Back to Search Start Over

Population pharmacokinetic (PK) analysis of laromustine, an emerging alkylating agent, in cancer patients

Population pharmacokinetic (PK) analysis of laromustine, an emerging alkylating agent, in cancer patients

Authors :
Ala F. Nassar
Adam V. Wisnewski
Ivan King
Source :
Xenobiotica. 47:394-407
Publication Year :
2016
Publisher :
Informa UK Limited, 2016.

Abstract

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.

Details

ISSN :
13665928 and 00498254
Volume :
47
Database :
OpenAIRE
Journal :
Xenobiotica
Accession number :
edsair.doi.dedup.....7870469eee68582a312b7747699634c1
Full Text :
https://doi.org/10.1080/00498254.2016.1201703