Population pharmacokinetic modelling of NS2330 (tesofensine) and its major metabolite in patients with Alzheimer's disease.
OBJECTIVE
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.
Lehr
Thorsten
T
Freie Universitaet Berlin, Institute of Pharmacy, Department of Clinical Pharmacy, Kelchstrasse 31, 12169 Berlin, Germany.
Staab
Alexander
A
Tillmann
Christiane
C
Trommeshauser
Dirk
D
Raschig
Andreas
A
Schaefer
Hans Guenter
HG
Kloft
Charlotte
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D017322:Clinical Trials, Phase II as Topic; D003404:Creatinine / Q000097:blood / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012737:Sex Factors
D019086:Bridged Bicyclo Compounds, Heterocyclic; D003404:Creatinine; C518479:Tesofensine