| Investigator: | Mary Relling, PharmD |
|---|---|
| Group: | PAAR |
| Genes Studied: | ABCB1, CYP3A4, CYP3A5 |
| Drugs Studied: | docetaxel, midazolam |
| Diseases Studied: | Neoplastic Processes |
| Number of columns (phenotypes): | 5 |
| Number of rows (subjects): | 25 |
Details
PURPOSE: To explain the variability of docetaxel pharmacokinetics through study of CYP3A phenotype and genotype, and MDR1 genotype.
PATIENTS AND 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.
CONCLUSION: 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.
This phenotype submission contains data on 25 of the 31 patients in the study because DNA could not be amplified for 2 of them, and consent was not obtained for 4 of them.
Categories of Pharmacogenetic Knowledge
PK
Pharmacokinetics
Publications
Primary phenotype data has been submitted and is available
Primary genotype data has been submitted and is available
Literature annotations available
| Relationship | Reference |
|---|---|
|
Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies. J Clin Oncol. 2002. Goh Boon-Cher, Lee Soo-Chin, Wang Ling-Zhi, Fan Lu, Guo Jia-Yi, Lamba Jatinder, Schuetz Erin, Lim Robert, Lim Hong-Liang, Ong Ai-Bee, Lee How-Sung. PMID: 12202670. |
| Subject ID | PharmGKB Accession IDs for subjects in the PharmGKB. |
|---|---|
| Gender | Male, female, or unknown. |
| Race/Ethnicity | Race/Ethnicity as defined by the Office of Management and Budget, followed by the self reported information in parentheses if available. |
| Midazolam clearance (mL/min) | 2.5 mg of midazolam was given to the subject as a bolus infusion over 30 seconds. |
| Docetaxel clearance (mL/hr) | 75 or 100 mg/m2 of docetaxel was given to the subject as an infusion over 1 hour, after the subject received midazolam intravenously (at least 2 days before). Blank = unknown. |
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