Design of optimized hypoxia-activated prodrugs using pharmacokinetic/pharmacodynamic modeling

Show simple item record Foehrenbacher, A en Secomb, TW en Wilson, William en Hicks, Kevin en
dc.coverage.spatial Switzerland en 2017-11-30T01:07:59Z en 2013-12-11 en 2013-12-27 en
dc.identifier.citation Frontiers in Oncology 3:17 pages Article number 314 27 Dec 2013 en
dc.identifier.issn 2234-943X en
dc.identifier.uri en
dc.description.abstract Hypoxia contributes to resistance of tumors to some cytotoxic drugs and to radiotherapy, but can in principle be exploited with hypoxia-activated prodrugs (HAP). HAP in clinical development fall into two broad groups. Class I HAP (like the benzotriazine N-oxides tirapazamine and SN30000), are activated under relatively mild hypoxia. In contrast, Class II HAP (such as the nitro compounds PR-104A or TH-302) are maximally activated only under extreme hypoxia, but their active metabolites (effectors) diffuse to cells at intermediate O2 and thus also eliminate moderately hypoxic cells. Here, we use a spatially resolved pharmacokinetic/pharmacodynamic (SR-PK/PD) model to compare these two strategies and to identify the features required in an optimal Class II HAP. The model uses a Green's function approach to calculate spatial and longitudinal gradients of O2, prodrug, and effector concentrations, and resulting killing in a digitized 3D tumor microregion to estimate activity as monotherapy and in combination with radiotherapy. An analogous model for a normal tissue with mild hypoxia and short intervessel distances (based on a cremaster muscle microvessel network) was used to estimate tumor selectivity of cell killing. This showed that Class II HAP offer advantages over Class I including higher tumor selectivity and greater freedom to vary prodrug diffusibility and rate of metabolic activation. The model suggests that the largest gains in class II HAP antitumor activity could be realized by optimizing effector stability and prodrug activation rates. We also use the model to show that diffusion of effector into blood vessels is unlikely to materially increase systemic exposure for realistic tumor burdens and effector clearances. However, we show that the tumor selectivity achievable by hypoxia-dependent prodrug activation alone is limited if dose-limiting normal tissues are even mildly hypoxic. en
dc.language eng en
dc.publisher Frontiers Media en
dc.relation.ispartofseries Frontiers in Oncology en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from en
dc.rights.uri en
dc.rights.uri en
dc.subject PR-104 en
dc.subject bystander effect en
dc.subject extravascular drug transport en
dc.subject hypoxia-activated prodrugs en
dc.subject pharmacokinetic/pharmacodynamic modeling en
dc.subject rational drug design en
dc.subject tirapazamine en
dc.subject tumor hypoxia en
dc.title Design of optimized hypoxia-activated prodrugs using pharmacokinetic/pharmacodynamic modeling en
dc.type Journal Article en
dc.identifier.doi 10.3389/fonc.2013.00314 en
pubs.volume 3 en
dc.description.version VoR - Version of Record en
dc.rights.holder Copyright: The author en
dc.identifier.pmid 24409417 en
pubs.publication-status Published online en
dc.rights.accessrights en
pubs.subtype Article en
pubs.elements-id 424085 en Science en Science Research en Maurice Wilkins Centre (2010-2014) en
pubs.number 314 en
pubs.record-created-at-source-date 2017-11-30 en
pubs.dimensions-id 24409417 en

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