edto that in subjects with normal hepatic function [see Dosage and Administration (2.6), Use inSpecific Populations (8.6)].
Drug Interaction Studies
Clinical Studies
Effect of Strong CYP3A Inhibitors: Coadministration of a single 100 mg dose of VITRAKVIcapsules with a strong CYP3A inhibitor (itraconazole) increased the AUC0-INF of larotrectinib by4.3-fold and the Cmax by 2.8-fold as compared to VITRAKVI administered alone [see Dosageand Administration (2.4), Drug Interactions (7.1)]. The effects of CYP3A moderate and weakinhibitors on the pharmacokinetics of larotrectinib have not been studied.
Effect of Strong CYP3A Inducers: Coadministration of a single 100 mg dose of VITRAKVIcapsules with a strong CYP3A inducer (rifampin) decreased the AUC0-INF of larotrectinib by81% and of Cmax by 71% as compared to VITRAKVI administered alone [see Dosage andAdministration (2.5), Drug Interactions (7.1)]. The effects of CYP3A weak and moderateinducers on the pharmacokinetics of larotrectinib have not been studied.
Effect of Strong P-glycoprotein (P-gp) Inhibitors: Coadministration of a single 100 mg dose ofVITRAKVI capsules with a P-gp inhibitor (rifampin) increased the AUC0-INF of larotrectinib by1.7-fold and the Cmax by 1.8-fold as compared to VITRAKVI administered alone.
Effect of Larotrectinib on CYP3A4 Substrates: Coadministration of VITRAKVI capsules 100 mgtwice daily with a sensitive CYP3A4 substrate (midazolam) increased both the AUC0-INF andCmax of midazolam by 1.7-fold as compared to midazolam administered alone. The AUC0-INF andCmax of 1-hydroxymidazolam, the main metabolite of midazolam, were both increased 1.4-fold ascompared to when midazolam was administered alone [see Drug Interactions (7.2)].
In Vitro Studies
Effect of Transporter on Larotrectinib: Larotrectinib is a substrate for P-gp and BCRP.
Larotrectinib is not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1, or OATP1B3.
Effect of Larotrectinib on Transporters: Larotrectinib is not an inhibitor of BCRP, P-gp, OAT1,OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, MATE1 and MATE2-K at clinicallyrelevant concentrations.
Effect of Larotrectinib on CYP Substrates: Larotrectinib is not an inhibitor or inducer ofCYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant
concentrations.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with larotrectinib. Larotrectinib was notmutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolicactivation, or in the in vitro mammalian mutagenesis assays, with or without metabolicactivation. In vivo, larotrectinib was negative in the mouse micronucleus test.
Fertility studies with larotrectinib have not been conducted. In a 3-month repeat-dose toxicitystudy in the rat, larotrectinib had no effects on spermatogenesis at 75 mg/kg/day (approximately7 times the human exposure at the 100 mg twice daily dose). Additionally, larotrectinib had nohistological effects on the male reproductive tract in rats or monkeys at doses resulting inexposures 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 seenat 200 mg/kg/day [approximately 45 times the human exposure (AUC) at the 100 mg twice dailydose]. Fewer corpora lutea and increased incidence of anestrus were a |
