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

Br J Cancer. 1999 Sep;81(1):99-107. doi: 10.1038/sj.bjc.6690657.

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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / therapeutic use
  • Dose-Response Relationship, Drug
  • Doxorubicin / analogs & derivatives*
  • Doxorubicin / blood
  • Doxorubicin / metabolism
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / therapeutic use
  • Drug Carriers / pharmacokinetics
  • Drug Carriers / therapeutic use
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neoplasms / blood
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Polymethacrylic Acids / metabolism
  • Polymethacrylic Acids / pharmacokinetics*
  • Polymethacrylic Acids / therapeutic use*

Substances

  • Antineoplastic Agents
  • Drug Carriers
  • Polymethacrylic Acids
  • doxorubicin-N-(2-hydroxypropyl)methacrylamide copolymer conjugate
  • Doxorubicin