to 2.0 × ULN and AST > ULN and < 10 × ULN): 200 mg/m2
Severe (bilirubin 2.01 to 5.0 × ULN and AST > ULN and < 10 × ULN): 130 mg/m2
The 260 mg/m2 dose for mild impairment and the 200 mg/m2 dose for moderate hepatic impairment adjusted the paclitaxel exposure to the range seen in patients with normal hepatic function (mean AUC0-∞ = 14789 ± 6703). The 130 mg/m2 dose in patients with severe hepatic impairment resulted in lower paclitaxel exposures than those seen in normal subjects. In addition, patients with severe hepatic impairment had higher mean cycle 1 absolute neutrophil count (ANC) nadir values than those with mild and moderate hepatic impairment.
Table 1: Exposure (AUC0-∞) of ABRAXANE administered IV over 30 minutes in patients with hepatic impairment. Mild
(n=5) Moderate
(n=5) Severe*
(n=5)
Dose 260 mg/m2 200 mg/m2 130 mg/m2
AUCinf(hr*ng/mL)
*
bilirubin 2.01 to 5.0 × ULN and AST > ULN and < 10 × ULN
Mean ± SD 17434 ± 11454 14159 ± 13346 9187 ± 6475
Median (range) 13755 (7618, 35262) 7866 (5919, 37613) 6134 (5627, 20684)
A starting dose of 130 mg/m2 is recommended in patients with severe hepatic impairment. Escalation of the dose up to 200 mg/m2 should be considered for subsequent cycles in patients with severe hepatic impairment based on individual tolerance. The 200 mg/m2 dose has not been eva luated in patients with severe hepatic impairment, but it is predicted to adjust the paclitaxel AUC to the range observed in patients with normal hepatic function. A starting dose reduction is also needed for patients with moderate hepatic impairment. There are no data for patients with AST > 10 × ULN and bilirubin > 5.0 × ULN. (see DOSAGE and ADMINISTRATION: Hepatic Impairment).
The effect of renal dysfunction on the disposition of ABRAXANE® has not been investigated.
Possible interactions of paclitaxel with concomitantly administered medications have not been formally investigated.
CLINICAL STUDIES
Metastatic Breast Carcinoma
Data from 106 patients accrued in two single arm open label studies and from 460 patients enrolled in a randomized comparative study were available to support the use of ABRAXANE in metastatic breast cancer.
Single Arm Open Label Studies
In one study, ABRAXANE was administered as a 30-minute infusion at a dose of 175 mg/m2 to 43 patients with metastatic breast cancer. The second trial utilized a dose of 300 mg/m2 as a 30 minute infusion in 63 patients with metastatic breast cancer. Cycles were administered at 3 week intervals. Objective responses were observed in both studies.
Randomized Comparative Study
This multicenter trial was conducted in 460 patients with metastatic breast cancer. Patients were randomized to receive ABRAXANE at a dose of 260 mg/m2 given as a 30-minute infusion, or paclitaxel injection at 175 mg/m2 given as a 3-hour infusion. Sixty-four percent of patients had impaired performance status (ECOG 1 or 2) at study entry; 79% had visceral metastases; and 76% had > 3 sites of metastases. Fourteen percent of the patients had not received prior chemotherapy; 27% had received chemotherapy in the adjuvant setting, 40% in the metastatic setting and 19% in both metastatic and adjuvant settings. Fifty-nine percent received study drug as second or greater than second-line therapy. Seventy-seven percent of the patients had been prev
