2007 - København - Denmark

PAGE 2007: Applications- Oncology
Gemma Dickinson

Population pharmacokinetics of a novel anticancer drug, RH1, in terminal cancer patients.

Dickinson GL (1), Dawson M (2), Ward TH (2), Danson S (3), Ranson M (2), Dive C (2), Aarons L (1).

(1) University of Manchester, UK; (2) Paterson Institute for Cancer Research, Manchester, UK; (3) Christie Hospital, Manchester, UK

Introduction & Objectives: RH1 (2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone) is a new bioreductive drug that has been developed as a cytotoxic agent with selectivity for solid tumour cells. The aim of the current study was to characterise the population pharmacokinetics (PK) of RH1 in a cancer patient population and explore the influence of patient covariates on drug disposition.

Methods: Eighteen patients affected by a number of different types of cancer were recruited to the study. PK data after intravenous dosing of patients were obtained during Phase I clinical development of RH1. Five daily doses of 40-1430 mcg/m2 were administered via intravenous (i.v.) infusion over 10-30 minutes with sampling on days 1 and 5 of treatment. Samples were analysed using HPLC methodology. A population PK analysis was performed using NONMEM version V. Extensive demographic (e.g. body weight, height, body surface area, age) and biochemical (e.g. creatinine clearance) data were recorded and examined as possible covariates to explain inter-individual variability in the PK of RH1.

Results: The plasma concentrations of RH1 were best described by a two compartment model with first order elimination from the central compartment. Body weight was identified as a covariate affecting clearance only. Other potential covariates had no impact on the objective function or fit of the data. The population PK parameters and the interindividual variabilities expressed as the coefficient of variation were: CL (total body clearance) = 3.1 L/h (94%); V1 (volume of distribution of the central compartment) = 27 L (57%); V2 (volume of distribution of the peripheral compartment) = 2.4 (66%); Q (intercompartmental clearance) = 266 (71%).

Conclusions & Further Work: A population PK model for RH1 after i.v. infusion has been developed. After validation in an external patient group, the current model could be used to predict exposure in target populations for phase II/III studies. Furthermore, pharmacodynamic (PD) information on DNA cross-linking for RH1 is available from the trial that will be used to develop a full PK-PD model.

Reference: PAGE 16 (2007) Abstr 1144 [www.page-meeting.org/?abstract=1144]
Poster: Applications- Oncology