Alectinib

Alectinib Uses, Dosage, Side Effects, Food Interaction and all others data.

Alectinib is a highly selective and potent ALK and RET tyrosine kinase inhibitor.In nonclinicalstudies, inhibition of ALK tyrosine kinase activity led to blockage of downstream signaling pathways including STAT 3 and PI3K/AKT and inducedtumor cell death (apoptosis).

Alectinib demonstratedin vitroand in vivoactivity against mutant forms of the ALK enzyme, including mutations responsible forresistance to crizotinib.The major metabolite of alectinib (M4) has shown similar in vitropotency and activity.

Based on nonclinicaldata, alectinib is not a substrate of p-glycoprotein (P-gp) or breast cancer resistance protein (BCRP), which are both efflux transporters in the blood brain barrier, and is therefore able to distribute into and be retained within the central nervous system. Alectinibinducedtumor regressionin nonclinicalmousexenograft models, including antitumor activity in the brain, and prolonged survival inintracranial tumor animal models.

Alectinib
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Alectinib
Availability	Prescription only
Generic	Alectinib
Alectinib Other Names	Alectinib
Related Drugs	Alecensa, Opdivo, methotrexate, Keytruda, pembrolizumab, cisplatin, Tagrisso, Avastin
Weight	150mg
Type	Oral capsule
Formula	C₃₀H₃₄N₄O₂
Weight	Average: 482.6166 Monoisotopic: 482.268176352
Protein binding	Alectinib and its major metabolite M4 are >99% bound to human plasma proteins.
Groups	Approved, Investigational
Therapeutic Class	Anti neoplastic preparations, Protein kinase inhibitor
Manufacturer
Available Country	United States
Last Updated:	September 19, 2023 at 7:00 am

Uses

Alectinib used for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, locally advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.

Alectinib is also used to associated treatment for these conditions: Refractory, metastatic Non small cell lung cancer

How Alectinib works

Alectinib is a second generation oral drug that selectively inhibits the activity of anaplastic lymphoma kinase (ALK) tyrosine kinase. It is specifically used in the treatment of non-small cell lung cancer (NSCLC) expressing the ALK-EML4 (echinoderm microtubule-associated protein-like 4) fusion protein that causes proliferation of NSCLC cells. Inhibition of ALK prevents phosphorylation and subsequent downstream activation of STAT3 and AKT resulting in reduced tumour cell viability. Both alectinib and its major active metabolite M4 demonstrate similar in vivo and in vitro activity against multiple mutant forms of ALK.

Dosage

Alectinib dosage

The recommended dose of Alectinib is 600 mg (four 150 mg capsules) given orally, twice daily (total daily dose of 1200 mg). Patients with underlying severe hepatic impairment should receive a dose of 450 mg given orally twice daily (total daily dose of 900 mg). Alectinib hard capsules should be taken with food, swallowed whole and must not be opened or dissolved.

Pediatric use: The safety and efficacy of alectinib in children and adolescents (<18 years) have not been studied.

Geriatric use: No dose adjustment of alectinib is required in patients≥65 years of age.

Renal impairment: No dose adjustment is required in patients with mild or moderate renal impairment. alectinib has not been studied in patients with severe renal impairment, however,since alectinib elimination via the kidney is negligible, no dose adjustment is required inpatients with severe renal impairment

Hepatic impairment: No dose adjustment is required in patients with underlying mild or moderate hepatic impairment. Patients with underlying severe hepatic impairment should receive a dose of 450 mg given orally twice daily (total daily dose of 900 mg)

Duration of Treatment: It is recommended that patients are treated with Alectinib until disease progression or unmanageable toxicity.

Dose Modifications: Management of adverse events may require temporary interruption, dosereduction, or discontinuation of treatment with Alectinib. The dose of Alectinib should be reduced in steps of 150 mg twice daily based on tolerability. Alectinib treatment should be permanently discontinued if patients are unable to tolerate the 300 mg twice-daily dose.

Side Effects

The most common adverse drug reactions were constipation, edema including peripheral, generalized, eyelid, periorbital; myalgia (31% including myalgia and musculoskeletal pain), nausea, increased bilirubin (21% including increased blood bilirubin, hyperbilirubinemia and increased bilirubin conjugated), anemia (20%, including anemia and hemoglobin decreased), and rash (20%, including rash, rash maculopapular, dermatitis acneiform, erythema, rash generalized, rash papular, rash pruritic and rash macular).

Toxicity

The most common adverse reactions (>5%) associated with alectinib use were fatigue, constipation, edema, and myalgia. Less common effects associated with use were hepatotoxicity, interstitial lung disease (ILD)/pneumonitis, bradycardia, severe myalgia and creatine phosphokinase (CPK) elevation, and embryo-fetal toxicity. Females of reproductive potential are advised to use effective contraception during treatment with alectinib and for 1 week following the final dose.

