<p>Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. In a broad panel of purified enzyme assays, larotrectinib inhibited TRKA, TRKB, and TRKC with IC50 values between 5-11 nM. One other kinase TNK2 was inhibited at approximately 100-fold higher concentrations. TRKA, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3. Chromosomal rearrangements involving in-frame fusions of these genes with various partner scan result in constitutively activated chimeric TRK fusion proteins that can act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines.<br />
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<strong>Absorption</strong>: The mean absolute bioavailability of Larotrectinib capsules was 34% (range: 32% to 37%).<br />
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<strong>Distribution</strong>: The mean (CV%) volume of distribution (Vss) of Larotrectinib is 48 (38%) L following intravenous administration of Larotrectinib in healthy subjects. Larotrectinib is 70% bound to human plasma proteins in vitro and binding is independent of drug concentrations. The blood-to-plasma concentration ratio is 0.9.<br />
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<strong>Elimination</strong>: The mean (CV%) clearance (CL/F) of Larotrectinib is 98 (44%) L/h and the half-life is 2.9 hours following oral administration of Larotrectinib in healthy subjects.<br />
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<strong>Metabolism</strong>: Larotrectinib is metabolized predominantly by CYP3A4. Following oral administration of a single [14C] radiolabeled 100 mg dose of Larotrectinib to healthy subjects, unchanged Larotrectinib constituted 19% and an O-linked glucuronide constituted 26% of the major circulating radioactive drug components in plasma.<br />
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<strong>Excretion</strong>: Following oral administration of a single [ 14 C] 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.</p>