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Pharmacokinetics of IV LMP744, a Novel Topoisomerase 1 Inhibitor, in Humans

Deppas, Joshua (2020) Pharmacokinetics of IV LMP744, a Novel Topoisomerase 1 Inhibitor, in Humans. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

During transcription and replication, DNA is supercoiled creating tension and strain downstream of the replication site. To relax supercoiling, DNA topoisomerase 1 (TOP1) generates temporary DNA single-strand breaks resulting in the cleaved strands ability to rotate freely around the DNA double helix, thereby relieving strain. TOP1, which is responsible for genetic recombination and religation of cleaved DNA, is overexpressed in tumor cells and ultimately results in an intact DNA duplex. Pharmacological TOP1 inhibitors prevent tension relief and religation ultimately resulting in lethal DNA strand breaks leading to cell death.
Consequently, TOP1 is a clinically proven target for the management and treatment of various cancers in humans. Currently, the FDA has approved two analogue TOP1 inhibitors, topotecan and irinotecan, that are derived from a less potent predecessor, camptothecins. The clinical drawbacks of camptothecin analogs, include chemical instability, short half-lives and common dose-limiting adverse events. These limitations have resulted in the discovery and development of the indenoisoquinolines, a non-camptothecin family of TOP1 inhibitors. Of these derivatives, LMP744 has been identified as a possible therapeutic and is being investigated clinically.
To support clinical development of LMP744, plasma samples were collected and concentration-time data was generated using two LC-MS/MS assays. Data was collected from 17 different patients who received intravenous infusions of LMP744 ranging from 6 to 190 mg/m2. Noncompartmental and compartmental analyses were performed to obtain LMP744 pharmacokinetic parameters and to evaluate dose linearity. The effect of BSA and body weight on the clearance and volume of distribution of LMP744 were also evaluated. The data presented here will hopefully support the development of this drug that is currently in clinical trials conducted to identify the safety, tolerability, optimal dose, and efficacy of LMP744 in cancer patients.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Deppas, Joshuajod102@pitt.edu
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBeumer, Janbeumerjh@upmc.edu
Committee ChairVenkataramanan, Ramanrv@pitt.edu
Committee ChairRohan, Lisalrohan@mwri.magee.edu
Date: 8 September 2020
Date Type: Publication
Defense Date: 10 August 2020
Approval Date: 8 September 2020
Submission Date: 8 September 2020
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 69
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Topoisomerase, pharmacokinetics, LMP744
Date Deposited: 08 Sep 2020 19:07
Last Modified: 08 Sep 2020 19:07
URI: http://d-scholarship.pitt.edu/id/eprint/39701

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