A Comparison of Letrozole and Tamoxifen
Tamoxifen is marketed under the brand name Nolvadex®. It is
indicated in patients with breast cancer or anovulatory infertility. It has
been shown in studies that a five year course of treatment with tamoxifen
reduces the risk of the recurrence of breast cancer by 47%. It also reduces the
risk of death of patients with a hormone receptor positive breast cancer by 26%.
Letrozole is marketed under the brand name Femara®. It is used as an
adjuvant treatment of patients with invasive early hormone receptor positive
breast cancer and as first line treatment in patients with advanced breast
cancer that is hormone dependant. Letrozole is most commonly used in
postmenopausal patients. Femara has not been studied with regards to the
treatment of breast cancer in men.
Compartment Models in pharmacokinetics are used to describe the path
the drug takes in the body, which is split into different compartments.
The One-Compartment Model can be applied to Tamoxifen. A
One-Compartment model can be explained as the body acting like a single
continuous compartment for the absorption, distribution and elimination of the
drug. This means that the rates of absorption, metabolism and excretion can be
assumed to have a direct proportionality to the concentration of Tamoxifen in
Letrozole is considered to follow the Two-Compartment Model. This
type of model divides the body into two compartments – peripheral and central
compartments. The central compartment includes the tissues and the plasma where
the drug is absorbed and distributed immediately. The peripheral compartment on
the other hand consists of tissues where the drug is distributed to at a slower
A paper by S. Yuan has also been published testing the above model
given to Tamoxifen. The paper published the results that there was a
significant difference in the absorption and metabolism rates in the peripheral
and central compartments, the central compartment having much higher rates,
proving that the Pharmacokinetic Model of Tamoxifen is a One-Compartment Model.
Letrozole is known to have a mean absolute bioavailability of 99%.
This means that it is fully absorbed through the gastrointestinal tract at a
Tamoxifen is also rapidly absorbed, post-oral administration, to
reach its highest concentrations in serum after 4-7 hours.
ADD ONE COMPARTMENT AND TWO COMPARTMENT DIAGRAMS
An important part of clinical trials is determining the affinity of
the drug to blood proteins, most commonly albumin. Letrozole has a plasma
protein binding of around 60%, 55% of it to albumin. On the other hand,
Tamoxifen is more highly bound to proteins, being 99% bound to serum albumin.
This leads to a very high apparent volume of distribution (Vd) at steady state
(50 liters/kg) when compared to the low apparent volume of distribution at
steady state of Letrozole (2 liters/kg). This shows how, as mentioned before,
Tamoxifen follows a One-Compartment Model since there is a very high
distribution to the peripheral tissues with only a small amount of the
administered drug in the other compartments of the body. This type of
pharmacokinetic feature is common with highly lipophilic and basic drugs such
The major pathway by which Letrozole
is eliminated in the body is by the clearance of Carbinol. The metabolism of
Letrozole to Carbinol is known to be due to the action of two Cytochrome P450
isoenzymes in the liver. The action of Letrozole is aided when the drug
competitively binds to the heme group of the cytochrome P450 subunit of the
aromatase enzyme resulting in the inhibition of the enzyme, thus the reduction
of oestrogen synthesis in the tissues.
Other forms of metabolism of Letrozole, such as excretion by faecal
route via the formation of other metabolites, among others, is considered to
play only a minor role.
Tamoxifen, on the
other hand, is highly metabolised after administration. The major metabolite is
N-Desmethyl-Tamoxifen and is found in high plasma concentrations. The extensive
metabolism of Tamoxifen does not prove to be problematic as the metabolite also
has a similar pharmacologic activity to Tamoxifen. 4-Hydroxy-Tamoxifen is also a
metabolite of Tamoxifen found in the plasma. This metabolite is formed by the
action of Cytochrome P450 along with other enzymes. Compared to Tamoxifen, its
metabolites have a greater affinity for oestrogen receptors and also inhibit
the oestrogen-dependant cell proliferation at a greater strength. Thus, the
metabolism of Tamoxifen aids the drugs’ action even further.
was found present on the first day of testing where as N-Desmethyl-Tamoxifen
was measured in urine and bile up to 4 days after administration. Thus,
4-Hydroxy is considered to be a metabolite obtained via First Pass Effect.
Studies have been
conducted on both Letrozole and Tamoxifen to obtain results on how much of the
drug is excreted by the body and through which routes excretion is most common.
These studies involve the reaction of the coumpounds with radioactive 14-C
compounds involve the reaction of the co to be able to measure the percentages
of each. Table 1 below shows the information gathered among several
studies for both Tamoxifen and Letrozole:
Zero Order or First Order
Rate of Drug Metabolism
Extensive and Immediate
Activity of Metabolites
30-100x more potent than Tamoxifen
Renal Elimination was the Main Route.
