Population Pharmacokinetic and Pharmacodynamic Modelling and Simulation of Linagliptin, a Novel Dipeptidyl-Peptidase 4 Inhibitor for the Treatment of Type 2 Diabetes [Elektronische Ressource] / Silke Retlich

Silke Retlich

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• Gesundheit

Informations

• Publié par: rheinische_friedrich-wilhelms-universitat_bonn
• Publié le: 01 janvier 2010
• Nombre de lectures: 57
• Langue: Deutsch
• Poids de l'ouvrage: 8 Mo

Extrait

Population Pharmacokinetic and Pharmacodynamic
Modelling and Simulation of Linagliptin,
a Novel Dipeptidyl-Peptidase 4 Inhibitor
for the Treatment of Type 2 Diabetes


Dissertation

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

vorgelegt von

Silke Retlich
geboren in Schorndorf, Deutschland









Bonn 2010

Angefertigt mit Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät
der Rheinischen Friedrich-Wilhelms-Universität Bonn.

















Erstgutachter: Prof. Dr. Ulrich Jaehde
Zweitgutachter: Prof. Dr. Charlotte Kloft
Tag der mündlichen Prüfung: 15. Juli 2010
Erscheinungsjahr: 2010
iii














Für Mama.












iv Table of Contents
Table of Contents
List of abbreviations .............................................................................................................vi
Acknowledgements ............................................................................................................. xii
1 Introduction.................................................................................................................. 1
1.1 Type 2 diabetes mellitus ................................................................................................. 1
1.2 New treatment options based on incretins.................................................................... 4
1.3 Linagliptin ....................................................................................................................... 7
1.4 Pharmacometrics in drug development ...................................................................... 13
1.5 Aim of the work............................................................................................................. 16
2 Methods and studies ................................................................................................... 18
2.1 Data acquisition............................................................................................................. 18
2.2 Datasets.......................................................................................................................... 21
2.3 Population analysis ....................................................................................................... 24
2.4 Statistical data analysis................................................................................................. 35
2.5 Project characteristics .................................................................................................. 36
3 Results......................................................................................................................... 60
3.1 Project 1: Population pharmacokinetic/pharmacodynamic analysis of
linagliptin in type 2 diabetic patients .......................................................................... 60
3.2 Project 2: Clinical trial simulations to support the development of linagliptin ...... 73
3.3 Project 3: Covariate analysis ....................................................................................... 82
3.4 Project 4: Estimation of the absolute bioavailability of linagliptin .......................... 96
3.5 Project 5: Model-based pharmacokinetic analysis of linagliptin in wildtype
and DPP-4-deficient rats ............................................................................................ 101 Table of Contents v

4 Discussion ................................................................................................................. 110
4.1 Nonlinear pharmacokinetics of linagliptin ............................................................... 110
4.2 Characterisation of the pharmacokinetics and the pharmacokinetic/
pharmacodynamic relationship of linagliptin .......................................................... 120
4.3 Clinical trial simulations to support the development of linagliptin...................... 131
4.4 Absolute bioavailability of linagliptin ....................................................................... 134
4.5 Impact of pharmacometrics on the drug development of linagliptin..................... 136
Summary ........................................................................................................................... 140
References......................................................................................................................... 142
Appendix ........................................................................................................................... 158
Statutory declaration ........................................................................................................ 205


vi List of abbreviations
List of abbreviations
°C degree Celsius
ACE angiotensin-converting enzyme
AIC Akaike information criterion
ALAG lag time
ALT alanine transaminase
A amount of binding partner in the peripheral compartment max,P
AP alkaline phosphatase
AST aspartate transaminase
AUC area under the plasma concentration-time curve
AUC area under the plasma concentration-time curve from time point 0 to 24 0-24h
hours
AUC area under the plasma concentration-time curve of one day at steady-state 24h,SS
AUC area under the plasma concentration-time curve from time point 0 to 0-inf
infinity
AUC area under the plasma concentration-time curve of one dosing interval
AUC area under the plasma concentration-time curve at steady-state of one ,ss
dosing interval
BCS biopharmaceutics classification system
bid bis in die (twice daily)
BIL total bilirubin
B concentration of binding partner in the central compartment max,C
BMI body mass index
BSA body surface area
BSL pre-dose DPP-4 activity (parameter estimate)
plasma concentration of linagliptin bound to DPP-4 CBplasmaList of abbreviations vii

CHOL cholesterol
CK creatine kinase
CL clearance
C maximum linagliptin plasma concentration max
CRCL creatinine clearance
CRF case report form
CRP C-reactive protein
C trough plasma concentration, i.e. concentration at the end of the dosing trough
interval, taken directly before next administration
CU unbound plasma linagliptin concentration plasma
CV% coefficient of variation
CYP cytochrome P450
df degree of freedom
DPP pre-dose DPP-4 activity in RFU
DPP-4 dipeptidyl-peptidase 4
DPP-8 dipeptidyl-peptidase 8
DPP-9 dipeptidyl-peptidase 9
EC concentration resulting in half-maximum effect 50
EC concentration resulting in 80% DPP-4 inhibition 80%
ECG electrocardiogram
EDTA ethylendiaminetetraacetic acid
E maximum effect max
EMEA European Medicines Agency
F bioavailability
FDA U.S. Food and Drug Administration
fe fraction excreted
viii List of abbreviations
FO first-order estimation method
FOCE first-order conditional estimation method
FOCE-I first-order conditional estimation method with interaction
FPG fasting plasma glucose
fu fraction unbound
gMean geometric mean
GAM generalised additive modelling
gCV geometric coefficient of variation
GGT gamma glutamyl transferase
GIP glucose-dependent insulinotropic peptide
GLP-1 glucagon-like peptide 1
HGT height
HPLC-MS/MS high performance liquid chromatography coupled to tandem mass
spectrometry
HV healthy volunteers
IC concentration leading to half-maximal inhibition 50
i.v. intravenous
K absorption rate constant a
K dissociation constant d
K dissociation rate constant OFF
K association rate constant ON
L litre
M mol/L
min minute
NA not applicable
nc nonclinical
OCT2 organic cation transporter 2 List of abbreviations ix

OBJF objective function
OGTT oral glucose tolerance test
p probability
PD pharmacodynamic
PK pharmacokinetic
p.o. peroral
qd quaque die (every day, once daily)
Q intercompartmental clearance between central and peripheral compart-P
ment
Q intercompartmental clearance between central and first peripheral P1
compartment
Q intercompartmental clearance between central and second peripheral P2
compartment
R accumulation ratio based on area under the plasma concentration-time A, AUC
curve
RFU relative fluorescence units
RSE relative standard error
SCR serum creatinine
SD single dose
SD standard deviation
SS steady-state
t terminal half-life 1/2
T2D type 2 diabetic patients
t time of maximum plasma concentration max
TRIG triglycerides
V central volume of distribution C
V volume of distribution of the peripheral compartment P
x List of abbreviations
V volume of distribution of the first peripheral compartment P1
V volume of distribution of the second peripheral compartment P2
V vol