Alectinib

L01X - Other antineoplastic agents ATC L01XE36 Small molecule approved 2015 Oral Natural product

JFDA label: Alecensa 150mg hard Capsule

Mechanism of Action

Alectinib is a tyrosine kinase receptor inhibitor which inhibits anaplastic lymphoma kinase (ALK) and RET (with similar potency to ALK; Ou 2016). ALK gene abnormalities due to mutations or translocations may result in expression of oncogenic fusion proteins (eg, ALK fusion protein) which alter signaling and expression and result in increased cellular proliferation and survival in tumors which express these fusion proteins. Inhibition of ALK phosphorylation and ALK-mediated activation of downstream signaling results in decreased tumor cell viability. Alectinib is more potent than crizotinib against ALK, and can inhibit most of the clinically observed acquired ALK resistance mutations to crizotinib (Ou 2016).

Indications

Approved

Non-small cell lung cancer, metastatic

Contraindications

Source: Lexicomp

Known hypersensitivity to alectinib or any component of the formulation Absolute
There are no contraindications listed in the manufacturer’s US labeling Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (3)

Very Common bradycardia · Edema

Common Pulmonary embolism

Nervous system disorders (2)

Very Common Fatigue · headache

Hepatobiliary disorders (4)

Very Common hyperbilirubinemia · increased serum alkaline phosphatase · increased serum ALT · Increased serum AST

Renal and urinary disorders (1)

Very Common Increased serum creatinine

Blood and lymphatic system disorders (2)

Very Common Anemia · lymphocytopenia

Metabolism and nutrition disorders (6)

Very Common Hyperglycemia · hypocalcemia · hypokalemia · hyponatremia · hypophosphatemia · weight gain

Gastrointestinal disorders (4)

Very Common Constipation · diarrhea · nausea · vomiting

Skin and subcutaneous tissue disorders (2)

Very Common Skin rash

Common Photosensitivity dermatitis

Musculoskeletal and connective tissue disorders (5)

Very Common back pain · Increased creatine phosphokinase · musculoskeletal pain · myalgia · weakness

Eye disorders (1)

Common Visual disturbances

Respiratory, thoracic and mediastinal disorders (2)

Very Common Cough · dyspnea

Dosing

Source: Lexicomp

Non-small cell lung cancer (NSCLC), metastatic (ALK-positive): Oral: 600 mg twice daily; continue until disease progression or unacceptable toxicity (Ou 2016; Peters 2017) Missed doses: If a dose is missed or if vomiting occurs, take the next dose at the regularly scheduled time.

Refer to adult dosing.

Preexisting renal impairment: CrCl ≥30 mL/minute: No dosage adjustment is necessary. CrCl Renal toxicity during treatment: Grade 3 renal impairment: Withhold alectinib until serum creatinine recovers to ≤1.5 times ULN, then resume at reduced dose (see Dosage Adjustment for Toxicity for recommended alectinib dosage reduction levels). Grade 4 renal impairment: Permanently discontinue.

Preexisting hepatic impairment: Mild impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST): No dosage adjustment is necessary. Moderate or severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Hepatotoxicity during treatment: ALT or AST >5 times ULN and total bilirubin ≤2 times ULN: Withhold alectinib; upon recovery to baseline or to ALT/AST ≤3 times ULN, may resume at a reduced dose (see Dosage Adjustment for Toxicity for recommended alectinib dosage reduction levels). ALT or AST >3 times ULN and total bilirubin >2 times ULN (in the absence of cholestasis or hemolysis): Permanently discontinue. Total bilirubin >3 times ULN: Withhold alectinib; upon recovery to baseline or to total bilirubin ≤1.5 times ULN, may resume at a reduced dose (see Dosage Adjustment for Toxicity for recommended alectinib dosage reduction levels).

Warnings & Precautions

Source: Lexicomp

Bradycardia

Symptomatic bradycardia may occur; heart rate • Hepatotoxicity: Liver function test abnormalities have been reported, including elevations of AST/ALT >5 times ULN and bilirubin >3 times ULN; most abnormalities occurred during the first 3 months of therapy. Concurrent ALT/AST elevations ≥3 times ULN and total bilirubin ≥2 times ULN with normal alkaline phosphatase occurred rarely. Liver biopsy demonstrated drug induced liver injury in some patients with grade 3 to 4 AST or ALT elevations. Monitor liver function tests (ALT, AST, and total bilirubin) every 2 weeks during the first 3 months of therapy and then once a month and as clinically necessary; monitor more frequently in patients who develop transaminase and bilirubin elevations. May require therapy interruption, dose reduction, or permanent discontinuation.

Myalgia

Myalgia or musculoskeletal pain occurred in over one-quarter of patients treated with alectinib (including grade 3 toxicity). Elevations of creatine phosphokinase (CPK) were commonly reported in clinical trials. The median time to grade 3 CPK elevations was 14 days. Monitor; advise patients to report unexplained muscle pain, tenderness, or weakness. Assess CPK every 2 weeks for the first month of therapy and then as clinically necessary. May require therapy interruption and/or dose reduction.