Renal, Faecal and Biliary Excretion Mechanisms
88% of Drug in
– 75% Carbinol
– 6% Unchanged Letrozole
– 7% Other Metabolites
4% of Drug in
<30%: Unchanged Drug and Unconjugated Metabolites Table 1: Comparing data obtained via international studies regarding the metabolism of Letrozole and Tamoxifen ADD FIRST ORDER GRAPH ABSORPTION Elimination DRUG Letrozole Tamoxifen Half-Life Two to Four Days Five to Seven Days Table 2: Comparing the Half Life of Letrozole and Tamoxifen Steady state levels of Letrozole were reached between two to six weeks of a 2.5mg dose administration daily. The plasma concentrations were predicted to be around two times higher after a single dose. However, it was found that the plasma concentrations were in fact seven times higher at the steady state after the single daily dose. This shows that the pharmacokinetic properties of Letrozole indicate a non-linear graph as shown in FIGURE … ABOVE. Tamoxifen, compared to Letrozole, has a longer half life and this is as Tamoxifen has a high volume of distribution. When a drug is absorbed, example by the oral route, it is first distributed to the plasma and then the tissues, mostly adipose tissue. Drugs with a high volume of distribution are distributed to a larger amount of tissues compared to drugs with a low volume of distribution. The elimination of drugs that are distributed to more tissues thus requires more time, leading to a longer half life. This explains why Tamoxifen (high Vd) has a longer half life than Letrozole (low Vd). Dosage Regimen DRUG Letrozole Tamoxifen Route of Administration Oral Route Oral Route Recommended Dose 2.5mg 20mg Dosage Frequency Once Daily Once Daily Elderly Patients No Dose Adjustment No Dose Adjustment. Children Not Recommended Not Recommended Renal Impairment No Dose Adjustment No Dose Adjustment Hepatic Impairment No Dose Adjustment for Mild Hepatic Insufficiency. Monitor patients with Hepatic Cirrhosis as some clinical trials have noted an increased exposure to Letrozole No Dose Adjustment Pregnancy and Breast Feeding Should not be used as known to cause birth defects such as Ambiguous Genitalia Should be avoided. Therapeutic Range of the Drug A phase 1 trial was conducted by Trump. D.L. et. al. where increasing doses of oral Tamoxifen on patients with advanced epithelial tumours. Treatment lasted a total of 13 days repeated with 15 day intervals between each treatment. A loading dose was given on Day 1. On days 2-13, two doses of Tamoxifen were given according to the dose that was assigned to the patient. The range of doses of Tamoxifen was as shown in the table below: Tamoxifen Loading Dose (DAY 1) Tamoxifen Oral Dosage Starting Dose 150mg/m2 40mg/m2 b.i.d Maximum Dose 680mg/m2 260mg/m2 Letrozole dosages were found to be pharmacokinetically proportional with doses up to 10mg daily. After a single dose of 30 mg orally, there was a slight increase over the proportional growth expected with a dose increase in the Area Under the Curve (AUC) value. This increase is attributed to the possible saturation of the metabolic elimination processes of Letrozole. Interactions Letrozole should not be used in conjunction with Tamoxifen or other anti-oestrogen therapies as these may decrease the pharmacological action of Letrozole. It has been proven through several clinical trials that co-administration of Letrozole and Tamoxifen cause a significant decrease in Letrozole plasma concentrations. It is known that Letrozole inhibits a number cytochrome P450 isoenzymes in vitro. Thus, Letrozole can only be used with caution in patients that are currently on medications with a narrow therapeutic index such as phenytoin and clopidogrel. This is as since the drug inhibits a number of metabolic enzymes, the possible decreased metabolism of drugs with a narrow therapeutic index will result in an increase in the plasma concentrations of these drugs, leading to the possibility of the drug concentrations entering toxic levels. Tamoxifen should not be used in conjunction with coumarin or coumarin derived anticoagulants such as warfarin as an increase in anticoagulation effect of these drugs may occur. Careful monitoring of the International Normalised Ratio of these patients is highly recommended to prevent blood clotting or internal bleeding. Due to this increased risk of thromboembolic events, Tamoxifen is contraindicated in women with a history of pulmonary emboli or deep vein thrombosis. Tamoxifen is metabolised by CYP2D6, a Cytochrome P450 isoenzyme. Thus, it is not recommended to give Tamoxifen in conjunction with CYP2D6 inhibitors such as Amiodarone and Paroxetine as this will result in a decreased concentration of 4-Hydroxy-Tamoxifen and N-Desmethyl-Tamoxifen resulting in a decreased pharmacological action. Paroxetine is also found under the Selective Serotonin Reuptake Inhibitors class as it is also used to treat depression by increasing serotonin levels in the brain.