title: Population pharmacokinetics in phase I drug development: a phase I study of PK1 in patients with solid tumours.
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 I h(-1); central compartment volume (V1) 4.48 x (1+0.00074 x dose (mg)) I; peripheral compartment volume (V2) 7.94 I; intercompartmental clearance 0.685 I 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 I h-(-1); apparent V1 (I) 1450 x (1+0.0013 x dose (mg)), apparent V2 (I) 21 300 x (1-0.0013 x dose (mg)) x (1+2.95 x height (m)) and apparent Q 6950 I h(-1). Distribution and elimination half-lives were 0.13 h and 85 h respectively.
authors.affiliation: Department of Medicine & Therapeutics, University of Glasgow, UK.
authors.forename: A H
authors.initials: AH
authors.lastname: Thomson
authors.forename: P A
authors.initials: PA
authors.lastname: Vasey
authors.forename: L S
authors.initials: LS
authors.lastname: Murray
authors.forename: J
authors.initials: J
authors.lastname: Cassidy
authors.forename: D
authors.initials: D
authors.lastname: Fraier
authors.forename: E
authors.initials: E
authors.lastname: Frigerio
authors.forename: C
authors.initials: C
authors.lastname: Twelves
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D004337:Drug Carriers / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D011109:Polymethacrylic Acids / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D011109:Polymethacrylic Acids; C055176:doxorubicin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate; D004317:Doxorubicin