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Clinical pharmacokinetic study of latrepirdine via in silico sublingual administration

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Abstract

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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Abbreviations

ACAT:

Advanced compartmental absorption and transit

ADME:

Absorption, distribution, metabolism, excretion

ASF:

Absorption scale factor

AUC:

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

CL:

Clearance

AD:

Alzheimer's disease

GI:

Gastro-Intestinal

HD:

Huntington disease

NMDA:

N-Methyl-d-aspartate

PBPK:

Physiologically Based Pharmacokinetic

PK:

Farmacokinetic

P eff :

Effective permeability

QSAR:

Quantitative structure–activity relationship

AR:

Adverse reaction

TID:

ter in die

References

  • Benedetti MS, Whomsley R, Poggesi I, Cawello W, Mathy FX, Delporte ML et al (2009) Drug metabolism and pharmacokinetics. Drug Metab Rev 41(3):344–390

    Article  CAS  Google Scholar 

  • Bezprozvanny I (2010) The rise and fall of Dimebon. Drug News Perspect 23(8):518–523

    Article  Google Scholar 

  • Cherkasov A, Muratov EN, Fourches D, Varnek A, Igor I, Cronin M et al (2015) NIH public access. J Med Chem 57(12):4977–5010

    Article  Google Scholar 

  • Chew ML, Mordenti J, Yeoh T, Ranade G, Qiu R, Fang J et al (2016) Minimization of CYP2D6 polymorphic differences and improved bioavailability via transdermal administration: latrepirdine example. Pharm Res 33(8):1873–1880

    Article  CAS  Google Scholar 

  • Daga PR, Bolger MB, Haworth IS, Clark RD, Martin EJ (2018) Physiologically based pharmacokinetic modeling in lead optimization. 1. Evaluation and adaptation of gastroplus to predict bioavailability of medchem series. Mol Pharm.15(3):821–30.

  • Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO et al (2008) Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomised, double-blind, placebo-controlled study. Lancet 372(9634):207–215

    Article  CAS  Google Scholar 

  • Eckert SH, Gaca J, Kolesova N, Friedland K, Gunter P (2018) Mitochondrial pharmacology of dimebon (Latrepirdine) calls for a new look at its possible therapeutic potential in Alzheimer ’ s Disease. Aging Dis.

  • Ferreira A, Lapa R, Vale N (2019) Combination of gemcitabine with cell-penetrating peptides: a pharmacokinetic approach using in silico tools. Biomolecules 9(11):693

    Article  CAS  Google Scholar 

  • Harris D, Robinson JR (1992) Drug delivery via the mucous membranes of the oral cavity. J Pharm Sci 81(1):1–10

    Article  CAS  Google Scholar 

  • Hughes JP, Rees SS, Kalindjian SB, Philpott KL (2011) Principles of early drug discovery. Br J Pharmacol 162(6):1239–1249

    Article  CAS  Google Scholar 

  • Kostewicz ES, Aarons L, Bergstrand M, Bolger MB, Galetin A, Hatley O et al (2014) PBPK models for the prediction of in vivo performance of oral dosage forms. Eur J Pharm Sci 57(1):300–321

    Article  CAS  Google Scholar 

  • Kozlov S, Afonin A, Evsyukov I, Bondarenko A (2017) Alzheimer’s disease: as it was in the beginning. Rev Neurosci 28(8):825–843

    Article  CAS  Google Scholar 

  • Lombardo F, Desai P V, Arimoto R, Desino KE, Fischer H, Keefer CE, et al (2017) In silico absorption, distribution, metabolism, excretion, and pharmacokinetics (ADME-PK): utility and best practices. An industry perspective from the international consortium for innovation through quality in pharmaceutical development. J Med Chem 60(22):9097–9113.

  • Maddison JE, Page SW, Dyke TM (2008) Chapter 2—Clinical pharmacokinetics. In: Atkinson AJ, Abernethy DR, Daniels CE, Dedrick RL, Markey SPBT-P of CP (Second E, editors) Small animal clinical pharmacology.Academic Press, Burlington, p. 27–40

  • Matveeva IA (1983) Action of dimebon on histamine receptors. Farmakol Toksikol 46(4):27–29

    CAS  PubMed  Google Scholar 

  • Pelkonen O, Turpeinen M, Raunio H (2011) In vivo-in vitro-in silico pharmacokinetic modelling in drug development current status and future directions. Clin Pharmacokinet 50(8):483–491

    Article  CAS  Google Scholar 

  • Rehfeld A, Nylander M, Karnov K (2017) The digestive system II: the associated organs. Compen Histol:475–493.

  • Simulations Plus I (2011) GastroPlus Manual. 9294: 661–723

  • Toomula N, Sathish kumar D, Kumar A, Phaneendra M, (2011) Role of pharmacokinetic studies in drug discovery. J Bioequival Bioavail 3(11):263–7

    CAS  Google Scholar 

  • Vrbanac J, Slauter (2013) ADME in drug discovery. In: A Comprehensive Guide to Toxicology in Preclinical Drug Development. Elsevier Inc. pp 3–30.

  • Waller DG, Sampson AP (2018) Pharmacokinetics. In: Waller DG, Sampson APBT-MP and T (Fifth E, editors) Medical pharmacology and therapeutics [Internet]. Elsevier. pp 33–62.

  • Wang Y, Zuo Z, Chen X, Tomlinson B, Chow MSS (2010) European Journal of Pharmaceutical Sciences Improving sublingual delivery of weak base compounds using pH max concept: application to propranolol 39:272–278

  • Wang Y, Wang Z, Zuo Z, Tomlinson B, Lee BTK, Bolger MB, et al (2013) Clinical Pharmacokinetics of Buffered Propranolol Sublingual Tablet (PromptolTM)—application of a New “ Physiologically Based ” Model to Assess Absorption and Disposition. 15(3).

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Acknowledgments

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

Funding

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.

Corresponding author

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). https://doi.org/10.1007/s40203-021-00083-0

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