A total of 21 patients with advanced cancer were entered into a phase I study to determine the maximum tolerable dose (MTD) of liposome-encapsulated doxorubicin (LED) given weekly for 3 consecutive weeks at doses of 20, 30, or 37.5 mg/m2 per week. For a comparison of the pharmacokinetic behavior of LED with that of standard-formulation doxorubicin, 13 patients received a dose of standard-formulation doxorubicin 2 weeks prior to the first dose of LED. All doses were given by 1-h infusion through a central vein. Toxicity was evaluated in 22 courses delivered to 17 patients. The MTD with this schedule was 30 mg/m2 per week x 3. The single patient treated at 37.5 mg/m2 weekly could not complete the entire course due to myelosuppression. At the dose of 30 mg/m2 per week, three of eight patients had grade > or = 3 leukopenia. Other toxicities included mild to moderate thrombocytopenia, nausea, vomiting, fever, alopecia, diarrhea, fatigue, stomatitis, and infection. At the dose of 30 mg/m2 per week, the total doxorubicin AUC and peak total doxorubicin concentrations in plasma were 8.75 +/- 8.80 microM h (mean +/- SD) and 3.07 +/- 1.45 microM, respectively, after LED administration. The total doxorubicin AUC and peak total doxorubicin concentrations in plasma were 3.92 +/- 2.47 microM h and 2.75 +/- 2.70 microM, respectively, after the infusion of standard-formulation doxorubicin. The total body clearance of doxorubicin was 18.42 +/- 11.23 l/h after the infusion of LED and 31.21 +/- 15.48 l/h after the infusion of standard-formulation doxorubicin. The mean elimination half-lives of doxorubicin were similar: 8.65 +/- 5.16 h for LED and 7.46 +/- 5.16 h for standard-formulation doxorubicin. Interpatient variability in pharmacokinetic parameters as demonstrated by the percentage of coefficients of variation was 33%-105%. There was no relationship between the percentage of WBC decrease or the duration of WBC suppression and the total doxorubicin or doxorubicinol AUC. There was no correlation between the duration of leukopenia and drug exposure as reflected by the AUC of liposome-associated doxorubicin. LED can be given in doses similar to those of standard-formulation doxorubicin and produces acute toxicities similar to those caused by standard doxorubicin.