Dexamethasone as a probe for vinorelbine clearance.
OBJECTIVE
To assess the value of using dexamethasone as an in vivo probe for predicting vinorelbine clearance (CL).


METHODS
A population approach (implemented with NONMEM) was used to analyse blood vinorelbine pharmacokinetic data from 20 patients who received a 20-min intravenous infusion of vinorelbine (from 20 to 30 mg m(-2)). Selected patient clinical data as well as known functional single CYP3A5 and ABCB1 genotype were also tested as covariates.


RESULTS
The best covariate model (with +/- 95% confidence intervals) was based on dexamethasone plasma clearance (DPC) and alkaline phosphatase (ALP): vinorelbine blood CL (l h(-1)) = 39.8(+/- 4.0) x (DPC/13.2)(0.524(+/-0.322)) x (ALP/137)(-0.198(+/-0.158)). Interindividual variability in vinorelbine CL decreased from 29.7% (model without covariate) to 14.7% when including DPC and ALP. Vinorelbine CL was not correlated with body surface area (BSA) or associated with CYP3A5 and ABCB1 genotype.


CONCLUSIONS
These results indicate that individualization of vinorelbine dose would be improved by using dexamethasone clearance rather than BSA. Dexamethasone merits further evaluation as a probe of CYP3A metabolism.
Puisset
Florent
F
EA3035, Institut Claudius-Regaud, Toulouse, France.
Dalenc
Florence
F
Chatelut
Etienne
E
Cresteil
Thierry
T
Lochon
Isabelle
I
Tisnes
Pierre
P
Roché
Henri
H
D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000097:blood / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D003907:Dexamethasone / Q000097:blood / Q000494:pharmacology*; D005260:Female; D005838:Genotype; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000077235:Vinorelbine
D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; D014747:Vinblastine; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D000077235:Vinorelbine