 106




















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INTRODUCTION

1 INTRODUCTION
1.1 General Introduction
A drug profile is continuously refined and qualified with progressive understanding of its
pharmacokinetics (PK) and pharmacodynamics (PD). Traditionally, understanding of PK [PD]
behaviour has been based on fitting a mathematical model to da