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A Physiologically Based Pharmacokinetic Model for Ganciclovir and Its Prodrug Valganciclovir in Adults and Children

The AAPS Journal volume 18, pages 1453–1463 (2016)Cite this article

Abstract

A physiologically based pharmacokinetic (PBPK) model has been developed for ganciclovir and its prodrug valganciclovir. Initial bottom-up modeling based on physicochemical drug properties and measured in vitro inputs was verified in preclinical animal species, and then, a clinical model was verified in a stepwise fashion with pharmacokinetic data in adult, children, and neonatal patients. The final model incorporated conversion of valganciclovir to ganciclovir through esterases and permeability-limited tissue distribution of both drugs with active transport processes added in gut, liver, and kidney. A PBPK model which accounted for known age-related tissue volumes, composition and blood flows, and renal filtration clearance was able to simulate well the measured plasma exposures in adults and pediatric patients. Overall, this work illustrates the stepwise development of PBPK models which could be used to predict pharmacokinetics in infants and neonates, thereby assisting drug development in a vulnerable patient population where clinical data are challenging to obtain.

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Authors and Affiliations

  1. Simulations Plus, Inc., 42505 10th Street West, Lancaster, California, 93534, USA

    V. Lukacova

  2. Teva Pharmaceuticals, West Chester, Pennsylvania, 19380, USA

    P. Goelzer

  3. Array BioPharma, Boulder, Colorado, 80301, USA

    M. Reddy

  4. Clinical Pharmacology, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland

    G. Greig & B. Reigner

  5. Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland

    N. Parrott

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  1. V. Lukacova
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  2. P. Goelzer
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  3. M. Reddy
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  4. G. Greig
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  5. B. Reigner
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  6. N. Parrott
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Correspondence to N. Parrott.

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Lukacova, V., Goelzer, P., Reddy, M. et al. A Physiologically Based Pharmacokinetic Model for Ganciclovir and Its Prodrug Valganciclovir in Adults and Children. AAPS J 18, 1453–1463 (2016). https://doi.org/10.1208/s12248-016-9956-4

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  • DOI: https://doi.org/10.1208/s12248-016-9956-4

KEY WORDS

  • esterases
  • pediatrics
  • permeability limited distribution
  • physiologically based pharmacokinetic models