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letro/plasma level question?
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TweetPharmacokinetics: Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway. About 90% of radiolabeled letrozole is recovered in urine. Letrozole's terminal elimination half-life is about 2 days and steady-state plasma concentration after daily 2.5 mg dosing is reached in 2-6 weeks. Plasma concentrations at steady-state are 1.5 to 2 times higher than predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. These steady-state levels are maintained over extended periods, however, and continuous accumulation of letrozole does not occur. Letrozole is weakly protein bound and has a large volume of distribution (approximately 1.9 L/kg).
What is letrozole?
Letrozole is a type of drug called an aromatase inhibitor. Aromatase inhibitors work by limiting the ability of an enzyme called aromatase to create estrogen—a major growth factor in hormone-receptor positive breast cancers
How is letrozole different from tamoxifen?
Letrozole suppresses the production of estrogen. Tamoxifen has no effect on the production of estrogen. Rather, it prevents the binding of estrogens to the estrogen-receptors of the cancer cells and therefore blocks the stimulation of the tumour.
Letrozole is in a class of drugs known as aromatase inhibitors; it prevents formation of estrogen. Although estrogen is a hormone naturally produced by the body, it can stimulate and maintain the growth of certain types of cancer. Letrozole slows or stops the growth of cancer cells by decreasing the amount of estrogen produced.
Precautions
Before taking letrozole,
tell your doctor and pharmacist if you are allergic to letrozole or any other drugs. tell your doctor or pharmacist what prescription and nonprescription medications you are taking, including vitamins. tell your doctor if you have or have ever had liver disease. Side effects Although side effects from letrozole are not common, they can occur.
Tell your doctor if any of these symptoms are severe or do not go away:
nausea
vomiting
muscle or bone pain
fatigue
headache
dizziness
muscle weakness
swelling of the hands, feet, or lower legs
loss of appetite
constipation
diarrhea
abdominal pain
hot flashes
cough
Letrozole is a potent and highly specific nonsteroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues.
Letrozole exerts its antitumor effect by depriving estrogen-dependent breast cancer cells of one of their growth stimuli. In postmenopausal women, estrogens are derived mainly from the action of the aromatase enzyme, which converts adrenal androgens--primarily androstenedione and testosterone--to estrone (E1) and estradiol (E2). The suppression of estrogen biosynthesis in peripheral tissues and the malignant tissue can be achieved by specifically inhibiting the aromatase enzyme.
In healthy postmenopausal women, single oral doses of 0.1, 0.5 and 2.5 mg letrozole suppressed serum estrone by 75 to 78% and estradiol by 78% from baseline. Maximum suppression is achieved in 48 to 78 hours.
In postmenopausal women with advanced breast cancer, daily letrozole doses of 0.1 to 5 mg suppress estradiol, estrone and estrone sulfate plasma levels by 75 to 95% from baseline in all patients treated. With 0.5 mg doses and higher, many plasma levels of estrone and estrone sulfate are below the limit of detection of the assays, indicating that higher estrogen suppression is achieved with these doses. Estrogen suppression was maintained throughout treatment in all patients.
Letrozole is highly specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not been observed. No clinically relevant changes in the plasma levels of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH (adrenocorticotropic hormone) or in plasma renin activity were found in postmenopausal patients treated with 0.1 to 5 mg letrozole daily. The ACTH stimulation test performed after 6 and 12 weeks of treatment with daily doses of 0.1 to 5 mg letrozole did not indicate any attenuation of aldosterone or cortisol production. Thus, glucocorticoid or mineralocorticoid supplementation is not required.
Letrozole had no effect on plasma androgen concentrations (androstenedione and testosterone) among healthy postmenopausal women after single doses of 0.1, 0.5 and 2.5 mg, or on plasma androstenedione concentrations among postmenopausal patients treated with daily doses of 0.1 to 5 mg. These results indicate that accumulation of androgenic precursors does not occur. Plasma levels of LH and FSH are not affected by letrozole in patients, nor is thyroid function as evaluated by TSH, T 4 and T 3 uptake.
Clinical Studies: First-line Therapy: One large, randomized, well-controlled, multinational, double-blind Phase III trial was conducted in 907 postmenopausal patients with locally advanced or metastatic breast cancer. Patients were randomized to letrozole 2.5 mg daily or tamoxifen 20 mg daily.
