Alectinib (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

, marketed as Alecensa) is an oral drug that blocks the activity of

anaplastic lymphoma kinase Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246) is an enzyme that in humans is encoded by the ''ALK'' gene. Identification Anaplastic lymphoma kinase (ALK) was originally d ...

(ALK)New Oral Therapy To Treat ALK-Positive Lung Cancer. Dec 2015
/ref> and is used to treat

non-small-cell lung cancer Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to s ...

(NSCLC). It was developed by Chugai Pharmaceutical Co. Japan, which is part of the Hoffmann-La Roche group.

History, clinical trials, Approvals and medical uses

Alectinib was approved in Japan in July 2014Japan becomes first country to approve Roche's alectinib for people with a specific form of advanced lung cancer
/ref> for the treatment of ALK fusion-gene positive, unresectable, advanced or recurrent non-small-cell lung cancer (NSCLC). It was granted an accelerated approval by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) in December 2015 to treat patients with advanced ALK-positive NSCLC whose disease worsened after, or who could not tolerate, treatment with

crizotinib Crizotinib, sold under the brand name Xalkori among others, is an anti-cancer medication used for the treatment of non-small cell lung carcinoma (NSCLC). It acts as an ALK ( anaplastic lymphoma kinase) and ROS1 ( c-ros oncogene 1) inhibitor. ...

(Xalkori). (This was converted into a full approval in Nov 2017). It got a conditional approval by the European Medicines Agency in February 2017 for the same indication. This means that additional studies are awaited to confirm a positive benefit-risk-ratio. The approvals were based mainly on two trials: In a Japanese Phase I–II trial, after approximately 2 years, 19.6% of patients had achieved a complete response, and the 2-year

progression-free survival Progression-free survival (PFS) is "the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse". In oncology, PFS usually refers to situations in which a tumor is p ...

rate was 76%. In February 2016 the J-ALEX phase III study comparing alectinib with crizotinib was terminated early because an interim analysis showed that

was longer with alectinib. In November 2017 the FDA approved alectinib for the

first-line treatment A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis. As a rule, each therapy has indications and contraindications. There are many different ...

of patients with ALK-positive metastatic non-small cell lung cancer.''FDA approves Alecensa for ALK-positive metastatic non-small cell lung cancer'' Nov 2017
/ref> This based on the phase 3 ALEX trial comparing it with

Contraindications

There are no

contraindication In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...

s under the US approval. on Alecensa. The European approval only has the default remark about

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...

being a contraindication.

Side effects

Apart from unspecific

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

effects such as

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...

(in 34% of patients) and

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

(22%), common adverse effects in studies included

oedema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels tight, the area ma ...

(swelling; 34%), myalgia (muscle pain; 31%),

anaemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...

(low red blood cell count), sight disorders, light sensitivity and

rash A rash is a change of the human skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, c ...

es (all below 20%). Serious side effects occurred in 19% of patients; fatal ones in 2.8%.

Interactions

Alectinib has a low potential for interactions. While it is metabolised by the liver enzyme CYP3A4, and blockers of this enzyme accordingly increase its concentrations in the body, they also ''decrease'' concentrations of the

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

M4, resulting in only a small overall effect. Conversely, CYP3A4

inducer In molecular biology, an inducer is a molecule that regulates gene expression. An inducer functions in two ways; namely: *By disabling repressors. The gene is expressed because an inducer binds to the repressor. The binding of the inducer to the r ...

s decrease alectinib concentrations and increase M4 concentrations. Interactions via other CYP enzymes and

transporter protein A transport protein (variously referred to as a transmembrane pump, transporter, escort protein, acid transport protein, cation transport protein, or anion transport protein) is a protein that serves the function of moving other materials within ...

s cannot be excluded but are unlikely to be of clinical significance.

Pharmacology

Mechanism of action

The substance potently and selectively blocks two

receptor tyrosine kinase Receptor tyrosine kinases (RTKs) are the high- affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kin ...

enzymes:

(ALK) and the RET proto-oncogene. The active metabolite M4 has similar activity against ALK. Inhibition of ALK subsequently blocks cell signalling pathways, including

STAT3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respons ...

and the PI3K/AKT/mTOR pathway, and induces death ( apoptosis) of tumour cells.

Pharmacokinetics

When taken with a meal, the absolute

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

of the drug is 37%, and highest

blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intr ...

concentrations are reached after four to six hours. Steady state conditions are reached within seven days.

Plasma protein binding Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse t ...

of alectinib and M4 is over 99%. The enzyme mainly responsible for alectinib metabolism is CYP3A4; other CYP enzymes and

aldehyde dehydrogenase Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have b ...

s only play a small role. Alectinib and M4 account for 76% of the circulating substance, while the rest are minor metabolites.

Plasma half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

of alectinib is 32.5 hours, and that of M4 is 30.7 hours. 98% are excreted via the faeces, of which 84% are unchanged alectinib and 6% are M4. Less than 1% are found in the urine.

Chemistry

Alectinib has a pK_a of 7.05. It is used in form of the

hydrochloride In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternative n ...

, which is a white to yellow-white lumpy powder.

References

External links

* {{Portal bar , Medicine Breakthrough therapy Hoffmann-La Roche brands Genentech brands Carbazoles Ketones 4-Morpholinyl compunds Nitriles Piperidines Receptor tyrosine kinase inhibitors