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

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 V_ss (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.

• Acute myelogenous leukemia
• alkylating agent
• cancer patients
• solid tumors
• VNP40101M (Cloretazine)

Acknowledgements

These studies were done at ICON Development Solutions, Skelton House, Manchester Science Park, Lloyd Street North, Manchester M15 6SH, UK for Vion Pharmaceuticals Inc. We would like to thank Drs. Maria Pitsiu and Ziad Hussein of ICON, Miganush Stepanians and Nicole LaVallee of PROMETRIKA for performing and supervising these studies. We would like to thank Ray F. Nassar for helping in the editing process.

In Memoriam to Dr. Alan C. Sartorelli. Alan C. Sartorelli, Ph.D. was a professor of pharmacology for over 50 years at Yale School of Medicine, director of the Yale Comprehensive Cancer Center and chair of the Department of Pharmacology. His career highlights include receiving the Yale Comprehensive Cancer Center Lifetime Achievement Award in 2011, the Otto Krayer Award in Pharmacology in 2002, the Experimental Therapeutics Award from the American Society of Pharmacology and Experimental Therapeutics, also in 2002, the Bruce F. Cain Memorial Award in 2001, and the Mike Hogg Award from the UTMD Anderson Cancer Center in 1989. Dr. Sartorelli authored and coauthored over 700 papers published in various scientific journals, and was the founding editor of Pharmacology and Therapeutics, and co-inventor on 16 U.S. patents for anti-cancer therapy. Laromustine is one of the compounds which was invented in his laboratory and has entered into advanced clinical trials.

Declaration of interest

We declare no financial conflict of interest.

Supplementary material available online

Please see Tables 1–8 and Figures 1–4 in the supplementary file for more details about the methods and data used in the manuscript.