Entrectinib

Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2 and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK) with IC₅₀ values of 0.1 to 2 nM. Entrectinib also inhibits JAK2 and TNK2 with IC₅₀ values >5 nM. The major active metabolite of entrectinib, M5, showed similar in vitro activity against TRK, ROS1, and ALK.

Fusion proteins that include TRK, ROS1, or ALK kinase domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple tumor types harboring NTRK, ROS1 and ALK fusion genes.

Entrectinib demonstrated steady-state brain-to-plasma concentration ratios of 0.4–2.2 in multiple animal species (mice, rats, and dogs) and demonstrated in vivo anti-tumor activity in mice with intracranial implantation of TRKA- and ALK-driven tumor cell lines.

Entrectinib exposure-response relationships and the time course of pharmacodynamic responses are unknown.

Cardiac Electrophysiology

Across clinical trials, 3.1% of 355 patients, who received entrectinib at doses ranging from 100 mg to 2600 mg daily under fasting or fed conditions (75% received 600 mg orally once daily) and had at least one post-baseline ECG assessment, experienced QTcF interval prolongation of >60 ms after starting entrectinib and 0.6% had a QTc interval >500 ms.

The pharmacokinetics for entrectinib and its pharmacologically active major circulating metabolite M5 were characterized in adult patients with ROS1-positive NSCLC, NTRK gene fusion-positive solid tumors, and healthy subjects. The pharmacokinetics of entrectinib and M5 are linear and are not dose-dependent or time-dependent. Steady state is achieved within one week for entrectinib and two weeks for M5 following daily administration of entrectinib. The pharmacokinetic parameters for entrectinib and M5 are described in the following table.

Pharmacokinetic Parameters for Entrectinib and Metabolite M5:

* Geometric mean

Absorption

The maximum entrectinib plasma concentration was reached 4 – 6 hours after oral administration of a 600 mg dose.

Effect of Food

A high-fat (approximately 50% of total caloric content), high-calorie (approximately 800 to 1000 calories) meal did not have a significant effect on entrectinib exposure.

Distribution

Entrectinib and its active major metabolite M5 are both >99% bound to human plasma proteins in vitro.

The estimated apparent volume of distribution (V/F) was 551 L and 81.1 L for entrectinib and M5, respectively.

Elimination

The estimated apparent clearance (CL/F) was 19.6 L/h and 52.4 L/h for entrectinib and M5, respectively. The elimination half-lives of entrectinib and M5 were estimated to be 20 and 40 hours, respectively.

Metabolism

Entrectinib is metabolized primarily by CYP3A4 (~76%). The active metabolite M5 (formed by CYP3A4) is the only major active circulating metabolite identified. M5 has similar pharmacological potency to entrectinib in vitro and circulating M5 exposures at steady-state in patients were 40% of the corresponding entrectinib exposure.

Excretion

Following oral administration of a single oral dose of [¹⁴C]-labeled entrectinib, 83% of radioactivity was excreted in feces (36% of the dose as unchanged entrectinib and 22% as M5) with minimal excretion in urine (3%).

Specific Populations

No clinically significant differences in the pharmacokinetics of entrectinib were observed based on age (12 years to 86 years), sex, race (White, Asian and Black), body weight (32 to 130 kg), mild to moderate renal impairment (CLcr 30 to <90 mL/min) and mild hepatic impairment (total bilirubin ≤1.5 times ULN). The impact of moderate to severe hepatic impairment or severe renal impairment on the pharmacokinetics of entrectinib is unknown.

Pediatric Patients

The predicted systemic exposures for body surface area-based doses of 600 mg (BSA >1.50 m²), 500 mg (BSA of 1.11 to 1.50 m²) and 400 mg (BSA of 0.91 to 1.10 m²) in pediatric patients 12 years and older are comparable to the exposure in adults at the 600 mg dose.

Drug Interaction Studies

Clinical Studies

Effect of CYP3A Inhibitors on Entrectinib: Coadministration of itraconazole (a strong CYP3A inhibitor) with a single 100 mg entrectinib dose increased entrectinib AUC_0-INF by 6-fold and C_max by 1.7-fold. Coadministration of a moderate CYP3A inhibitor with entrectinib is predicted to increase entrectinib AUC_0-Tau by 3-fold and C_max by 2.9-fold.

Effect of CYP3A Inducers on Entrectinib: Coadministration of rifampin (a strong CYP3A inducer) with a single 600 mg entrectinib dose reduced entrectinib AUC_0-INF by 77% and C_max by 56%. Coadministration of a moderate CYP3A inducer with entrectinib is predicted to reduce entrectinib AUC_0-Tau by 56% and C_max by 43%.

Effect of Gastric Acid Reducing Drugs on Entrectinib: Coadministration of a proton pump inhibitor (PPI), lansoprazole with a single 600 mg entrectinib dose reduced entrectinib AUC by 25% and C_max by 23%.

Effect of Entrectinib on CYP Substrates: Coadministration of entrectinib 600 mg once daily with oral midazolam (a sensitive CYP3A substrate) in patients increased the midazolam AUC by 50% but reduced midazolam C_max by 21%.

Effect of Entrectinib on Transporters: Coadministration of a single 600 mg entrectinib dose with digoxin [a sensitive P-glycoprotein (P-gp) substrate] increased digoxin C_max by 28% and AUC by 18%.

In Vitro Studies

Entrectinib is not a substrate of P-gp or BCRP, but M5 is a substrate of P-gp and BCRP. Entrectinib and M5 are not substrates of OATP1B1 or OATP1B3.