Trial reportBritish journal of clinical pharmacology2007
Population pharmacokinetic modelling of NS2330 (tesofensine) and its major metabolite in patients with Alzheimer's disease.
Trial report in British journal of clinical pharmacology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
10 citing papers in PubMed, 20 citations in OpenAlex.
- Integrated Population Pharmacokinetics of Daprodustat in Patients with Chronic Kidney Disease with Anemia.Clinical pharmacokinetics · 2024Trial
- Quantitative pharmacology approach in Alzheimer's disease: efficacy modeling of early clinical data to predict clinical outcome of tesofensine.The AAPS journal · 2010Trial
- A quantitative enterohepatic circulation model: development and evaluation with tesofensine and meloxicam.Clinical pharmacokinetics · 2009Trial
- Population Pharmacokinetic Analysis of Quizartinib in Healthy Volunteers and Patients With Relapsed/Refractory Acute Myeloid Leukemia.Journal of clinical pharmacology · 2020Article
- Population pharmacokinetics of modafinil acid and estimation of the metabolic conversion of modafinil into modafinil acid in 5 major ethnic groups of China.Acta pharmacologica Sinica · 2012Article
- New acetylcholinesterase inhibitors for Alzheimer's disease.International journal of Alzheimer's disease · 2012Article
- Substrate and drug binding sites in LeuT.Current opinion in structural biology · 2010Review
- Semi-mechanistic population pharmacokinetic drug-drug interaction modelling of a long half-life substrate and itraconazole.Clinical pharmacokinetics · 2010Article
- Antidepressant specificity of serotonin transporter suggested by three LeuT-SSRI structures.Nature structural & molecular biology · 2009Article
- Contribution of the active metabolite M1 to the pharmacological activity of tesofensine in vivo: a pharmacokinetic-pharmacodynamic modelling approach.British journal of pharmacology · 2008Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsTo 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.
methodsPlasma data from 320 subjects undergoing multiple oral dosing, and consisting of 1969 NS2330 and 1714 metabolite concentrations were fitted simultaneously using NONMEM.
resultsPlasma 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.
conclusionsA 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.
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