Lack of association of single-nucleotide polymorphisms in pregnane X receptor, hepatic nuclear factor 4alpha, and constitutive androstane receptor with docetaxel pharmacokinetics.
OBJECTIVE
This study aims to describe a population pharmacokinetic model for docetaxel in Asian breast cancer patients and to evaluate the effects of single-nucleotide polymorphisms (SNP) in the cytochrome P450 3A (CYP3A) gene expression regulators, constitutive androstane receptor (CAR), pregnane X receptor (PXR), and hepatic nuclear factor 4alpha (HNF4alpha), on the pharmacokinetics of docetaxel.


METHODS
Docetaxel was given as an i.v. infusion of 75 mg/m(2) over 1 h to 101 female breast cancer patients. CAR, PXR, and HNF4alpha were comprehensively sequenced. Docetaxel concentrations were measured using a liquid chromatography/tandem mass spectrometry method and its population pharmacokinetic variables, and the covariate effects of clearance predictors were estimated using a nonlinear mixed effects model.


RESULTS
Final estimates for docetaxel clearance was 47.1 L/h/70 kg/1.75 m. Between subject variability in docetaxel clearance was 22.5%. Covariates that showed significant association with docetaxel clearance included body size, alpha1 acid glycoprotein and liver function. SNPs identified in the coding regions of CAR and HNF4alpha and 5' untranslated region of PXR in this Asian breast cancer cohort did not seem to improve predictability of docetaxel clearance.


CONCLUSIONS
SNPs identified in CYP3A gene expression regulators CAR, HNF4alpha, and PXR in the Asian female breast cancer population do not seem to have any significant effect on the clearance of docetaxel, a CYP3A substrate.
Tham
Lai-San
LS
Department of Hematology-Oncology, National University Hospital, Singapore. Tham_lai_san@lilly.com
Holford
Nicholas H G
NH
Hor
Sok-Ying
SY
Tan
Theresa
T
Wang
Lingzhi
L
Lim
Rui-Chen
RC
Lee
How-Sung
HS
Lee
Soo-Chin
SC
Goh
Boon-Cher
BC
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000077143:Docetaxel; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D051557:Hepatocyte Nuclear Factor 4 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014157:Transcription Factors / Q000235:genetics*
D000970:Antineoplastic Agents; D000090702:Constitutive Androstane Receptor; D051557:Hepatocyte Nuclear Factor 4; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D043823:Taxoids; D014157:Transcription Factors; D000077143:Docetaxel; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A