Indications
Larotrectinib is used to treat adults and children who have solid tumours with a neurotrophic receptor tyrosine kinase (NTRK) gene fusion, as long as there is no known acquired resistance mutation. The tumour must also be metastatic, or surgery to remove it must be likely to cause severe morbidity. On top of that, there should be no satisfactory alternative treatments, or the tumour should have progressed after treatment.
⚠️ Always consult a registered physician before taking any medicine.
Pharmacology
Larotrectinib blocks the tropomyosin receptor kinases (TRK), which are TRKA, TRKB and TRKC. In a broad panel of purified enzyme assays, larotrectinib inhibited all three with IC50 values between 5 and 11 nM. One other kinase, TNK2, was inhibited at concentrations approximately 100-fold higher. TRKA, B and C are encoded by the genes NTRK1, NTRK2 and NTRK3. When chromosomal rearrangements fuse these genes in-frame with various partners, the result can be constitutively activated chimeric TRK fusion proteins. These can act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines.
Absorption: The mean absolute bioavailability of larotrectinib capsules was 34% (range: 32% to 37%).
Distribution: After intravenous administration in healthy subjects, the mean (CV%) volume of distribution (Vss) of larotrectinib is 48 (38%) L. In vitro, larotrectinib is 70% bound to human plasma proteins, and the binding does not depend on drug concentration. The blood-to-plasma concentration ratio is 0.9.
Elimination: After oral administration in healthy subjects, the mean (CV%) clearance (CL/F) of larotrectinib is 98 (44%) L/h and the half-life is 2.9 hours.
Metabolism: Larotrectinib is metabolized mainly by CYP3A4. Healthy subjects were given a single oral 100 mg dose of [14C] radiolabeled larotrectinib. Among the major circulating radioactive drug components in plasma, unchanged larotrectinib made up 19% and an O-linked glucuronide made up 26%.
Excretion: In the same kind of study, with a single oral 100 mg dose of [14C] radiolabeled larotrectinib given to healthy subjects, 58% of the administered radioactivity was recovered in feces (5% unchanged) and 39% in urine (20% unchanged).
Pregnancy & Breastfeeding
Larotrectinib can harm an unborn baby when it is given to a pregnant woman. There are no data on its use in pregnant women, so a pregnant woman should be told about the possible risk to the fetus.
We also don't know whether Larotrectinib or its metabolites pass into human milk. There are no data on what it might do to a breastfed child or to milk production. Because breastfed children could have serious adverse reactions, women should be advised not to breastfeed during treatment with Larotrectinib and for 1 week after the final dose.
⚠️ Talk to your doctor before taking any medicine during pregnancy or while breastfeeding.
Dosage Reference
⚠️ Reference ranges from official sources only. Consult your doctor for personalized dosing.