Population Pharmacokinetic (PK) Analysis of Laromustine, an Emerging Alkylating Agent, in Cancer Patients

Details

• Personal Author:
  King I ; Nassar AF ; Wisnewski AV
• Description:
  1. Alkylating agents are capable of introducing an alkyl group into nucleophilic sites on DNA or RNA through covalent bond. Laromustine is an active member of a relatively new class of sulfonylhydrazine prodrugs under development as antineoplastic alkylating agents, and displays significant single-agent activity. 2. This is the first report of the population pharmacokinetic analysis of laromustine, 106 patients, 66 with hematologic malignancies and 40 with solid tumors, participated in five clinical trials worldwide. Of these, 104 patients were included in the final NONMEM analysis. 3. The population estimates for total clearance (CL) and volume of distribution of the central compartment (V1) were 96.3 L/h and 45.9 L, associated with high inter-patient variability of 52.9% and 79.8% and inter-occasion variability of 26.7% and 49.3%, respectively. The population estimates for Q and V2 were 73.2 L/h and 29.9 L, and inter-patient variability in V2 was 63.1%, respectively. 4. The estimate of Vss (75.8 L) exceeds total body water, indicating that laromustine is distributed to tissues. The half-life is short, less than 1 h, reflecting rapid clearance. Population PK analysis showed laromustine pharmacokinetics to be independent of dose and organ function with no effect on subsequent dosing cycles. [Description provided by NIOSH]
• Subjects:
  Biopharmaceutics Neoplasms Occupational Health Safety
• Keywords:
  Alkylating Agent Alkylating Agents Antineoplastic Agents Author Keywords: Acute Myelogenous Leukemia Cancer Cancer Patients Cloretazine Pharmaceuticals Pharmacology Solid Tumors Tumors VNP40101M

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• ISSN:
  0049-8254
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Connecticut ; Delaware ; OSHA Region 1 ; OSHA Region 3
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  394-407
• Volume:
  47
• Issue:
  5
• NIOSHTIC Number:
  nn:20059505
• Citation:
  Xenobiotica 2017 May; 47(5):394-407
• Contact Point Address:
  Ala F. Nassar, Ph.D., Yale University, School of Medicine, 300 Cedar St/TAC s416, New Haven, CT 06510, USA
• Email:
  ala.nassar@yale.edu
• CAS Registry Number:
  Laromustine (CAS RN 173424-77-6)
• Federal Fiscal Year:
  2017
• NORA Priority Area:
  Manufacturing ; Construction
• Performing Organization:
  Yale University, New Haven, Connecticut
• Peer Reviewed:
  True
• Start Date:
  20160801
• Source Full Name:
  Xenobiotica
• End Date:
  20200731
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:5fc809c0226ca878d532c0c5b63db674db1e4816c6cc1f1c3751a85e23338a92f3986b0941e9f1b98e4812313c59edff88c48f24bdb6a5b7a39661674e02ba5b
• Download URL:
  https://stacks.cdc.gov/view/cdc/223705/cdc_223705_DS1.pdf
• File Type:
  [PDF - 1.00 MB ]