Time to progression (TTP) was the primary endpoint of the trial. In 907 women, letrozole was superior to tamoxifen in TTP (P=0.0001). Median TTP was 9.4 months for letrozole versus 6 months for tamoxifen. Letrozole was also superior to tamoxifen in secondary endpoints consisting of overall objective tumor response [Complete Response (CR) + Partial Response (PR)], time to treatment failure (TTF) and clinical benefit (CR+PR+NC>24 weeks). Objective response rate was statistically significant (P=0.0006) for letrozole as compared to tamoxifen: 30% of patients in the letrozole arm achieved a confirmed response (CR, 8%; PR, 23%), compared with 20% (CR, 3%; PR, 17%) in the tamoxifen arm. There was no significant difference in duration of objective response rate (median duration 17 months for letrozole; 16 months for tamoxifen), although duration of tumor response favored letrozole. TTF was statistically significant for letrozole as compared to tamoxifen (P=0.0001). Median TTF was 9.1 months for letrozole versus 5.7 months for tamoxifen. Clinical benefit was statistically significant for letrozole when compared to tamoxifen (49% vs 38%, P=0.001). There were no significant differences in duration of clinical benefit (median duration 15 months for letrozole; 15 months for tamoxifen).
In conclusion, in the above large, well-controlled, double-blind, multinational, phase III clinical trial, women treated with letrozole had better results on primary, and secondary endpoints (TTP, TTF objective tumor response and clinical benefit) than women treated with tamoxifen. There are no data yet, however, whether treatment with letrozole confers survival advantage over therapy with tamoxifen.
Second-line Therapy: In a controlled double-blind clinical trial, the overall objective tumor response rate (complete and partial response) was 23.6% in letrozole-treated patients compared to 16.4% in patients on 160 mg megestrol acetate. Treatment comparison of the response rate showed a statistically significant difference in favor of 2.5 mg letrozole (p=0.04).
In an open-label, randomized clinical trial, survival at 2 years was 55.1% for patients treated with letrozole compared to 38.8% for patients treated with 500 mg aminoglutethimide. Treatment comparison showed a statistically significantly prolonged overall survival with letrozole (adjusted Cox regression hazard ratio 0.68, 95%, Cl 0.52-0.87, p=0.003).
Pharmacokinetics: Absorption: Letrozole is rapidly and completely absorbed from the gastrointestinal tract (absolute bioavailability=99.9%). Food slightly decreases the rate of absorption (median t max 1 hour fasted vs 2 hours fed and mean C max 129±20.3 nmol/L fasted vs 98.7±18.6 nmol/L fed), but the extent of absorption (area under the curve (AUC)) remains unchanged. This minor effect on absorption rate is not considered to be of clinical relevance and therefore letrozole may be taken with or without food.
Distribution: Letrozole is rapidly and extensively distributed into tissues (Vd ss=1.87±0.47 L/kg). Plasma protein binding is approximately 60%, mainly to albumin. The letrozole concentration in erythrocytes is about 80% of that in plasma. After administration of 2.5 mg 14C-labeled letrozole, approximately 82% of the radioactivity in plasma was unchanged compound. Systemic exposure to metabolites is therefore low.
Biotransformation and Elimination: Metabolic clearance to a pharmacologically inactive carbinol metabolite, CGP 44645, is the major elimination pathway of letrozole (Cl m=2.1 L/h), but it is relatively slow when compared to hepatic blood flow (about 90 L/h). The cytochrome P450 isoenzymes 3A4 and 2A6 were found to be capable of converting letrozole to this metabolite. Formation of minor unidentified metabolites and direct renal and fecal excretion play only a minor role in the overall elimination of letrozole. Within 2 weeks after administration of 2.5 mg 14C-labeled letrozole to healthy postmenopausal volunteers, 88.2±7.6% of the radioactivity was recovered in urine and 3.8±0.9% in feces. At least 75% of the radioactivity recovered in urine up to 216 hours (84.7±7.8% of the dose) was attributed to the glucuronide of the carbinol metabolite, about 9% to 2 unidentified metabolites, and 6% to unchanged letrozole.
The apparent terminal elimination half-life in plasma is about 2 days. After daily administration of 2.5 mg steady-state levels are reached within 2 to 6 weeks. Plasma concentrations at steady-state are approximately 7 times higher than concentrations measured after a single dose of 2.5 mg, while they are 1.5 to 2 times higher than steady-state values predicted from the concentrations measured after a single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. Since steady-state levels are maintained over time, it can be concluded that no continuous accumulation of letrozole occurs.
