Authors: Lehr, Thorsten¹; Staab, Alexander²; Tillmann, Christiane²; Trommeshauser, Dirk²; Raschig, Andreas³; Schaefer, Hans Guenter²; Kloft, Charlotte

Source: British Journal of Clinical Pharmacology, Volume 64, Number 1, July 2007 , pp. 36-48(13)

Publisher: Wiley-Blackwell

Abstract:

What is already known about this subject

• Several studies in predominantly healthy subjects have investigated the pharmacokinetics of NS2330 and its major metabolite M1.

• However, its pharmacokinetics have not been characterized in Alzheimer's disease patients, the target population for NS2330.

• In addition, no covariates have previously been found to influence the plasma concentration-time profiles of NS2330 and/or M1.

What this study adds

• A descriptive and predictive population pharmacokinetic model for NS2330 and its metabolite was successfully developed in a population of patients with Alzheimer's disease.

• A covariate analysis elucidated sex and creatinine clearance as having an influence on the plasma concentration-time profiles of NS2330 after long-term treatment. Aims

To develop a population pharmacokinetic model for NS2330 and its major metabolite M1 based on data from a 14 week proof of concept study in patients with Alzheimer's disease, and to identify covariates that might influence the pharmacokinetic characteristics of the drug and/or its metabolite. Methods

Plasma data from 320 subjects undergoing multiple oral dosing, and consisting of 1969 NS2330 and 1714 metabolite concentrations were fitted simultaneously using NONMEM. Results

Plasma concentration-time profiles of NS2330 and M1 were best described by one-compartment models with first-order elimination for both compounds. Absorption of NS2330 was best modelled by a first-order process. Low apparent clearances together with large apparent volumes of distribution resulted in long half-lives of 234 h (NS2330) and 374 h (M1). The covariate analysis identified weight, sex, CL_CR, BMI and age as influencing the pharmacokinetics of NS2330 and/or M1. However, simulations performed revealed that only CL_CR and sex had a significant effect on the steady-state plasma concentration-time profiles. Females with a creatinine clearance of 35.6 ml min⁻¹ showed a 62% increased exposure compared with males without renal impairment. The robustness and accuracy of the model were demonstrated by the successful predictivity of an external dataset. Conclusions

A descriptive, robust and predictive model for NS2330 and its M1 metabolite was developed. Important covariates influencing pharmacokinetics were identified, which might guide the further development of NS2330 and optimize its long-term use in the treatment of Alzheimer's disease.

Keywords: active metabolite; Alzheimer's disease; NONMEM; NS2330; population pharmacokinetic modelling; sex

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1365-2125.2007.02855.x

Affiliations: 1: Freie Universitaet Berlin, Institute of Pharmacy, Department of Clinical Pharmacy, Kelchstrasse 31, 12169 Berlin, 2: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Drug Metabolism and Pharmacokinetics, 88397 Biberach an der Riss, 3: Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Clinical Research, 88397 Biberach an der Riss and

Publication date: 2007-07-01

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