Pharmacokinetic parameters of paclitaxel following 3- and 24-hour infusions of paclitaxel at dose levels of 135 and 175 mg/m2 were determined in a Phase 3 randomized study in ovarian cancer patients and are summarized in the following table:

Table 1: Summary of Pharmakokinetic Parameters – Mean Values Dose (mg/m2)
 Infusion Duration (h)
 N
(patients)
 Cmax
(ng/mL)
 AUC (0-∞) (ng•h/mL)
 T-HALF
(h)
 CLT
(L/h/m2)
 
135
 24
 2
 195
 6300
 52.7
 21.7
 
175
 24
 4
 365
 7993
 15.7
 23.8
 
135
 3
 7
 2170
 7952
 13.1
 17.7
 
175
 3
 5
 3650
 15007
 20.2
 12.2
Cmax = Maximum plasma concentration
AUC (0-∞) = Area under the plasma concentration-time curve from time 0 to infinity

CLT = Total body clearance
It appeared that with the 24-hour infusion of paclitaxel, a 30% increase in dose (135 mg/m2 versus 175 mg/m2) increased the Cmax by 87%, whereas the AUC (0-∞) remained proportional. However, with a 3-hour infusion, for a 30% increase in dose, the Cmax and AUC (0-∞) were increased by 68% and 89%, respectively. The mean apparent volume of distribution at steady state, with the 24-hour infusion of paclitaxel, ranged from 227 to 688 L/m2, indicating extensive extravascular distribution and/or tissue binding of paclitaxel.
The pharmacokinetics of paclitaxel were also eva luated in adult cancer patients who received single doses of 15-135 mg/m2 given by 1-hour infusions (n=15), 30-275 mg/m2 given by 6-hour infusions (n=36), and 200-275 mg/m2 given by 24-hour infusions (n=54) in Phase 1 & 2 studies. Values for CLT and volume of distribution were consistent with the findings in the Phase 3 study.
In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 µg/mL, indicate that between 89%-98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.
After intravenous administration of 15-275 mg/m2 doses of Paclitaxel Injection as 1-, 6-, or 24-hour infusions, mean values for cumulative urinary recovery of unchanged drug ranged from 1.3% to 12.6% of the dose, indicating extensive non-renal clearance. In five patients administered a 225 or 250 mg/m2 dose of radiolabeled paclitaxel as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in the urine. Total recovery of radioactivity ranged from 56% to 101% of the dose. Paclitaxel represented a mean of 5% of the administered radioactivity recovered in the feces, while metabolites, primarily 6α-hydroxypaclitaxel, accounted for the balance. In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor metabolites, 3’-p-hydroxypaclitaxel and 6α, 3’-p-dihydroxy-paclitaxel, by CYP3A4. In vitro, the metabol