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Clinical pharmacokinetic study of latrepirdine via in silico sublingual administration

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In recent decades, numerous in silico methodologies have been developed focused on the study of pharmacodynamic, pharmacokinetics and toxicological properties of drugs. The study of the pharmacokinetic behavior of new chemical entities is an essential part of the successful development of a new drug and Gastroplus™ is a simulation software used to predict the pharmacokinetic behavior of chemical entities. Latrepirdine is a drug that has been studied for Alzheimer's disease and Huntington's disease and later abandoned by the pharmaceutical industry already in the clinical trials because it has not demonstrated therapeutic efficacy. During this project, through Gastroplus™ simulations, it was possible to achieve predicted values of Cmax coincident with those found in clinical trials, showing its utility in the prediction of pharmacokinetic parameters. Besides, sublingual delivery has the potential to offer improved bioavailability by circumventing first-pass metabolism. This study used GastroPlus™ to simulate sublingual administration of latrepirdine and the results showed improvements in bioavailability and plasma concentrations achieved though this route of administration.

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Advanced compartmental absorption and transit


Absorption, distribution, metabolism, excretion


Absorption scale factor


Area under the curve

C max :

Maximum plasma concentration

T max :

The time after administration of a drug when the maximum plasma concentration is reached




Alzheimer's disease




Huntington disease




Physiologically Based Pharmacokinetic



P eff :

Effective permeability


Quantitative structure–activity relationship


Adverse reaction


ter in die


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NV thanks Dr. Terence Fullerton from Global Product Development (Pfizer, USA) for pharmacokinetic data from clinical study with latrepirdine.


This research was funded from “Fundação para a Ciência e Tecnologia” (FCT, Portugal and FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, in the framework of the project IF/00092/2014/CP1255/CT0004. NV thanks FCT by supporting these studies through project from National Funds, within CINTESIS, R&D Unit (reference UIDB/4255/2020).

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JS and NV conceived and planned the experiments. JS and NV carried out the experiments and planned and carried out the simulations. JS, LL and NV contributed to the interpretation of the results. JS and NV took the lead in writing the manuscript. All authors provided critical feedback and helped shape the research, analysis and manuscript.

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Correspondence to Nuno Vale.

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All authors have no conflicts of interest to disclose.

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Santos, J., Lobato, L. & Vale, N. Clinical pharmacokinetic study of latrepirdine via in silico sublingual administration. In Silico Pharmacol. 9, 29 (2021).

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