Regular Article

British Journal of Cancer (1999) 81, 99–107. doi:10.1038/sj.bjc.6690657 www.bjcancer.com
Published online 13 August 1999

Population pharmacokinetics in phase I drug development: a phase I study of PK1 in patients with solid tumours

A H Thomson1, P A Vasey2, L S Murray1, J Cassidy4, D Fraier3, E Frigerio3 and C Twelves2

  1. 1Department of Medicine & Therapeutics, University of Glasgow Western Infirmary, Glasgow G11 6NT, UK
  2. 2CRC Department of Medical Oncology Beatson Oncology Centre, Western Infirmary, Glasgow G11 6NT, UK
  3. 3Bioanalytical Laboratory Pharmacokinetics and Metabolism Department, Pharmacia & Upjohn, Nerviano, Italy
  4. 4Department of Medicine & Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill Aberdeen AB25 2ZD, UK

Received 19 November 1998; Revised 25 March 1999; Accepted 12 April 1999.

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Abstract

Doxorubicin pharmacokinetics were determined in 33 patients with solid tumours who received intravenous doses of 20–320 mg m–2 HPMA copolymer bound doxorubicin (PK1) in a phase I study. Since assay constraints limited the data at lower doses, conventional analysis was not feasible and a 'population approach' was used. Bound concentrations were best described by a biexponential model and further analyses revealed a small influence of dose or weight on V1 but no identifiable effects of age, body surface area, renal or hepatic function. The final model was: clearance (Q) 0.194 l h–1; central compartment volume (V1) 4.48 times (1+0.00074 times dose (mg)) l; peripheral compartment volume (V2) 7.94 l; intercompartmental clearance 0.685 l h–1. Distribution and elimination half-lives had median estimates of 2.7 h and 49 h respectively. Free doxorubicin was present at most sampling times with concentrations around 1000 times lower than bound doxorubicin values. Data were best described using a biexponential model and the following parameters were estimated: apparent clearance 180 l h–1; apparent V1 (l) 1450 times (1+0.0013 times dose (mg)), apparent V2 (l) 21 300 times (1–0.0013 times dose (mg)) times (1+2.95 times height (m)) and apparent Q 6950 l h–1. Distribution and elimination half-lives were 0.13 h and 85 h respectively.

Keywords:

PK1-doxorubicin, solid tumours, population pharmacokinetics

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