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

• Published in: British Journal of Cancer 1999-09, Vol.81 (1), p.99-107
• Main Authors: Thomson, A H, Vasey, P A, Murray, L S, Cassidy, J, Fraier, D, Frigerio, E, Twelves, C
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chemotherapy; Dose-Response Relationship, Drug; Doxorubicin - analogs & derivatives; Doxorubicin - blood; Doxorubicin - metabolism; Doxorubicin - pharmacokinetics; Doxorubicin - therapeutic use; Drug Carriers - pharmacokinetics; Drug Carriers - therapeutic use; Drug Resistance; Epidemiology; Female; Humans; Male; Medical sciences; Middle Aged; Molecular Medicine; Neoplasms - blood; Neoplasms - drug therapy; Neoplasms - metabolism; Oncology; Pharmacology. Drug treatments; Polymethacrylic Acids - metabolism; Polymethacrylic Acids - pharmacokinetics; Polymethacrylic Acids - therapeutic use; Regular; regular-article
• ISSN: 0007-0920; 1476-5381; 1532-1827
• DOI: 10.1038/sj.bjc.6690657

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.