Analysis of docetaxel pharmacokinetics in humans with the inclusion of later sampling time-points afforded by the use of a sensitive tandem LCMS assay.
OBJECTIVE
Docetaxel is a semisynthetic taxane derived from the needles of the European yew ( Taxus baccata) and it is an important chemotherapeutic agent in the treatment of recurrent ovarian, breast and non-small-cell lung cancers. Traditional dosing regimens with docetaxel involve doses of 60-100 mg/m(2) by infusion every 3 weeks. Now weekly low-dose (30-36 mg/m(2)) regimens are being evaluated in phase I trials. Such low-dose studies require a more sensitive, specific and rapid assay of docetaxel in biological fluids for the determination of pharmacokinetic parameters. Because docetaxel is primarily metabolized by CYP3A4 and is highly protein-bound in the plasma, there is potential for drug-drug interactions and high interpatient variability in pharmacokinetics. Therefore, pharmacokinetic studies are an important component to understanding the therapeutic variability of docetaxel-containing chemotherapeutic regimens.


METHODS
To this end, we developed an analytical assay for docetaxel based upon tandem LCMS and paclitaxel as an internal standard. The sensitivity of the new assay allowed us to monitor plasma levels of docetaxel out to 48 h after the end of the infusion in patients enrolled in a phase I trial of exisulind (orally, twice daily) receiving weekly docetaxel doses of 30 or 36 mg/m(2) where plasma docetaxel levels are below the lower limit of quantitation for traditional HPLC/UV-based assays at later time-points.


RESULTS
The inclusion of the 48-h time-point had significant effects on the calculated pharmacokinetic parameters when using either a three-compartment or non-compartmental analysis. The terminal half-life was significantly increased when the 48-h time-point was included in the pharmacokinetic analysis, and the use of model parameters derived with the inclusion of the 48-h time-point were able to more accurately predict plasma levels at later times.


CONCLUSIONS
The results reflect the importance of accurate and sensitive analytical methods for the determination of pharmacokinetic parameters and the effect of this later time-point on docetaxel pharmacokinetic modeling. Further, with the increased use of weekly docetaxel in combination with other agents, the inclusion of these later sampling time-points and sensitive methods for drug level determinations are important components in the description of pharmacokinetic drug interactions.
Gustafson
Daniel L
DL
Department of Pharmaceutical Sciences, C-238, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado, 80220, USA. Daniel.Gustafson@UCHSC.edu
Long
Michael E
ME
Zirrolli
Joseph A
JA
Duncan
Mark W
MW
Holden
Scott N
SN
Pierson
A Scott
AS
Eckhardt
S Gail
SG
D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002853:Chromatography, Liquid; D000077143:Docetaxel; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D013058:Mass Spectrometry; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D015203:Reproducibility of Results; D013048:Specimen Handling; D043823:Taxoids; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel