Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1

S. J. Danson, P. Johnson, T. H. Ward, M. Dawson, O. Denneny, G. Dickinson, L. Aarons, A. Watson, D. Jowle, J. Cummings, L. Robson, Gavin Halbert, C. Dive, M. Ranson

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Abstract

This trial describes a first-in-man evaluation of RH1, a novel bioreductive drug activated by DT-diaphorase (DTD), an enzyme overexpressed in many tumours.  A dose-escalation phase I trial of RH1 was carried out. The primary objective was to establish the maximum tolerated dose (MTD) of RH1. Secondary objectives were assessment of toxicity, pharmacokinetic determination of RH1 and pharmacodynamic assessment of drug effect through measurement of DNA cross linking in peripheral blood mononuclear cells (PBMCs) and tumour, DTD activity in tumour and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphism status.  Eighteen patients of World Health Organization performance status of zero to one with advanced refractory solid malignancies were enrolled. MTD was 1430 mu g/m(2)/day with reversible bone marrow suppression being dose limiting. Plasma pharmacokinetic analysis showed RH1 is rapidly cleared from blood (t(1/2) = 12.3 min), with AUC increasing proportionately with dose. The comet-X assay demonstrated dose-related increases in DNA cross linking in PBMCs. DNA cross linking was demonstrated in tumours, even with low levels of DTD. Only one patient was homozygous for NQO1 polymorphism precluding any conclusion of its effect.
RH1 was well tolerated with predictable and manageable toxicity. The MTD of 1430 mu g/m(2)/day is the dose recommended for phase II trials. The biomarkers of DNA cross linking, DTD activity and NQO1 status have been validated and clinically developed.

Original languageEnglish
Pages (from-to)1653-1660
Number of pages8
JournalAnnals of Oncology
Volume22
Issue number7
Early online date4 Mar 2011
DOIs
Publication statusPublished - Jul 2011

Keywords

  • chemotherapy
  • DT-diaphorase
  • pharmacodynamic
  • pharmacokinetic
  • phase I
  • RH1
  • nadph cytochrome-P450 reductase
  • DNA cross-linking
  • antitumor quinones
  • cell-lines
  • oxidoreductases
  • NAD(P)H
  • agent
  • cytotoxicity
  • activation

Cite this

Danson, S. J., Johnson, P., Ward, T. H., Dawson, M., Denneny, O., Dickinson, G., Aarons, L., Watson, A., Jowle, D., Cummings, J., Robson, L., Halbert, G., Dive, C., & Ranson, M. (2011). Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1. Annals of Oncology, 22(7), 1653-1660. https://doi.org/10.1093/annonc/mdq638