Population pharmacokinetic and pharmacodynamic modelling of NS2330 and its major metabolite in Alzheimer's disease [Elektronische Ressource] / von Thorsten Lehr

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• Gesundheit

Informations

• Publié par: martin-luther-universitat_halle-wittenberg
• Publié le: 01 janvier 2006
• Nombre de lectures: 30
• Langue: English
• Poids de l'ouvrage: 6 Mo

Extrait

Dissertation
zur Erlangung des akademischen Grades
doctor rerum naturalium (Dr.rer.nat.)
Vorgelegt der
Mathematisch-Naturwissenschaftlich-Technischen Fakultät
der Martin-Luther-Universität Halle-Wittenberg
von Thorsten Lehr
geb. am 05.02.1977 in Hanau
Gutachter:
1. Prof. Dr. Charlotte Kloft
2. Prof. Dr. Reinhardt Neubert
3. Prof. Dr. Inaki Troconiz
Halle (Saale), 19. Juli 2006
urn:nbn:de:gbv:3-000010896
[http://nbn-resolving.de/urn/resolver.pl?urn=nbn%3Ade%3Agbv%3A3-000010896]

Meiner Mutter
in Liebe und Dankbarkeit
gewidmet.This thesis aims to contribute to a comprehensive characterisation of the pharmacokinetics
(PK) and pharmacodynamics (PD) of NS2330, a new compound under clinical development
for Alzheimer’s disease (AD), and its major metabolite M1 using the population PK/PD mo-
delling approach. Several PK and PD development questions were investigated in six different
modelling projects. The population PK properties of NS2330 and its metabolite were explored
in healthy volunteers and AD patients within projects I and II. The PK between healthy vol-
unteers and AD patients were comparable. Low clearances and large volumes of distributions
resulted in long terminal half-lives of more than 200 h for both compounds. Sex and crea-
tinine clearance were identified as important covariates influencing the steady-state plasma
concentrations of both compounds. Project III investigated whether an enterohepatic circula-
tion (EHC) serves as an explanation for the long half-life and a multiple peak phenomenon
of NS2330. Using a mechanistic modelling approach a generic EHC model was developed
capable of describing the multiple peak phenomenon as well as the long half-life. It was de-
monstrated that an EHC might be a plausible mechanism to account for both observations.
Simulations suggested that the interruption of the EHC might be an appropriate detoxifica-
tion method for NS2330. Project IV applied a mechanistic modelling approach investigating
the maximum impact of the inhibition of the CYP3A4 enzyme system by itraconazole on the
elimination of NS2330. This project revealed a significant reduction of the NS2330 clearance
by itraconazole, which might guide recommendations for the co-administration of CYP3A4
inhibiting drugs. The in vivo potency of the metabolite M1 in mice was explored within pro-
ject V using a PK/PD modelling approach. M1 showed a 4.1 - 5.0-fold lower in vivo potency
in mice in comparison to NS2330. This finding together with the approximately 60% lower
steady-state plasma concentrations of M1 in humans compared to NS2330 suggested that the
contribution of the metabolite M1 to the overall efficacy was probably low. Project VI, finally,
investigated the concentration-response relationship of NS2330 and M1 in mild AD patients.
Age and the baseline value of the efficacy parameter ADAS-COG were identified as import-
ant patient characteristics influencing the maximum achievable effect of both compounds in
mild AD patients. By application of the population PK/PD modelling approach a significant
contribution to the understanding of the PK and PD of NS2330 and M1 was achieved. The
models developed underline the necessity for population PK/PD modelling in clinical deve-
lopment in order to understand dose-concentration-response relationships. The models and
results can be used to scientifically interpret clinical results and to improve the planning of
further clinical studies for an optimized therapeutic use.
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