Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies.
OBJECTIVE
To explain the variability of docetaxel pharmacokinetics through study of CYP3A phenotype and genotype, and MDR1 genotype.


METHODS
We studied the pharmacokinetics and pharmacodynamics of docetaxel in patients in whom it was indicated and who had not received known CYP3A4 substrates. Midazolam was administered intravenously to these patients at least 2 days before docetaxel treatment, and systemic clearances of both drugs were correlated. Patients were characterized for polymorphisms in the CYP3A4 promoter region, CYP3A5, and the C3435T polymorphism of MDR1.


RESULTS
Thirty-two patients were enrolled, of whom 31 had full pharmacokinetic data sets. Docetaxel clearance correlated with midazolam clearance, body-surface area, serum albumin, and performance status. Docetaxel and midazolam clearances were normally distributed. In multiple linear regression analyses, midazolam clearance and performance status were the only significant covariates of docetaxel clearance, and the area under the curve of docetaxel, serum levels of alpha-1-acid glycoprotein, and ALT were significant predictors of nadir neutrophil count. No polymorphisms were detected in the 5' regulatory region of CYP3A4. Nine patients of 25 studied were homozygous for the CYP3A5*3 genotype, and had lower mean clearance of midazolam but not docetaxel. The T/T genotype at the C3435T of MDR1, which is associated with reduced P-glycoprotein function, was found in eight of 27 patients.


CONCLUSIONS
Midazolam may be used as a probe drug for CYP3A activity to predict docetaxel clearances, hence reducing interindividual variability. Homozygotes for CYP3A5*3 and C3435T of MDR1 are common in our population, and their effects on pharmacokinetics of relevant substrates should be studied further.
Department of Hematology-Oncology, National University Hospital, Singapore. gohbc@nuh.com.sg
Boon-Cher
BC
Goh
Soo-Chin
SC
Lee
Ling-Zhi
LZ
Wang
Lu
L
Fan
Jia-Yi
JY
Guo
Jatinder
J
Lamba
Erin
E
Schuetz
Robert
R
Lim
Hong-Liang
HL
Lim
Ai-Bee
AB
Ong
How-Sung
HS
Lee
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000077143:Docetaxel; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D019450:Genes, MDR / Q000235:genetics*; D005838:Genotype; D006801:Humans; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000493:pharmacokinetics; D008875:Middle Aged; D015999:Multivariate Analysis; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D043823:Taxoids
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D017239:Paclitaxel; D008874:Midazolam