Photosensitivity

Photosensitivity occurred in some patients. Patients should avoid sun exposure (during treatment and for 7 days after the final dose) and use a broad spectrum sunscreen and lip balm (SPF ≥50).

Pulmonary toxicity

Severe interstitial lung disease (ILD) has been reported rarely. Monitor for ILD/pneumonitis; evaluate promptly in patients who present with worsening of respiratory symptoms or who have signs/symptoms suggestive of ILD/pneumonitis (eg, cough, dyspnea, fever). Immediately interrupt therapy for confirmed ILD/pneumonitis; permanently discontinue if alectinib is determined to be the causative factor.

Renal toxicity

Renal impairment has been reported, including grade 3 and fatal events. May require therapy interruption, dose reduction, or permanent discontinuation. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Other warnings/precautions:

Anaplastic lymphoma kinase testing

Approved for use only in patients with metastatic non-small cell lung cancer (NSCLC) who test positive for the abnormal anaplastic lymphoma kinase (ALK) gene.

Pregnancy & Lactation

Pregnancy

Based on data from animal reproduction studies and its mechanism of action, alectinib may be expected to cause fetal harm if administered during pregnancy. Women of reproductive potential should use effective contraception during therapy and for 1 week after the final dose. Males with female partners of reproductive potential should use effective contraception during therapy and for 3 months after the last dose.

Lactation

It is not known if alectinib is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer does not recommend breastfeeding during therapy or for 1 week after the final dose.

Monitoring

Clinical pearl	Test for ALK positivity. Liver function tests (ALT, AST, total bilirubin) every 2 weeks during the first 3 months of therapy, then monthly and as clinically necessary (monitor more frequently in patients who develop transaminase and bilirubin elevations; CPK levels every 2 weeks for the first month of therapy, then as clinically necessary; monitor heart rate and blood pressure regularly; monitor for signs/symptoms of interstitial lung disease/pneumonitis and myalgia. Monitor adherence.

Clinical pearl

Test for ALK positivity. Liver function tests (ALT, AST, total bilirubin) every 2 weeks during the first 3 months of therapy, then monthly and as clinically necessary (monitor more frequently in patients who develop transaminase and bilirubin elevations; CPK levels every 2 weeks for the first month of therapy, then as clinically necessary; monitor heart rate and blood pressure regularly; monitor for signs/symptoms of interstitial lung disease/pneumonitis and myalgia. Monitor adherence.

Chemistry & Properties

Formula	C30H34N4O2
Molecular weight	482.63 g/mol
IUPAC name	9-ethyl-6,6-dimethyl-8-(4-morpholin-4-ylpiperidin-1-yl)-11-oxo-5H-benzo[b]carbazole-3-carbonitrile
CAS	1256580-46-7
PubChem CID	49806720
InChIKey	`KDGFLJKFZUIJMX-UHFFFAOYSA-N`
logP	4.77 (XLogP 5.2)
Polar surface area	72.36 Å²
H-bond acceptors / donors	5 / 1
Drug-likeness (QED)	0.58
Lipinski violations	0

SMILES

CCc1cc2c(cc1N1CCC(N3CCOCC3)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	0.392 h
Volume of distribution	4.679 L/kg
Protein binding	99.2%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2B6	Inhibitor	—
CYP2B6	Substrate	—
CYP2C19	Substrate	—
CYP2C8	Inhibitor	—
CYP3A4	Substrate	—

Receptor binding (top 2)

Target	Action	Affinity
ALK receptor tyrosine kinase (ALK)	Inhibitor	pIC50 8.7
MET proto-oncogene, receptor tyrosine kinase (MET)	Inhibitor	pIC50 5.3

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (90, DDInter)

Interacting drug	Severity	Management
Aminolevulinic acid	major
Leflunomide	major
Lomitapide	major
Mipomersen	major
Pexidartinib	major
Siponimod	major
Teriflunomide	major
Acebutolol	moderate
Ambenonium	moderate
Aminolevulinic acid (topical)	moderate
Asparaginase Erwinia chrysanthemi	moderate
Asparaginase Escherichia coli	moderate
Atazanavir	moderate
Atenolol	moderate
Bedaquiline	moderate
Betaxolol	moderate
Betaxolol (ophthalmic)	moderate
Bisoprolol	moderate
Brentuximab vedotin	moderate
Brigatinib	moderate
Calaspargase pegol	moderate
Cannabidiol	moderate
Carteolol	moderate
Carteolol (ophthalmic)	moderate
Carvedilol	moderate
Cevimeline	moderate
Clofarabine	moderate
Demecarium (ophthalmic)	moderate
Digitoxin	moderate
Digoxin	moderate
Diltiazem	moderate
Dolasetron	moderate
Donepezil	moderate
Echothiophate (ophthalmic)	moderate
Edrophonium	moderate
Efavirenz	moderate
Epirubicin	moderate
Esmolol	moderate
Fingolimod	moderate
Flecainide	moderate

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Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Alecensa 150mg hard Capsule	Capsule 161.33 mg	224 cap	Shawi & Rushedat Drug Store	—