PLX038: a PEGylated prodrug of SN-38 independent of UGT1A1 activity
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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.
We measured CPT-11 and PLX038A metabolites in plasma and bile, and determined pharmacokinetics of PLX038A in UGT1A-deficient and replete rats.
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.
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.
KeywordsProdrug UGT1A1 SN-38 Pharmacokinetics Drug delivery
Compliance with ethical standards
Conflict of interest
Shaun D. Fontaine, Angelo D. Santi, Ralph Reid, Gary W. Ashley and Daniel V. Santi are all employees and shareholders of ProLynx LLC. Philip C. Smith is an employee of the Eshelman School of Pharmacy, University of North Carolina at Chapel Hill.
Research involving animals
All studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.
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