Actions of Arinib in details
Pharmacology: Pharmacodynamics: Arinib is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, estradiol is produced primarily from the conversion of androstenedione to estrone through the aromatase enzyme complex in peripheral tissues. Estrone is subsequently converted to estradiol. Reducing circulating estradiol levels has been shown to produce a beneficial effect in women with breast cancer.
In postmenopausal women, Arinib at a daily dose of 1 mg produced estradiol suppression of greater than 80% using a highly sensitive assay.
Arinib does not possess progestogenic, androgenic or estrogenic activity.
Daily doses of Arinib up to 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard ACTH challenge testing. Corticoid supplements are therefore not needed.
An extensive phase III clinical study programme showed that Arinib is an effective treatment of early breast cancer and advanced breast cancer in postmenopausal women suitable for endocrine therapy.
Primary Adjuvant Treatment of Early Breast Cancer: In a large phase III study conducted in 9366 postmenopausal women with operable breast cancer treated for 5 years, Arinib was shown to be statistically superior to tamoxifen in disease free survival. A greater magnitude of benefit was observed for disease free survival in favour of Arinib versus tamoxifen for the prospectively defined hormone receptor positive population.
Arinib was statistically superior to tamoxifen in time to recurrence. The difference was of greater magnitude than in disease free survival for both the Intention To Treat (ITT) population and hormone receptor positive population.
Arinib was statistically superior to tamoxifen in terms of time to distant recurrence. There was also a numerical trend in favour of Arinib for distant disease free survival.
The incidence of contralateral breast cancer was statistically reduced for Arinib compared to tamoxifen.
The overall survival benefit of tamoxifen was maintained with Arinib. The additional analysis of time to death following recurrence showed a numerical trend in favour of Arinib compared to tamoxifen.
Overall, Arinib was well tolerated. The following adverse events were reported regardless of causality. Patients receiving Arinib had a decrease in hot flushes, vaginal bleeding, vaginal discharge, endometrial cancer, venous thromboembolic events and ischemic cerebrovascular events compared with patients receiving tamoxifen. Patients receiving Arinib had an increase in joint disorders (including arthritis, arthrosis and arthralgia) and fractures compared with patients receiving tamoxifen. A fracture rate of 22 per 1000 patient years was observed on Arinib and 15 per 1000 patient years with the tamoxifen group with a median follow up of 68 months. The fracture rate for Arinib falls within the broad range of the fracture rates reported in an age matched postmenopausal population.
The combination of Arinib and tamoxifen did not demonstrate any efficacy benefits in comparison with tamoxifen in all patients as well as in the hormone receptor positive population. This treatment arm was discontinued from the study.
Adjuvant Treatment of Early Breast Cancer for Patients Being Treated With Adjuvant Tamoxifen: In a phase III trial (ABCSG 8) conducted in 2579 postmenopausal women with hormone receptor positive early breast cancer being treated with adjuvant tamoxifen, patients had a superior disease-free survival when switched to Arinib compared with those continuing on tamoxifen.
Time to any recurrence, time to local or distant recurrence and time to distant recurrence confirmed a statistical advantage for Arinib, consistent with the results of disease free survival. The incidence of contralateral breast cancer was very low in the two treatment arms, with a numerical advantage for Arinib. Overall survival was similar for the two treatment groups.
Two further similar trials (GABG/ARNO 95 and ITA) with Arinib, as well as a combined analysis of ABCSG 8 and GABG/ARNO 95, supported these results.
The Arinib safety profile in these 3 studies was consistent with the known safety profile established in post-menopausal women with hormone-receptor positive early breast cancer.
Study on Arinib with Bisphosphonate Risedronate (SABRE): BMD: In the phase III/IV SABRE study, 234 postmenopausal women with hormone receptor positive early breast cancer scheduled for treatment with Arinib were stratified to low, moderate and high-risk groups according to their existing risk of fragility fracture. All patients received treatment with vitamin D and calcium. Patients in the low risk group received Arinib alone, those in the moderate group were randomised to Arinib plus bisphosphonate or Arinib plus placebo and those in the high risk group received Arinib plus bisphosphonate.
