Pharmacokinetics Profile
In phase I studies, the pharmacokinetics of Taxotere® (docetaxel) have been
evaluated in cancer patients after administration of doses ranging from 20 mg/m2
to 115 mg/m2. Following intravenous doses of 70 mg/m2 to 115 mg/m2, the pharmacokinetics
of Taxotere® were dose-independent and consistent with a 3-compartment model, with
mean population α, ß, γ half-lives of 4 minutes, 36 minutes, and
11.1 hours, respectively. The approved dosing range for Taxotere® is 60 mg/m²
to 100 mg/m².1
After intravenous (I.V.) administration of a 100-mg/m2 dose, the mean peak plasma
level was 3.7 µg/mL (SD=0.8), with a corresponding area under the curve (AUC)
of 4.6 µg/mL • h (SD=0.8).
Taxotere® plasma concentrations and AUC were found to be directly proportional to
dose, although drug clearance was independent of dose or schedule of administration,
which is consistent with a linear pharmacokinetic profile. Mean values for total
body clearance and steady-state volume of distribution were 21 L/h/m2 and 113 L,
respectively.1
Metabolism and Excretion
Taxotere® is rapidly and extensively distributed following I.V. administration. In
vitro studies show that it is approximately 94% bound to plasma proteins, primarily
to albumin, α1-acid glycoproteins and lipoproteins.1
Profile of the plasma concentration–time curve of Taxotere® after 1-hour
I.V. infusion of 100 mg/m2 in a patient with cancer
In vitro studies also suggest that the cytochrome P450-3A4 (CYP-3A4) subfamily of
isoenzymes plays a role in the metabolism of Taxotere.1
The primary Taxotere® metabolite is formed by oxidative metabolism of the tert-butyl
ester group. Within 7 days after I.V. administration, approximately 75% of the drug
is excreted in the feces via biliary elimination and 6% in the urine. About 80%
of the radioactivity recovered in feces is excreted during the first 48 hours as
one major and three minor metabolites with very small amounts (less than 8%) of
unchanged drug.1
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Population Pharmacokinetics
A population pharmacokinetic analysis was completed after Taxotere® treatment of
535 patients dosed at 100 mg/m2. Pharmacokinetic parameters estimated by this analysis
were very close to those estimated from phase I studies.1
Pharmacokinetic parameters were not influenced by patient gender or age. In addition,
Taxotere® clearance was not altered in patients who had received dexamethasone premedication.1 These analyses revealed that impaired hepatic function had clinically significant
effects on Taxotere® clearance. Patients with serum glutamic-oxaloacetic transaminase
and/or serum glutamic-pyruvic transaminase greater than 1.5 times the upper limit
of normal (ULN) concomitant with elevated alkaline phosphatase
levels greater than 2.5 times the ULN had an average 27% decrease in Taxotere® total
body clearance, resulting in a 38% increase in Taxotere® exposure (AUC).1
After adjustment for the effects of other covariants, Taxotere® clearance and AUC
were strong predictors of grade 4 neutropenia and febrile neutropenia.At present, there is no measurement that would allow recommendation for dose adjustment
in such patients. Based on this population's pharmacokinetic/pharmacodynamic analysis
and the clinical evidence, patients with combined abnormalities of transaminase
and alkaline phosphatase should, in general, not be treated with Taxotere.1
Taxotere® in patients with elevated liver function tests
Clearance of Taxotere® in combination therapy with cisplatin was similar to that
previously observed following monotherapy with Taxotere®. The pharmacokinetic profile
of cisplatin in combination therapy with Taxotere® was similar to that observed with
cisplatin alone.1
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References
- Taxotere® Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; November 2007.