Dexamethasone as a probe for docetaxel clearance.
OBJECTIVE
A pilot study was conducted in 23 patients in order to assess the correlation between docetaxel clearance (CL) and pharmacokinetics of dexamethasone. Dexamethasone is mainly 6-beta hydroxylated by CYP3A4, and is regularly used as standard docetaxel premedication. Genotyping of known functional single nucleotide polymorphism (SNP) of CYP3A5 (G22893A) and mdr-1 (G2677T, G2677A, and C3435T) have been performed in order to tentatively correlate genotype with docetaxel and dexamethasone pharmacokinetics.


METHODS
To be eligible for this study, patients were required to have a solid malignancy for which docetaxel was indicated. A population pharmacokinetic approach was used to determine individual pharmacokinetic parameters of both docetaxel and dexamethasone by Bayesian analysis, and to screen relationships between docetaxel CL and patients' demographic, phenotype and genotype covariates.


RESULTS
Three different pharmacokinetic parameters of dexamethasone were significantly correlated with docetaxel CL: dexamethasone plasma clearance (DPC) that ranged between 7.7 and 27.2 l/h, urinary amount of 6beta-hydroxydexamethasone, and the ratio between urinary amount of 6beta-hydroxydexamethasone and unchanged dexamethasone. The best covariate model was docetaxel CL (l/h) = 356 x fu(alpha1-AG) x (1-0.17 x HPMT)(1+0.126 x DPC) where fu(alpha1-AG) is the unbound plasma fraction of docetaxel calculated from alpha1-acid glycoprotein plasma level, and HPMT is hepatic metastasis coded as 1 if present or 0 if absent. No significant difference in docetaxel CL was observed between the several genotypes.


CONCLUSIONS
Dexamethasone may be used as a probe to predict docetaxel clearances, hence reducing interindividual variability.
Puisset
Florent
F
Institut Claudius-Regaud, Université Paul-Sabatier, 31052 Toulouse, France.
Chatelut
Etienne
E
Dalenc
Florence
F
Busi
Florent
F
Cresteil
Thierry
T
Azéma
Joëlle
J
Poublanc
Muriel
M
Hennebelle
Isabelle
I
Lafont
Thierry
T
Chevreau
Christine
C
Roché
Henri
H
D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015415:Biomarkers; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000494:pharmacology; D003907:Dexamethasone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077143:Docetaxel; D005260:Female; D019450:Genes, MDR; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics*
D018931:Antineoplastic Agents, Hormonal; D015415:Biomarkers; D043823:Taxoids; D000077143:Docetaxel; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human