The 12-month main analysis has shown that patients already at moderate to high risk of fragility fracture had their bone health (assessed by bone mineral density and bone formation and resorption markers) successfully managed by using Arinib in combination with a bisphosphonate. In addition, no changes in BMD were seen in the low risk group treated with Arinib alone and given vitamin D and calcium. These findings were mirrored in the secondary efficacy variable of change from baseline in total hip BMD at 12 months.
This study provides evidence that postmenopausal women with early breast cancer scheduled to be treated with Arinib should have their bone status managed according to treatment guidelines already available for postmenopausal women at similar risk of fragility fracture.
Lipids: In the SABRE study there was a neutral effect on plasma lipids both in those patients treated with Arinib alone and in those treated with Arinib plus a bisphosphonate.
Pediatrics: Three clinical trials were conducted in pediatric patients (2 in pubertal boys with gynecomastia and 1 in pediatric girl with McCune Albright syndrome).
Gynecomastia Study: Trial 0006 was a randomized, double-blind, multi-center study, of 80 pubertal boys with gynecomastia of greater than 12 months duration (aged 11-18 years inclusive) treated with Arinib 1 mg/day or placebo daily for up to 6 months. A decrease of ≥50% in total breast volume measured by ultrasound was seen in 38.5% (15/39) of the Arinib and 31.4% (11/35) of the placebo treated group, (odds ratio=1.513, 95% CI 0.496 to 4.844, p=0.4687).
Trial 0001 was an open label, multiple-dose pharmacokinetic (PK) study of Arinib 1 mg/day in 36 pubertal boys with gynecomastia of less than 12 months duration. A decrease in total breast volume of 50% or greater at 6 months was seen in 55.6% (20/36) of the boys.
McCune Albright Syndrome (MAS) Study: Trial 0046 was an international, multi-center, open-label, exploratory trial of Arinib in 28 girls (aged 2 to ≤10 years) with McCune-Albright Syndrome (MAS). No statistically significant change in the frequency of vaginal bleeding days on treatment was observed. Of the patients with baseline vaginal bleeding, 28% experienced a ≥50% reduction in the frequency of bleeding days on treatment; 40% experienced a cessation over a 6-month period, and 12% experienced a cessation over a 12-month period. There were no clinically significant changes in Tanner staging, mean ovarian volume or mean uterine volume. No statistically significant change in the rate of increase in bone age on treatment compared to the rate during baseline was observed. Growth rate (in cm/year) was significantly reduced (p<0.05) from pre-treatment through month 0 to month 12, and from pre-treatment to the second 6 months (month 7 to month 12).
The overall assessment of the AEs in children less than 18 years of age raised no safety and tolerability concerns.
Pharmacokinetics: Absorption of Arinib is rapid and maximum plasma concentrations typically occur within two hours of dosing (under fasted conditions). Arinib is eliminated slowly with a plasma elimination half-life of 40 to 50 hours. Food slightly decreases the rate but not the extent of absorption. The small change in the rate of absorption is not expected to result in a clinically significant effect on steady-state plasma concentrations during once daily dosing of Arinib tablets. Approximately 90 to 95% of plasma Arinib steady-state concentrations are attained after 7 daily doses. There is no evidence of time or dose-dependency of Arinib pharmacokinetic parameters.
Arinib pharmacokinetics is independent of age in postmenopausal women.
In boys with pubertal gynecomastia, Arinib was rapidly absorbed, was widely distributed, and was eliminated slowly with a half-life of approximately 2 days. PK parameters in boys were comparable to those of postmenopausal women. Clearance of Arinib was lower in girls than in boys and exposure higher. Arinib in girls was widely distributed and slowly eliminated, with an estimated half-life of approximately 0.8 days.
Arinib is only 40% bound to plasma proteins.
Arinib is extensively metabolised by postmenopausal women with less than 10% of the dose excreted in the urine unchanged within 72 hours of dosing. Metabolism of Arinib occurs by N-dealkylation, hydroxylation and glucuronidation. The metabolites are excreted primarily via the urine. Triazole, a major metabolite in plasma and urine, does not inhibit aromatase.
The apparent oral clearance of Arinib in volunteers with stable hepatic cirrhosis or renal impairment was in the range observed in healthy volunteers.
