].
11 DESCRIPTION
Larotrectinib is a kinase inhibitor. VITRAKVI (larotrectinib) capsules and oral solution areformulated using larotrectinib sulfate. The molecular formula for larotrectinib sulfate isC21H24F2N6O6S and the molecular weight is 526.51 g/mol for the sulfate salt and 428.44 g/molfor the free base. The chemical name is (3S)-N-{5-[(2R)-2-(2,5-difluorophenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxy-1-pyrrolidinecarboxamide sulfate.
Larotrectinib sulfate has the following chemical structure:
Larotrectinib sulfate is an off-white to pinkish yellow solid that is not hygroscopic. The aqueoussolubility of larotrectinib at 37ᴼC is pH dependent (very soluble at pH 1.0 and freely soluble atpH 6.8, according to USP descriptive terms of solubility).
VITRAKVI (larotrectinib) capsules and oral solution are for oral use. Each capsule contains 25mg or 100 mg larotrectinib (30.7 mg and 123 mg larotrectinib sulfate, respectively) in a hardgelatin capsule. The capsule is composed of gelatin, titanium dioxide, and edible ink.
The oral solution contains 20 mg/mL larotrectinib (24.6 mg/mL larotrectinib sulfate) and thefollowing inactive ingredients: purified water, hydroxypropyl betadex, sucrose, glycerin,sorbitol, citric acid, sodium phosphate, sodium citrate dihydrate, propylene glycol and flavoring.Preserved with methylparaben and potassium sorbate.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, andTRKC. In a broad panel of purified enzyme assays, larotrectinib inhibited TRKA, TRKB, andTRKC with IC50 values between 5-11 nM. One other kinase TNK2 was inhibited atapproximately 100-fold higher concentration. TRKA, B, and C are encoded by the genesNTRK1, NTRK2, and NTRK3.Chromosomal rearrangements involving in-frame fusions of thesegenes with various partners can result in constitutively-activated chimeric TRK fusion proteins
that can act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines.
In in vitro and in vivo tumor models, larotrectinib demonstrated anti-tumor activity in cells withconstitutive activation of TRK proteins resulting from gene fusions, deletion of a proteinregulatory domain, or in cells with TRK protein overexpression. Larotrectinib had minimalactivity in cell lines with point mutations in the TRKA kinase domain, including the clinicallyidentified acquired resistance mutation, G595R. Point mutations in the TRKC kinase domainwith clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.
12.2 Pharmacodynamics
Cardiac Electrophysiology
At a dose 9-fold higher than the recommended adult dose, VITRAKVI does not prolong QTcintervals to any clinically relevant extent.
12.3 Pharmacokinetics
The pharmacokinetics of larotrectinib were studied in healthy subjects and adult and pediatricpatients with locally advanced or metastatic solid tumors. In healthy subjects who received asingle dose of VITRAKVI capsules, systemic exposure (Cmax and AUC) of larotrectinib wasdose proportional over the dose range of 100 mg to 400 mg(1 to 4 times the recommended adultdose) and slightly greater than proportional at doses of 600 mg to 900 mg (6 to 9 times therecommended adult dose). In adult patients who received VITRAKVI capsules 100 mg twicedaily in Study LOXO-TRK-14001, peak plasma levels (Cmax) of larotrect |
