Alecensa (alectinib HCl)

Alectinib hydrochloride, an inhibitor of several receptor tyrosine kinases including anaplastic lymphoma kinase (ALK), is an antineoplastic agent.

Alectinib hydrochloride, an inhibitor of receptor tyrosine kinases, including anaplastic lymphoma kinase (ALK) and ret proto-oncogene (RET), is an antineoplastic agent. The drug inhibits ALK phosphorylation and ALK-mediated activation of the downstream signaling proteins signal transducer and activator of transcription 3 (STAT3) and AKT serine/threonine kinase. The drug also inhibits leukocyte tyrosine kinase receptor (LTK) and cyclin-G-associated kinase (GAK).

Activating mutations or translocations of the ALK gene have been identified in several malignancies and can result in the expression of oncogenic fusion proteins (e.g., echinoderm microtubule-associated protein-like 4 (EML4)-ALK). Such ALK gene rearrangements have been identified in approximately 3-7% of patients with non-small cell lung cancer (NSCLC). Formation of ALK fusion proteins such as EML4-ALK results in activation and dysregulation of the gene's expression and signaling, which can contribute to increased cell proliferation and survival in tumors expressing these proteins.

Although the ALK inhibitor crizotinib has demonstrated improved outcomes in patients with NSCLC harboring ALK mutations, secondary resistance to crizotinib eventually develops, generally within the first 1-2 years of treatment. Clinical resistance to crizotinib has been attributed to several possible mechanisms, including acquired resistance mutations of ALK, amplification of gene expression, and activation of alternate signaling pathways. Secondary mutations of ALK are responsible for about 30% of cases of acquired crizotinib resistance and gene amplification is implicated in 9% of these cases.

In vitro, alectinib is approximately fivefold more potent than crizotinib in its activity against ALK. Alectinib demonstrated dose-dependent antitumor activity and increased survival in mice bearing NSCLC tumor xenografts that expressed EML4-ALK, including several cell lines with demonstrated resistance to crizotinib. In preclinical studies in vitro and in vivo, alectinib was active against several crizotinib-resistant ALK mutations (e.g., L1196M, C1156Y, F1174L, G1269A).

The CNS is a common site of disease progression in crizotinib-treated patients because of poor distribution of crizotinib into CSF; development and/or progression of brain metastases occurs in approximately one-half of patients during crizotinib treatment. Alectinib crosses the blood-brain barrier, distributing into CSF at concentrations similar to estimated alectinib free plasma concentrations; the drug demonstrated antitumor activity and increased survival in mice bearing intracranial ALK-positive NSCLC tumor xenografts. In clinical studies, alectinib demonstrated antitumor activity in patients with crizotinib-resistant disease and baseline CNS metastases.

Exposure to alectinib is dose proportional over the oral dose range of 460-900 mg in the fed state. Following oral administration under fed conditions, peak plasma concentrations of alectinib are achieved within 4 hours. Steady-state concentrations of alectinib and its major active metabolite (M4) are achieved within 7 days.

The absolute oral bioavailability of alectinib under fed conditions is 37%. Oral administration of a single 600-mg dose of the drug with a high-calorie, high-fat meal increases total systemic exposure to alectinib and M4 by 3.1-fold compared with administration in the fasting state. Alectinib and M4 are more than 99% bound to plasma proteins; the drug distributes into CSF at concentrations similar to estimated alectinib free plasma concentrations.

Alectinib is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 to its major active metabolite, M4, which also is metabolized by CYP3A4. M4 exhibits in vitro potency and activity similar to those of alectinib. Following oral administration of radiolabeled alectinib, 98% of the dose is eliminated in feces, mainly as unchanged drug (84%) and, to a lesser extent, as M4 (6%); less than 0.5% of the dose is eliminated in urine.

The mean elimination half-lives of alectinib and M4 in patients with ALK-positive NSCLC are 33 and 31 hours, respectively.

USES: Alectinib is used to treat a certain type of lung cancer. It works by slowing or stopping the growth of cancer cells. Alectinib belongs to a class of drugs known as tyrosine kinase inhibitors.

Generic name: alectinib HCl
Pronunciation: (al-EK-ti-nib)
Drug class: Antineoplastic - Protein-Tyrosine Kinase Inhibitors
Therapeutic class: Antineoplastics

The following indications are listed for Alecensa:

• Anaplastic Lymphoma Kinase Positive Non-Small Cell Lung Cancer

Also known as: Alk Positive Nsclc.