Toxicology: Preclinical Safety Data: Acute Toxicity: In acute toxicity studies in rodents the median lethal dose of Arinib was greater than 100 mg/kg by the oral route and greater than 50 mg/kg by the intraperitoneal route. In an oral acute toxicity study in the dog the median lethal dose was greater than 45 mg/kg.
Chronic Toxicity: Multiple dose toxicity studies utilised rats and dogs. No no-effect levels were established for Arinib in the toxicity studies, but those effects that were observed at the low dose (1 mg/kg/day) and mid doses (dog 3 mg/kg/day; rat 5 mg/kg/day) were related to either the pharmacological or enzyme inducing properties of Arinib, and were unaccompanied by significant toxic or degenerative changes.
Mutagenicity: Genetic toxicology studies with Arinib show that it is not a mutagen or a clastogen.
Reproductive Toxicology:
Oral administration of Arinib to pregnant rats and rabbits caused no teratogenic effects at doses up to 1.0 and 0.2 mg/kg/day respectively. Those effects that were seen (placental enlargement in rats and pregnancy failure in rabbits) were related to the pharmacology of the compound.
Oral administration of Arinib to female rats produced a high incidence of infertility at 1 mg/kg/day and increased pre-implantation loss at 0.02 mg/kg/day. These effects were related to the pharmacology of the compound and were completely reversed after a 5-week compound withdrawal period.
The survival of litters born to rats given Arinib at 0.02 mg/kg/day and above (from day 17 of pregnancy to day 22 post-partum) was compromised. These effects were related to the pharmacological effects of the compound on parturition. There were no adverse effects on behaviour or reproductive performance of the first generation offspring attributable to maternal treatment with Arinib.
Carcinogenicity: A two-year rat oncogenicity study resulted in an increase in incidence of hepatic neoplasms and uterine stromal polyps in females and thyroid adenomas in males at the high dose (25 mg/kg/day) only. These changes occurred at a dose, which represents 100-fold greater exposure than occurs at human therapeutic doses, and are considered not to be clinically relevant to the treatment of patients with Arinib.
A two-year mouse oncogenicity study resulted in the induction of benign ovarian tumours and a disturbance in the incidence of lymphoreticular neoplasms (fewer histiocytic sarcomas in females and more deaths as a result of lymphomas). These changes are considered to be mouse-specific effects of aromatase inhibition and not clinically relevant to the treatment of patients with Arinib.
How should I take Arinib?
Take Arinib only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance for side effects.
You may take Arinib with or without food.
Arinib sometimes causes nausea, vomiting, or diarrhea. However, it is very important that you continue to use the medicine, even if you begin to feel ill. Ask your doctor for ways to prevent these effects or make them less severe.
Arinib comes with a patient information leaflet. Read and follow these instructions carefully. Ask your doctor if you have any questions.
Dosing
The dose of Arinib will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Arinib. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
- For oral dosage form (tablets):
- For breast cancer:
- Adults—1 milligram (mg) once a day.
- Children—Use and dose must be determined by your doctor.
- For breast cancer:
Missed Dose
If you miss a dose of Arinib, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Storage
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Arinib administration
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Arinib is usually taken once per day. You may need to keep taking this medication for up to 5 years. Follow your doctor's instructions.
You may take Arinib with or without food.
Store at room temperature away from moisture and heat.
Arinib pharmacology
Mechanism of Action
The growth of many cancers of the breast is stimulated or maintained by estrogens.
In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
Arinib is a selective non-steroidal aromatase inhibitor. It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone.
Pharmacodynamics
Effect on EstradiolMean serum concentrations of estradiol were evaluated in multiple daily dosing trials with 0.5, 1, 3, 5, and 10 mg of Arinib in postmenopausal women with advanced breast cancer. Clinically significant suppression of serum estradiol was seen with all doses. Doses of 1 mg and higher resulted in suppression of mean serum concentrations of estradiol to the lower limit of detection (3.7 pmol/L). The recommended daily dose, Arinib 1 mg, reduced estradiol by approximately 70% within 24 hours and by approximately 80% after 14 days of daily dosing. Suppression of serum estradiol was maintained for up to 6 days after cessation of daily dosing with Arinib 1 mg.
The effect of Arinib in premenopausal women with early or advanced breast cancer has not been studied. Because aromatization of adrenal androgens is not a significant source of estradiol in premenopausal women, Arinib would not be expected to lower estradiol levels in premenopausal women.
