ism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4. (See PRECAUTIONS: Drug Interactions section.) The effect of renal or hepatic dysfunction on the disposition of paclitaxel has not been investigated.
Possible interactions of paclitaxel with concomitantly administered medications have not been formally investigated.
CLINICAL STUDIES
Ovarian Carcinoma:
Second-Line Data- Data from five Phase 1 & 2 clinical studies (189 patients), a multicenter randomized Phase 3 study (407 patients), as well as an interim analysis of data from more than 300 patients enrolled in a treatment referral center program were used in support of the use of paclitaxel in patients who have failed initial or subsequent chemotherapy for metastatic carcinoma of the ovary. Two of the Phase 2 studies (92 patients) utilized an initial dose of 135 to 170 mg/m2 in most patients (>90%) administered over 24 hours by continuous infusion. Response rates in these two studies were 22% (95% Cl: 11% to 37%) and 30% (95% Cl: 18% to 46%) with a total of 6 complete and 18 partial responses in 92 patients. The median duration of overall response in these two studies measured from the first day of treatment was 7.2 months (range: 3.5-15.8 months) and 7.5 months (range: 5.3-17.4 months), respectively. The median survival was 8.1 months (range: 0.2-36.7 months) and 15.9 months (range: 1.8-34.5+ months).
The Phase 3 study had a bifactorial design and compared the efficacy and safety of paclitaxel, administered at two different doses (135 or 175 mg/m2 and schedules (3- or 24-hour infusion). The overall response rate for the 407 patients was 16.2% (95% Cl: 12.8% to 20.2%), with 6 complete and 60 partial responses. Duration of response, measured from the first day of treatment was 8.3 months (range: 3.2-21.6 months). Median time to progression was 3.7 months (range: 0.1+ - 25.1+ months). Median survival was 11.5 months (range: 0.2-26.3+ months).
Response rates, median survival, and median time to progression for the 4 arms are given in the following table.
Table 2: Efficacy in the Phase 3 Second-Line Ovarian Carcinoma Study
175/3
(n=96)
175/24
(n=106)
135/3
(n=99)
135/24
(n=106)
• Response
- rate (percent)
14.6
21.7
15.2
13.2
- 95% Confidence Interval
(8.5-23.6)
(14.5-31.0)
(9.0-24.1)
(7.7-21.5)
• Time to Progression
- median (months)
4.4
4.2
3.4
2.8
- 95% Confidence Interval
(3.0-5.6)
(3.5-5.1)
(2.8-4.2)
(1.9-4.0)
• Survival
- median (months)
11.5
11.8
13.1
10.7
- 95% Confidence Interval
(8.4-14.4)
(8.9-14.6)
(9.1- |
