Summary
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 × (1+0.00074 × 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 × (1+0.0013 × dose (mg)), apparent V2 (l) 21 300 × (1–0.0013 × dose (mg)) × (1+2.95 × height (m)) and apparent Q 6950 l h–1. Distribution and elimination half-lives were 0.13 h and 85 h respectively.
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Thomson, A., Vasey, P., Murray, L. et al. Population pharmacokinetics in phase I drug development: a phase I study of PK1 in patients with solid tumours. Br J Cancer 81, 99–107 (1999). https://doi.org/10.1038/sj.bjc.6690657
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DOI: https://doi.org/10.1038/sj.bjc.6690657
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