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 tumo urs 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 d ata at lower doses, conventional analysis was not feasible and a 'populatio n approach' was used. Bound concentrations were best described by a biexpon ential model and further analyses revealed a small influence of dose or wei ght on V1 but no identifiable effects of age, body surface area, renal or h epatic function. The final model was: clearance (Q) 0.194 l h(-1); central compartment volume (V1) 4.48 x (1+0.00074 x dose (mg)) I; peripheral compar tment volume (V2) 7.94 l; intercompartmental clearance 0.685 l h(-1). Distr ibution and elimination half-lives had median estimates of 2.7 h and 49 h r espectively. Free doxorubicin was present at most sampling times with conce ntrations around 1000 times lower than bound doxorubicin values. Data were best described using a biexponential model and the following parameters wer e estimated: apparent clearance 180 l h(-1); apparent V1 (l) 1450 x (1+0.00 13 x dose (mg)), apparent V2 (l) 21 300 x (1-0.0013 x dose (mg)) x (1+2.95 x height (m)) and apparent Q 6950 1 h(-1). Distribution and elimination hal f-lives were 0.13 h and 85 h respectively.