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

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

LanguageEnglish
Pages1653-1660
Number of pages8
JournalAnnals of Oncology
Volume22
Issue number7
Early online date4 Mar 2011
DOIs
Publication statusPublished - Jul 2011

Fingerprint

NAD(P)H Dehydrogenase (Quinone)
Pharmacokinetics
Maximum Tolerated Dose
Pharmaceutical Preparations
DNA
Neoplasms
Blood Cells
Comet Assay
NAD
Area Under Curve
Oxidoreductases
Biomarkers
Bone Marrow
Enzymes

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., ... 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
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, Gavin ; Dive, C. ; Ranson, M. / Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1. In: Annals of Oncology. 2011 ; Vol. 22, No. 7. pp. 1653-1660.
@article{6ba0964f3cee446db2ebc76e1593ab4a,
title = "Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1",
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.",
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",
author = "Danson, {S. J.} and P. Johnson and Ward, {T. H.} and M. Dawson and O. Denneny and G. Dickinson and L. Aarons and A. Watson and D. Jowle and J. Cummings and L. Robson and Gavin Halbert and C. Dive and M. Ranson",
year = "2011",
month = "7",
doi = "10.1093/annonc/mdq638",
language = "English",
volume = "22",
pages = "1653--1660",
journal = "Annals of Oncology",
issn = "1569-8041",
number = "7",

}

Danson, SJ, Johnson, P, Ward, TH, 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, vol. 22, no. 7, pp. 1653-1660. https://doi.org/10.1093/annonc/mdq638

Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1. / 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, Gavin; Dive, C.; Ranson, M.

In: Annals of Oncology, Vol. 22, No. 7, 07.2011, p. 1653-1660.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1

AU - Danson, S. J.

AU - Johnson, P.

AU - Ward, T. H.

AU - Dawson, M.

AU - Denneny, O.

AU - Dickinson, G.

AU - Aarons, L.

AU - Watson, A.

AU - Jowle, D.

AU - Cummings, J.

AU - Robson, L.

AU - Halbert, Gavin

AU - Dive, C.

AU - Ranson, M.

PY - 2011/7

Y1 - 2011/7

N2 - 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.

AB - 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.

KW - chemotherapy

KW - DT-diaphorase

KW - pharmacodynamic

KW - pharmacokinetic

KW - phase I

KW - RH1

KW - nadph cytochrome-P450 reductase

KW - DNA cross-linking

KW - antitumor quinones

KW - cell-lines

KW - oxidoreductases

KW - NAD(P)H

KW - agent

KW - cytotoxicity

KW - activation

U2 - 10.1093/annonc/mdq638

DO - 10.1093/annonc/mdq638

M3 - Article

VL - 22

SP - 1653

EP - 1660

JO - Annals of Oncology

T2 - Annals of Oncology

JF - Annals of Oncology

SN - 1569-8041

IS - 7

ER -

Danson SJ, Johnson P, Ward TH, Dawson M, Denneny O, Dickinson G et al. Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1. Annals of Oncology. 2011 Jul;22(7):1653-1660. https://doi.org/10.1093/annonc/mdq638