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Cancer Chemotherapy and Pharmacology

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01-01-2020 | Pharmacokinetics | Short Communication

PLX038: a PEGylated prodrug of SN-38 independent of UGT1A1 activity

Authors: Shaun D. Fontaine, Angelo D. Santi, Ralph Reid, Philip C. Smith, Gary W. Ashley, Daniel V. Santi

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2020

Abstract

Purpose

The purpose of this study was to determine the importance of UGT1A1 activity on the metabolism and pharmacokinetics of a releasable PEG ~ SN-38 conjugate, PLX038A. Irinotecan (CPT-11) is converted to the topoisomerase 1 inhibitor SN-38 by first-pass hepatic metabolism and is converted to its glucuronide SN-38G by UGT1A1. With diminished UGT1A1 activity, the high liver exposure to SN-38 can cause increased toxicity of CPT-11. In contrast, releasable PEG ~ SN-38 conjugates—such as PLX038—release SN-38 in the vascular compartment, and only low levels of SN-38 are expected to enter the liver by transport through the OATP1B1 transporter.

Methods

We measured CPT-11 and PLX038A metabolites in plasma and bile, and determined pharmacokinetics of PLX038A in UGT1A-deficient and replete rats.

Results

Compared to CPT-11, treatment of rats with PLX038A results in very low levels of biliary SN-38 and SN-38G, a low flux through UGT1A, and a low SN-38G/SN-38 ratio in plasma. Further, the pharmacokinetics of plasma PLX038A and SN-38 in rats deficient in UGT1A is unchanged compared to normal rats.

Conclusions

The disposition of PEGylated SN-38 is independent of UGT1A activity in rats, and PLX038 may find utility in full-dose treatment of patients who are UGT1A1*28 homozygotes or have metastatic disease with coincidental or incidental liver dysfunction.

Available only for authorised users

The nomenclature uses all capitals for human UGTs, while for other species only the U is capitalized.

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Title: PLX038: a PEGylated prodrug of SN-38 independent of UGT1A1 activity
Authors: Shaun D. Fontaine
Angelo D. Santi
Ralph Reid
Philip C. Smith
Gary W. Ashley
Daniel V. Santi
Publication date: 01-01-2020
Publisher: Springer Berlin Heidelberg
Keyword: Pharmacokinetics
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2020
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03987-z

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Abstract

Purpose

Methods

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Conclusions

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