Research Article Open Access Clinical Pharmacology & Biopharmaceutics C l i n i c a l P h a r m a c o l o g y & B i o p h a r m a c e u t i c s ISSN: 2167-065X Omran et al., Clin Pharmacol Biopharm 2016, 5:2 DOI: 10.4172/2167-065X.1000156 Volume 5 • Issue 2 • 1000156 Clin Pharmacol Biopharm ISSN: 2167-065X CPB, an open access journal A Prospective Pharmacokinetic Study of Docetaxel in Breast Cancer Patients in Relation to CYP3A4 Activity Mervat Omran 1 , Osama Badary 2 , Amany Helal 3 and Samia Shouman 1 * 1 Cancer Biology Department, National Cancer Institute, Cairo University, Egypt 2 Clinical Pharmacy Department, Ain-Shams University, Cairo, Egypt 3 Medical Oncology Department, National Cancer Institute, Cairo University, Egypt Abstract Purpose: To study the correlation between pharmacokinetics & pharmacodynamic of docetaxel and CYP3A4 activity in Egyptian cancer patients. Patients and methods: Fourteen Egyptian female Patients with metastatic breast cancer, World Health Organization (WHO) performance status 0 to 2, had received prior chemotherapy regimen, were treated with single-agent docetaxel (100 mg/m 2 ), given every 21 days. Hydrocortisone 300 mg IV was administered 2 days before docetaxel treatment and Cytochrome 3A4 activity was determined by measuring the level of urinary metabolites of 6β-hydroxy cortisol (6β-OHF) and cortisol (FC). For the pharmacokinetic study, Blood samples were taken before and after IV infusion for 1 hr of 100 mg/m 2 docetaxel. The level of the drug was determined using HPLC and the correlation between pharmacokinetics and CYP3A4 activity were determined. Results: After cortisol administration, the total amount of 24-hour urinary 6β-OHF and FC were19.97 ± 10.43 and 16.84 ± 10.36 mg/24 h (mean ± SD) respectively. On the other hand, the 6β-OHF/FC ratio after cortisol administration was 1.86 ± 1.933. The pharmacokinetic parameters of docetaxel were clearance 19.9 ± 4.5 L/hr, the volume of distribution 65.6 ± 28.6 L (mean ± SD) and AUC 7.2 µg/ml.hr (range 5-8.8 µg/ml.hr) ± SD). A signifcant correlation was found between 6β-OHF/FC ratio and neutropenia (p=0.04) in addition correlation between 6β-OHF and C max (p=0.04). Conclusion: The interpatient variability of CYP3A4 activity in each patient could be predicted by measuring the total amount of 24 hour urinary 63-OHF after cortisol administration. Individualized dosing to optimize drug exposure for each patient could be performed based on this method. A farther study of fxed versus individualized dosing of docetaxel is needed to determine whether individualized chemotherapy with the application of this method can reduce PK and toxicity variability. Keywords: Docetaxel pharmacokinetic; CYP3A4 activity; Neutropenia; Response Introduction Docetaxel (DCX) is a toxoid derivative that displays antitumoral activity against many solid tumors, including prostate, lung, ovarian and breast cancers [1] and promising activity against metastatic breast cancer [2]. Individuals display signifcant diferences in term of efcacy and adverse efects afer exposure to docetaxel. Te drug is not efective for all breast cancers patients; an identical dosage of a drug can result in widely diferent concentrations of the therapeutically active compound or metabolites [3]. Terefore, it is very important to develop a diagnostic method for the prediction of the response to docetaxel in order to avoid over or under treatment. Currently, it is impossible to identify, before the initiation of therapy, the patients for whom docetaxel will be used. Te presence of genetic variability in both content and catalytic activity of enzymes involved in drug metabolism could lead to clinically important variations in efcacy and adverse efects of some drugs. Te cytochrome P450 is a family of heme-containing enzymes responsible for the metabolism of many drugs including taxane [4]. Docetaxel is metabolized by CYP3A4 in the liver into four major metabolites with minimal or no antitumor activity so that metabolism of docetaxel depends on the enzyme activity of CYP3A4 in the liver of individual patients. Te CYP3A4 enzyme displays large interpatient diferences in both content and catalytic activity in humans. Tese diferences exist even in the absence of medications known to induce or inhibit the enzyme and are thus likely to refect genetic variability [4,5]. We hypothesized that the interpatient variability of docetaxel pharmacokinetics and pharmacodynamic is due diferences in CYP3A4 activity. Exogenous cortisol was used as a probe to measure CYP3A4 activity through determination of its urinary 6β-hydroxy metabolite (6β-OHC) and free cortisol (FC) metabolites [6]. Material and Methods Drugs Te docetaxel (Taxotere ® Sanof-Aventis, Paris, France) vial was obtained as concentrated sterile solution that contained 20 or 80 mg of the drug in 0.5 ml polysorbate 80. Hydrocortisone (Solu-cortif, EIPICO, Cairo, Egypt) was available as a vial containing 100 mg lyophilized powder. Both drugs were from the drug store of the National Cancer Institute (NCI) Hospital. Chemical and reagents For HPLC, an authentic sample of docetaxel was supplied by National Organization for Drug Control and Research (NODCAR, *Corresponding author: Samia Shouman, Professor of Clinical Biochemistry, Cancer Biology Department, National Cancer Institute, Cairo University, Egypt, Tel: 0020123952527; E-mail: samiasshouman@yahoo.com Received April 20, 2016; Accepted May 09, 2016; Published May 17, 2016 Citation: Omran M, Badary O, Helal A, Shouman S (2016) A Prospective Pharmacokinetic Study of Docetaxel in Breast Cancer Patients in Relation to CYP3A4 Activity. Clin Pharmacol Biopharm 5: 156. doi:10.4172/2167- 065X.1000156 Copyright: © 2016 Omran M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.