Precaution

Interstitial lung disease (ILD)/pneumonitis: Cases of ILD/pneumonitishave been reported in clinical trials with Alectinib. Patients should be monitored for pulmonary symptoms indicative of pneumonitis. Alectinib should be immediately interrupted in patients diagnosed with ILD/pneumonitis and should be permanently discontinued if no other potential causes of ILD/pneumonitis have been identified.

Hepatotoxicity: Elevations in alanine amino transferase (ALT) and aspartate amino transferase (AST) greater than 5 times the upper limit of normal (ULN) as well as bilirubin elevations of more than 3 times the ULN occurred in patients in pivotal clinical trials with Alectinib. The majority of these events occurred during the first 3months of treatment. In the pivotal Alectinib clinical trials it was reported that three patients with Grade 3‒4 AST/ALT elevations had drug-induced liver injury. Concurrent elevations in ALT or AST greater than or equal to three times the ULN and total bilirubin greater than or equal to two times the ULN, with normal alkaline phosphatase, occurred in 1 patient treated in Alectinib clinical trials.

Interaction

In vitro studies indicate that neither alectinib nor its major active metabolite (M4) inhibits CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations. Alectinib and M4 show weak time-dependent inhibition of CYP3A4. In vitro, alectinib exhibits a weak induction potential of CYP3A4 and CYP2B6 at clinical concentrations. Results from a clinical drug-drug interaction study in ALK-positive NSCLC patients demonstrated that multiple doses of alectinib had no influence on the exposure of midazolam, a sensitive CYP3A substrate. Therefore, no dose adjustment is required for co-administered CYP3A substrates. Although in vitro studies indicate that alectinib is an inhibitor of CYP2C8, physiologically based pharmacokinetic (PBPK) modeling supports that at clinically relevant concentrations alectinib does not have the potential to increase plasma concentrations of co-administered substrates of CYP2C8.

Food Interaction

Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of alectinib.
Exercise caution with St. John's Wort. This herb induces CYP3A metabolism, which may reduce serum levels of alectinib.
Take with food.

[Moderate] ADJUST DOSING INTERVAL: Food significantly enhances the oral bioavailability of alectinib and its major active metabolite, M4.

According to the manufacturer, a high-fat, high-calorie meal increased the combined systemic exposure (AUC) of alectinib and M4 by 3.1-fold following oral administration of a single 600 mg dose of alectinib.

MANAGEMENT: To ensure maximal oral absorption, alectinib should be administered with food.

Alectinib Drug Interaction

Moderate: diltiazem, metoprololUnknown: paclitaxel protein-bound, charcoal, doxorubicin, naproxen, calcium carbonate, calcium / vitamin d, sulfamethoxazole / trimethoprim, ubiquinone, copper gluconate, ubiquinone, rosuvastatin, cholecalciferol, glucose, apixaban, sodium iodide, cyanocobalamin, ascorbic acid, cholecalciferol

Alectinib Disease Interaction

Moderate: bradycardia, hepatic impairment, myalgia, renal impairment, lung toxicity

Volume of Distribution

4016 L

Elimination Route

Alectinib reached maximal concentrations at 4 hours following administration of 600 mg twice daily under fed conditions in patients with ALK-positive NSCLC. The absolute bioavailability was 37% in the fed state. A high-fat, high-calorie meal increased the combined exposure of alectinib and its major metabolite M4 by 3.1-fold following oral administration of a single 600 mg dose.

Half Life

The mean elimination half life is 33 hr for alectinib and 31 hr for M4.

Clearance

The apparent clearance is 81.9L/hr for alectinib and 217 L/hr for M4.

Elimination Route

When radioactively labeled, 98% of radioactivity was found in feces with 84% of that amount excreted as unchanged alectinib and 6% as M4. Less than 0.5% was found to be recovered in urine.

Pregnancy & Breastfeeding use

Pregnancy: Women of childbearing potential must be advised to avoid pregnancy while on Alectinib. No clinical studies of Alectinib in pregnant women have been performed. Based on its mechanism of action, Alectinib may cause fetal harm when administered to a pregnant woman. Female patients or women who are partners of male patients receiving Alectinib, who become pregnant while taking Alectinib or during the 3 months following the last dose of Alectinib must contact their doctor and should be advised of the potential harm to the fetus.

Lactation: It is not known whether Alectinib is excreted in human breast milk. No studies have been conducted to assess the impact of Alectinib on milk production or its presence in breast milk. As many drugs are excreted in human milk and because of the potential harm to the infant, mothers should be advised against breastfeeding while receiving Alectinib.

Contraception: Female patients of child-bearing potential, or women of child-bearing potential who are partners of male patients receiving Alectinib, must use highly effective contraceptive methods during treatment and for at least 3 months following the last dose of Alectinib.