Tamoxifen is metabolized in the liver by the cytochrome P450 isoform CYP2D6 and CYP3A4 into active metabolites such as afimoxifene (4-hydroxytamoxifen; 4-OHT) and endoxifen (N-desmethyl-4-hydroxytamoxifen) which have 30 to 100 times greater affinity for the Estrogen Receptor (ER) than tamoxifen itself.Endoxifen has a half-life of approximately 14 days and has also been shown to inhibit aromatase activity.
Our buccal Z-endoxifen produces therapeutic concentrations using once daily-dosing and those concentrations can be maintained by once or at most twice weekly administration.
Buccal endoxifen is designed for the treatment of estrogen receptor positive, metastatic breast cancer, especially women with endocrine refractory metastatic breast cancer. Specifically, the use of Z-endoxifen by a non-oral route overcomes the problem of low bioavailability due to rapid first pass metabolism via O-glucuronidation. Unlike the oral route of administration, the buccal route does not produce excessively high levels of Z-endoxifen metabolites.
The product is designed so that that therapeutic levels of endoxifen can be achieved via the
buccal route but metabolites of endoxifen can be maintained at the levels that closely resemble those seen after administration of therapeutic doses of tamoxifen while avoiding adverse events often observed with tamoxifen.
Buccal administration would also address the pharmacokinetic variations of CYP2D6 which accounts for approximately 30% to 50% of the variation in endoxifen concentrations, after the administration of tamoxifen. Patients who poorly metabolize tamoxifen owing to low CYP2D6 enzyme activity have very low concentrations of endoxifen and a higher risk of breast cancer recurrence, as shown in multiple studies. In a secondary analysis of the ABCSG 8 clinical trial (Austrian Breast and Colorectal Cancer Study Group 8), women who were poor metabolizers of CYP2D6 had a higher risk of breast cancer recurrence if they were treated with tamoxifen, but not if they were switched from tamoxifen to the AI, anastrozole.1
Polymorphisms are phenotypic differences in a population that can stop or impair enzyme function. CYP2D6 polymorphisms are common in all ethnic groups, and more than 100 allelic variants with varying impact on CYP2D6 enzyme function have been reported.2 Caucasians may be the most affected: 7% carry a single type CYP2D6 null allele with no enzymatic activity, and studies indicate that 5.5%–7% of the Caucasian population are classified as CYP2D6 poor metabolizers (PM) with 2 genes that confer poor enzymatic function.3,4 Common variant alleles with decreased activity are also found in 50% of Asians and 24% of African and African American populations.5
Poor metabolizers have only 26% (74% reduction) of the plasma endoxifen concentration as their extensive metabolizer (EM) counterparts.6 Medications classified as strong inhibitors of tamoxifen biotransformation reduce plasma concentrations of active metabolites by as much as 64%.7
The oral mucosa (check) of the buccal cavity is covered with a superficial layer of stratified squamous epithelium approximately 40 to 50 cells thick. Below this lies a basement membrane, a lamina propria followed by the submucosa. A layer of saliva approximately 70:m thick blankets the epithelium. As a result, this non-keratinized epithelium offers less of a permeation barrier than skin. On the other hand, the gingiva is keratinized and represents a major barrier to drug permeation. A network of capillaries provides blood flow to the oral mucosa. (The buccal region is the most perfused mucosa in the oral cavity.) The external carotid artery supplies arterial blood, while the jugular vein carries away the venous backflow. Various substances in the epithelium are drained by diffusion into the network of microcirculation, which provides access to the systemic circulation. Drug molecules absorbed by the oral mucosa thus avoid “first pass” metabolism.
Although .75-2.0 liters of saliva are produced daily only a tiny fraction of that amount is available in the limited space in which the tablet resides, probably no more than 5 to 10 ml in a day. (Saliva has a pH of 6.8 to 7.2.)
- Goetz MP. The development of endoxifen for breast cancer. Clinical Advances in Hematology and Oncology. 2018; 16(2) 1-6.
- Westbrook K, Stearns V. Pharmacogenomics of breast cancer therapy: An update.Pharmacol Ther. 2013;139(1):1-11.
- Mizutani T. PM frequencies of major CYPs in Asians and Caucasians. Drug Metab Rev.2003;35(2-3):99-106.
- Tamminga WJ, Werner J, Oosterhuis B, de Zeeuw RA, de Leij LF, Jonkman JH. The prevalence of CYP2D6 and CYP2C19 genotypes in a population of healthy Dutch volunteers. Eur J Clin Pharmacol. 2001;57(10):717-722.
- Higgins MJ, Stearns V. Pharmacogenetics of endocrine therapy for breast cancer. Annu Rev Med. 2011;62:281-293.
- Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst.2005; 97:30-39.
- Stearns V, Johnson MD, Rae JM, et al. Active tamoxifen metabolite plasma concentrations after co-administration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine.J Natl Cancer Inst. 2003;95(23):1758-1764.