Effect on Corticosteroids
In multiple daily dosing trials with 3, 5, and 10 mg, the selectivity of Arinib was assessed by examining effects on corticosteroid synthesis. For all doses, Arinib did not affect cortisol or aldosterone secretion at baseline or in response to ACTH. No glucocorticoid or mineralocorticoid replacement therapy is necessary with Arinib.
Other Endocrine Effects
In multiple daily dosing trials with 5 and 10 mg, thyroid stimulating hormone (TSH) was measured; there was no increase in TSH during the administration of Arinib. Arinib does not possess direct progestogenic, androgenic, or estrogenic activity in animals, but does perturb the circulating levels of progesterone, androgens, and estrogens.
Pharmacokinetics
AbsorptionInhibition of aromatase activity is primarily due to Arinib, the parent drug. Absorption of Arinib is rapid and maximum plasma concentrations typically occur within 2 hours of dosing under fasted conditions. Studies with radiolabeled drug have demonstrated that orally administered Arinib is well absorbed into the systemic circulation. Food reduces the rate but not the overall extent of Arinib absorption. The mean Cmax of Arinib decreased by 16% and the median Tmax was delayed from 2 to 5 hours when Arinib was administered 30 minutes after food. The pharmacokinetics of Arinib are linear over the dose range of 1 to 20 mg, and do not change with repeated dosing. The pharmacokinetics of Arinib were similar in patients and healthy volunteers.
Distribution
Steady-state plasma levels are approximately 3- to 4-fold higher than levels observed after a single dose of Arinib. Plasma concentrations approach steady-state levels at about 7 days of once daily dosing. Arinib is 40% bound to plasma proteins in the therapeutic range.
Metabolism
Metabolism of Arinib occurs by N-dealkylation, hydroxylation and glucuronidation. Three metabolites of Arinib (triazole, a glucuronide conjugate of hydroxy-Arinib, and a glucuronide conjugate of Arinib itself) have been identified in human plasma and urine. The major circulating metabolite of Arinib, triazole, lacks pharmacologic activity.
Arinib inhibited reactions catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which were approximately 30 times higher than the mean steady-state Cmax values observed following a 1 mg daily dose. Arinib had no inhibitory effect on reactions catalyzed by cytochrome P450 2A6 or 2D6 in vitro. Administration of a single 30 mg/kg or multiple 10 mg/kg doses of Arinib to healthy subjects had no effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites.
Excretion
Eighty-five percent of radiolabeled Arinib was recovered in feces and urine. Hepatic metabolism accounts for approximately 85% of Arinib elimination. Renal elimination accounts for approximately 10% of total clearance. The mean elimination half-life of Arinib is 50 hours.
Effect of Gender and Age
Arinib pharmacokinetics have been investigated in postmenopausal female volunteers and patients with breast cancer. No age-related effects were seen over the range <50 to >80 years.
Effect of Race
Estradiol and estrone sulfate serum levels were similar between Japanese and Caucasian postmenopausal women who received 1 mg of Arinib daily for 16 days. Arinib mean steady-state minimum plasma concentrations in Caucasian and Japanese postmenopausal women were 25.7 and 30.4 ng/mL, respectively.
Effect of Renal Impairment
Arinib pharmacokinetics have been investigated in subjects with renal impairment. Arinib renal clearance decreased proportionally with creatinine clearance and was approximately 50% lower in volunteers with severe renal impairment (creatinine clearance < 30 mL/min/1.73m2) compared to controls. Total clearance was only reduced 10%. No dosage adjustment is needed for renal impairment.
Effect of Hepatic Impairment
Arinib pharmacokinetics have been investigated in subjects with hepatic cirrhosis related to alcohol abuse. The apparent oral clearance (CL/F) of Arinib was approximately 30% lower in subjects with stable hepatic cirrhosis than in control subjects with normal liver function. However, these plasma concentrations were still with the range of values observed in normal subjects. The effect of severe hepatic impairment was not studied. No dose adjustment is necessary for stable hepatic cirrhosis.
References
- DailyMed. "ANASTROZOLE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Anastrozole: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Anastrozole: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
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Information checked by Dr. Sachin Kumar, MD Pharmacology
