Population pharmacokinetics in phase I drug development: a phase I study of PK1 in patients with solid tumours.
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.
Thomson
A H
AH
Department of Medicine & Therapeutics, University of Glasgow, UK.
Vasey
P A
PA
Murray
L S
LS
Cassidy
J
J
Fraier
D
D
Frigerio
E
E
Twelves
C
C
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*
D000970:Antineoplastic Agents; D004337:Drug Carriers; D011109:Polymethacrylic Acids; C055176:doxorubicin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate; D004317:Doxorubicin