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Prediction of the Vitreal Half-Life of Small Molecular Drug-Like Compounds

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Abstract

Purpose

To build a fast, user-friendly computational model to predict the intravitreal half-lives of drug-like compounds.

Methods

We used multivariate analysis to build intravitreal half-life models using two data sets, one with experimental data derived from both pigmented and albino rabbits and another including only data from experiments with albino rabbits.

Results

The final models had a Q2 value of 0.65 and 0.75 for the mixed and albino rabbit models, respectively. The models performed well in predicting the intravitreal half-life of an external test set. In addition, the models are physiologically interpretable, containing mainly hydrogen bonding and lipophilicity descriptors.

Conclusion

The developed models enable reliable predictions of intravitreal half-lives for use in the early drug development stages, without the need for prior experimental data.

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Abbreviations

FRB:

freely rotatable bonds

HA:

number of hydrogen bond acceptors

HD:

number of hydrogen bond donors

Htot :

total number of putative hydrogen bonds, i.e. HD+HA

logP:

the logarithm of the octanol-water partition coefficient of the neutral form

log t½ :

the logarithm of the intravitreal half-life, logDx, the logarithm of the octanol-water partition coefficient at pH x

MW:

molecular weight

PCA:

principal component analysis

P-gp:

P-glycoprotein

PLS:

partial least squares

QSPR:

quantitative structure-property relationship

RMSE:

root mean squared error

RMSEP:

root mean squared error of prediction

VIP:

variable importance in the projection

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Acknowledgments and Disclosures

The Academy of Finland, Magnus Ehrnooth Foundation, Medicinska Understödsföreningen för Liv och Hälsa, Orion-Farmos Research Foundation, and the Graduate School in Pharmaceutical Research are acknowledged for their support.

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Author notes

  1. Kati-Sisko Vellonen

    Present address: School of Pharmacy, University of Eastern Finland, Kuopio, Finland

Authors and Affiliations

  1. Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, FIN-00014, Helsinki, Finland

    Heidi Kidron, Eva M. del Amo & Arto Urtti

  2. Division of Biopharmacy and Pharmacokinetics, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland

    Eva M. del Amo & Kati-Sisko Vellonen

Authors
  1. Heidi Kidron
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  2. Eva M. del Amo
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Correspondence to Heidi Kidron.

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Kidron, H., del Amo, E.M., Vellonen, KS. et al. Prediction of the Vitreal Half-Life of Small Molecular Drug-Like Compounds. Pharm Res 29, 3302–3311 (2012). https://doi.org/10.1007/s11095-012-0822-5

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  • DOI: https://doi.org/10.1007/s11095-012-0822-5

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