Phase I and pharmacokinetic study of a stable, polyethylene-glycolated liposomal doxorubicin in patients with solid tumors - The relation between pharmacokinetic property and toxicity

BACKGROUND. Compared with free drug, sterically stabilized liposomal drug h as prolonged circulation time and, thereby, higher tumor selectivity and an titumor activity. The stability in plasma is an important consideration in the formulation of clinically useful liposomal drug. A Phase I study of a s table liposomal doxorubicin with polyethylene glycol (PEG) coating and phos pholipid component of distearoyl phosphatidylcholine (DSPC) was performed t o characterize its pharmacokinetic properties, toxicity profile, and maxima l tolerated dose. METHODS. The starting dose was 30 mg/m(2) every 3 weeks with an increment o f 10 mg/m(2) for each level. A cohort of at least three patients was entere d for each level. Dose escalation stopped when more than one-third of patie nts had dose limiting toxicity (DLT), which was equal to or more than Grade 3 nonhematologic toxicity. Blood was sampled immediately before and at 5 m inutes, 2 hours, 4 hours, 10 hours, 24 hours, 48 hours, 72 hours, and 168 h ours after the completion of PEGylated liposomal doxorubicin (PLD) infusion . Plasma level of doxorubicin was determined with fluorometry, and the phar macokinetic properties were analyzed. RESULTS. Twenty-six patients were entered. and 101 courses were studied. Th is DSPC PLD had a steady-state distribution volume (Vss) of 2.4 +/- 0.9 lit ers (mean +/- standard deviation), a clearance of 0.027 +/- 0.010 liters pe r hour, and a beta half-life of 65.0 +/- 17.8 per hour. These characteristi cs were dose independent, and the Vss and clearance were smaller than those of a well characterized PLD comprised of hydrogenated soybean phosphatidyl choline (HSPC). At the dose level of 50 mg/m2, its plasma area under the co ncentration time curve was approximately twice that of HSPC PLD. Attenuatio n of acute toxicity, such as nausea, emesis, and alopecia, was noted in all dose levels. However, stomatitis was common from the dose level of 30 mg/m (2), and its incidence and severity increased with dosage and became dose l imiting at 50 mg/m2. A dose of 45 mg/m(2) every 3 weeks was then given in e ight patients, and the side effects were acceptable. This dose was recommen ded for Phase II clinical trials. Fourteen of 17 patients with a dose level greater than or equal to 40 mg/m2 were evaluable for response, but none ac hieved partial remission. CONCLUSIONS. This DSPC PLD had the characteristics of second-generation lip osomal drug pharmacokinetically and toxicologically. The incidence of sever e stomatitis was higher than that of HSPC PLD, corresponding to the differe nce in pharmacokinetics. Only limited antitumor activity was observed, alth ough defining its therapeutic application will need further Phase II studie s. Further prolongation of plasma stability of PLD may not be clinically be neficial considering the increased stomatitis and the reduced achievable do se intensity. (C) 2001 American Cancer Society.