Doxorubicin Hydrochloride (Page 2 of 8)

Pharmacokinetics in Special Populations


Following administration of 10 to 75 mg/m 2 doses of doxorubicin to 60 children and adolescents ranging from 2 months to 20 years of age, doxorubicin clearance averaged 1,443 ± 114 mL/min/m 2. Further analysis demonstrated that clearance in 52 children greater than 2 years of age (1,540 mL/min/m 2) was increased compared with adults. However, clearance in infants younger than 2 years of age (813 mL/min/m 2) was decreased compared with older children and approached the range of clearance values determined in adults.


While the pharmacokinetics of elderly subjects (≥65 years of age) have been evaluated, no dosage adjustment is recommended based on age (see PRECAUTIONS, Geriatric Use).


A published clinical study involving 6 men and 21 women with no prior anthracycline therapy reported a significantly higher median doxorubicin clearance in the men compared to the women (1,088 mL/min/m 2 versus 433 mL/min/m 2). However, the terminal half-life of doxorubicin was longer in men compared to the women (54 versus 35 hours).


The influence of race on the pharmacokinetics of doxorubicin has not been evaluated.

Hepatic Impairment

The clearance of doxorubicin and doxorubicinol was reduced in patients with impaired hepatic function (see DOSAGE AND ADMINISTRATION).

Renal Impairment

The influence of renal function on the pharmacokinetics of doxorubicin has not been evaluated.


The effectiveness of doxorubicin-containing regimens in the adjuvant therapy of early breast cancer has primarily been established based on data collected in a meta-analysis published in 1998 by the Early Breast Cancer Trialists Collaborative Group (EBCTCG). The EBCTCG obtains primary data on all relevant studies, both published and unpublished, for early stage breast cancer and regularly updates these analyses. The principal endpoints for the adjuvant chemotherapy trials were disease-free survival (DFS) and overall survival (OS). The meta-analyses allowed comparisons of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) to no chemotherapy (19 trials including 7,523 patients) and comparisons of doxorubicin-containing regimens with CMF as an active control (6 trials including 3,510 patients). The pooled estimates of DFS and OS from these trials were used to calculate the effect of CMF relative to no therapy. The hazard ratio for DFS for CMF compared to no chemotherapy was 0.76 (95% Cl, 0.71 to 0.82) and for OS was 0.86 (95% Cl, 0.8 to 0.93). Based on a conservative estimate of CMF effect (lower 2-sided 95% confidence limit of hazard ratio) and 75% retention of CMF effect on DFS, it was determined that the doxorubicin-containing regimens would be considered as non-inferior to CMF if the upper 2-sided 95% confidence limit of the hazard ratio was less than 1.06, i.e., not more than 6% worse than CMF. A similar calculation for OS would require a non-inferiority margin of 1.02.

Six randomized trials in the EBCTCG meta-analysis compared doxorubicin-containing regimens to CMF. A total of 3,510 women with early breast cancer involving axillary lymph nodes were evaluated; approximately 70% were premenopausal and 30% were postmenopausal. At the time of the meta-analysis, 1,745 first recurrences and 1,348 deaths had occurred. Analyses demonstrated that doxorubicin-containing regimens retained at least 75% of the historical CMF adjuvant effect on DFS and are effective. The hazard ratio for DFS (dox:CMF) was 0.91 (95% Cl, 0.82 to 1.01) and for OS was 0.91 (95% Cl, 0.81 to 1.03). Results of these analyses for both DFS and OS are provided in Table 1 and Figures 1 and 2.

Table 1. Summary of Randomized Trials Comparing Doxorubicin-Containing Regimens Versus CMF in EBCTCG Meta-Analysis

Study (starting year) Regimens No. of Cycles No. of Patients Doxorubicin-Containing Regimens vs CMF HR (95% CI)
NSABP B-15 (1984) AC 4 1,562* 0.93 (0.82 to 1.06) 0.97 (0.83 to 1.12)
CMF 6 776
SECSG 2 (1976) FAC 6 260 0.86 (0.66 to 1.13) 0.93 (0.69 to 1.26)
CMF 6 268
ONCOFRANCE (1978) FACV 12 138 0.71 (0.49 to 1.03) 0.65 (0.44 to 0.96)
CMF 12 113
SE Sweden BCG A (1980) AC 6 21 0.59 (0.22 to 1.61) 0.53 (0.21 to 1.37)
CMF 6 22
NSABC Israel Br0283 (1983) AVbCMF CMF 4 6 6 55 50 0.91 (0.53 to 1.57) 0.88 (0.47 to 1.63)
Austrian BCSG 3 (1984) CMFVA 6 121 1.07 (0.73 to 1.55) 0.93 (0.64 to 1.35)
CMF 8 124
Combined Studies Doxorubicin-Containing Regimens 2,157 0.91 (0.82 to 1.01) 0.91 (0.81 to 1.03)
CMF 1,353

Abbreviations: DFS = disease free survival; OS = overall survival; AC = doxorubicin, cyclophosphamide; AVbCMF = doxorubicin, vinblastine, cyclophosphamide, methotrexate, 5-fluorouracil; CMF = cyclophosphamide, methotrexate, 5-fluorouracil; CMFVA = cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, doxorubicin; FAC = 5-fluorouracil, doxorubicin, cyclophosphamide; FACV = 5-fluorouracil, doxorubicin, cyclophosphamide, vincristine; HR = hazard ratio; CI = confidence interval


* Includes pooled data from patients who received either AC alone for 4 cycles, or who were treated with AC for 4 cycles followed by 3 cycles of CMF.

Patients received alternating cycles of AVb and CMF.

(click image for full-size original)

(click image for full-size original)

With respect to DFS, 2 of 6 studies (NSABP B-15 and ONCOFRANCE) met the non-inferiority standard individually and with respect to OS, 1 study met the non-inferiority margin individually (ONCOFRANCE). The largest of the 6 studies in the EBCTCG meta-analysis, a randomized, open-label, multicenter trial (NSABP B-15) was conducted in approximately 2,300 women (80% premenopausal; 20% postmenopausal) with early breast cancer involving axillary lymph nodes. In this trial, 6 cycles of conventional CMF was compared to 4 cycles of doxorubicin and cyclophosphamide (AC) and 4 cycles of AC followed by 3 cycles of CMF. No statistically significant differences in terms of DFS or OS were observed (see Table 1).

All resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2023. All Rights Reserved.