Larotrectinib

Uses

Larotrectinib is a kinase inhibitor used to treat solid tumors with neurotrophic receptor tyrosine kinase gene fusion, are metastatic, high risk for surgery, or have no alternative treatments.

Larotrectinib is a tyrosine kinase inhibitor that is currently indicated for the treatment of adult and pediatric patients with solid tumors that either a) have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, b) are metastatic or where surgical resection is likely to result in severe morbidity, and c) have no satisfactory alternative treatments or that have progressed following treatment .

At the moment, these uses of larotrectinib are only approved under the auspices of an accelerated approval by the US FDA based on overall response rate and duration of response and continuation of support for these indications may be contingent upon the verification and description of continued clinical benefit in confirmatory trials .

Larotrectinib is also used to associated treatment for these conditions: NTRK1 Fusion Positive, NTRK2 Fusion Positive, NTRK3 Fusion Positive

How Larotrectinib works

Tropomysoin Receptor Kinases (TRK) like TRKA, TRKB, and TRKC elicit activities that regulate the natural growth, differentiation, and survival of neurons when they interact with endogenous neutrotrophin ligands . TRKA, TRKB, and TRKC are themselves encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively . It has been discovered that chromosomal rearrangements involving in-frame fusions of these genes with various partners, translocations in the TRK kinase domains, mutations in the TRK ligand-binding site, amplifications of NTRK, or the expression of TRK splice variants can result in constitutively-activated chimeric TRK fusion proteins that can act as oncogenic drivers that promote cell proliferation and survival in tumor cell lines .

Subsequently, larotrectinib functions as an inhibitor of TRKs including TRKA, B, and C . In in vitro and in vivo tumor models, larotrectinib demonstrated anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression . Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R . Point mutations in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L .

Toxicity

Although there is no available data on larotrectinib use in pregnant women, based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and the agent's mechanism of action it is believed that larotrectinib can cause embryo-fetal harm when administered to a pregnant woman . Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis . Furthermore, animal studies data note that lacrotrectinib can cross the placenta in animals . Advise pregnant women of the potential risk to a fetus .

There are no data on the presence of larotrectinib or its metabolites in human milk and no data on its effects on the breastfed child or on milk production . Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with larotrectinib and for 1 week after the final dose .

Female patients of reproductive potential who are being treated with larotrectinib are advised to use effective contraception during larotrectinib treatment and for at least one week after the final dose . Males with female partners of reproductive potential are also advised to use effective contraception during larotrectinib therapy and for one week after the final dose .

Based on histopathological findings in the reproductive tracts of female rats in a 1-month repeated-dose study, larotrectinib use may reduce fertility in females .

The safety and effectiveness of larotrectinib in pediatric patients was established based upon data from clinical trials in adult or pediatric patients 28 days and older . The pharmacokinetics of larotrectinib in the pediatric population have also been determined to be similar to those seen in adults .

Clinical studies of larotrectinib did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects .

No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A). Larotrectinib clearance was reduced in subjects with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment .

No dose adjustment is recommended for patients with renal impairment of any severity .

Carcinogenicity studies have not been conducted with larotrectinib . Larotrectinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or in the in vitro mammalian mutagenesis assays, with or without metabolic activation . In vivo, larotrectinib was negative in the mouse micronucleus test .

Fertility studies with larotrectinib have not been conducted. In a 3-month repeat-dose toxicity study in the rat, larotrectinib had no effects on spermatogenesis at 75 mg/kg/day (approximately 7 times the human exposure at the 100 mg twice daily dose) [FDA Label. Additionally, larotrectinib had no histological effects on the male reproductive tract in rats or monkeys at doses resulting in exposures up to 10 times the human exposure (AUC0-24hr) at the 100 mg twice daily clinical dose .

In a 1-month repeat-dose study in the rat, decreased uterine weight and uterine atrophy were seen at 200 mg/kg/day [approximately 45 times the human exposure (AUC) at the 100 mg twice daily dose] . Fewer corpora lutea and increased incidence of anestrus were also noted at doses ≥ 60 mg/kg/day (approximately 10 times the human exposure at the 100 mg twice daily dose] . There were no findings in female reproductive organs in repeat-dose studies in monkeys at exposures up to 22 times the human exposure at the 100 mg twice daily dose .

In a 1-month repeat-dose study in the rat, decreased uterine weight and uterine atrophy were seen at 200 mg/kg/day [approximately 45 times the human exposure (AUC) at the 100 mg twice daily dose] . Fewer corpora lutea and increased incidence of anestrus were also noted at doses ≥ 60 mg/kg/day (approximately 10 times the human exposure at the 100 mg twice daily dose) . Decreased fertility occurred in a juvenile animal study . There were no findings in female reproductive organs in repeat-dose studies in monkeys at exposures up to 22 times the human exposure at the 100 mg twice daily dose .

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of larotrectinib.
• Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of larotrectinib.
• Take with or without food.

[Moderate] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of larotrectinib.

The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of larotrectinib by certain compounds present in grapefruit.

When a single 100 mg dose of larotrectinib was coadministered with itraconazole, a potent CYP450 3A4 inhibitor, larotrectinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.8- and 4.3-fold, respectively, compared to administration of larotrectinib alone.

The interaction has not been studied with grapefruit juice.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Increased exposure to larotrectinib may increase the risk of adverse effects such as neurotoxicity (delirium, dysarthria, dizziness, gait disturbance, paraesthesia, encephalopathy, memory impairment, tremor) and hepatotoxicity (elevations in liver transaminases).

Food does not alter the pharmacokinetics of larotrectinib to a clinically significant extent.

When a single 100 mg dose of larotrectinib was administered with a high-fat meal (approximately 900 calories; 58 g carbohydrate, 56 g fat, 43 g protein) in healthy study subjects, larotrectinib peak plasma concentration (Cmax) was reduced by 35% while systemic exposure (AUC) was similar compared to administration in the fasted state.

MANAGEMENT: Larotrectinib may be taken with or without food.

Patients should avoid the consumption of grapefruit and grapefruit juice during treatment.

Larotrectinib Disease Interaction

Moderate: hepatotoxicity/liver impairment

Volume of Distribution

The mean volume of distribution Vss of larotrectinib has been documented as being 48L following intravenous administration in healthy subjects .

Elimination Route

The mean absolute bioavailability of larotrectinib capsules has been recorded as 34%, from a range spanning 32% to 37% . In adult patients who received larotrectinib capsules 100 mg twice daily, peak plasma levels Cmax were achieved at about one hour after dosing and steady-state was reached within the time span of three days . The mean steady-state of these administered larotrectinib capsules was Cmax 788 ng/mL and the AUC(0-24hr) was 4351 ng*h/mL . Concurrently, in healthy subjects, the AUC of the administered larotrectinib oral solution formulation was similar to that of the capsules and the particular Cmax was 36% greater with the oral solution .

The AUC of larotrectinib was similar but the Cmax was reduced by 35% after oral administration of a single 100 mg capsule of larotrectinib to healthy subjects taken with a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to the Cmax and AUC in the fasted state .

Half Life

The half-life of larotrectinib has been determined to be 2.9 hours .

Clearance

The mean clearance CL/F of larotrectinib has been documented as 98 L/h .

Elimination Route

Following oral administration of a single [14C] radiolabeled 100 mg dose of larotrectinib to healthy subjects, 58% (5% unchanged) of the administered radioactivity was recovered in feces and 39% (20% unchanged) was recovered in urine .

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