Taletrectinib

Taletrectinib is an inhibitor of tyrosine kinase ROS1, including ROS1 resistance mutations. Taletrectinib also showed inhibitory effects on tropomyosin receptor kinases (TRKs) TRKA, TRKB, and TRKC.

Fusion proteins that include ROS1 domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Taletrectinib inhibited growth of cancer cells expressing ROS1 fusion genes and mutations.

In mice subcutaneously implanted with tumors harboring ROS1 fusions, including the G2032R mutation, administration of taletrectinib resulted in tumor growth inhibition. Taletrectinib had anticancer activity in an intracranial NSCLC xenograft model harboring a ROS1 fusion.

Exposure-response relationship

Higher taletrectinib exposure is associated with an increased risk of Grade ≥3 increased AST/ALT.

Taletrectinib exposure-response relationships for efficacy and the time course of pharmacodynamic response have not been fully characterized.

Cardiac Electrophysiology

The largest mean increase in the QTc interval was 12.8 msec (upper confidence interval of 15.4 msec) at the mean steady-state maximum concentration (C_max,ss) after administration of taletrectinib 600 mg once daily. The increase in the QTc internal was concentration-dependent. At plasma concentrations achieved with administration of taletrectinib 600 mg once daily with high fat food, the predicted increase in the QTc interval is 20.5 (16.3, 24.7) msec.

Taletrectinib pharmacokinetics (PK) were characterized at steady state for the approved recommended dosage and the PK parameters presented below are as mean (CV%), unless otherwise specified.

Taletrectinib maximum concentration (C_max) is 476 (36%) ng/mL and systemic exposure (AUC) is 9,649 (36%) ng•h/mL. Taletrectinib C_max and AUC increase in a dose proportional manner over the dose range of 50 mg to 1200 mg (0.08 to 2 times the approved recommended dosage). Taletrectinib accumulation is approximately 4-fold and steady state reached within 7 days.

Absorption

Taletrectinib time to maximum plasma concentration (T_max) is 2 to 6 hours.

Effect of Food

Both taletrectinib AUC and C_max increased by 1.5-fold following administration with high-fat food (1000 calories, 50% fat).

Distribution

The estimated apparent (oral) volume of distribution is 9,820 L. Taletrectinib in vitro plasma protein binding is concentration-dependent and decreases with increasing taletrectinib concentrations (from 96% at 100 ng/mL to 93% at 10,000 ng/mL). The blood-to-plasma ratio is 1.3 to 1.4 in vitro.

Elimination

Taletrectinib effective half-life is approximately 66 hours with an apparent (oral) clearance of 63 L/h (36%).

Metabolism

Taletrectinib is eliminated by CYP450 and non-CYP450 (i.e., sulfation and acetylation) metabolism. CYP3A and, to a lesser extent, CYP2C8 and CYP2C9 are the CYP450 enzymes involved in taletrectinib metabolism.

Excretion

Following a single oral dose of radiolabeled taletrectinib 200 mg, 75% of the dose was recovered in feces (15% as unchanged) and 11% in urine (2.9% as unchanged).

Specific Populations

No clinically significant differences in the pharmacokinetics of taletrectinib were observed based on age (18 to 80 years), sex, mild to moderate renal impairment (eGFR 30 to 89 mL/min), or mild hepatic impairment (total bilirubin >1 to 1.5 times ULN or AST >ULN). The effect of moderate (total bilirubin >1.5 to 3 times ULN with any AST) or severe (total bilirubin >3 x ULN with any AST) hepatic impairment, severe renal impairment (eGFR <30 mL/min), or dialysis on taletrectinib pharmacokinetics is unknown.

A 30% increase in taletrectinib exposure (AUC) was observed in Asian patients compared to White patients. No clinically significant differences in the AUC were observed between White and Black patients.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Strong CYP3A and P-gp Inhibitors: Taletrectinib C_max increased by 1.8-fold and AUC by 3.3-fold following concomitant administration of itraconazole (strong CYP3A and P-gp inhibitor) 200 mg daily.

Moderate CYP3A Inhibitors: Concomitant use with moderate CYP3A inhibitors (fluconazole, erythromycin, or verapamil) is predicted to increase taletrectinib AUC up to 2.6-fold and C_max up to 1.5-fold.

Strong CYP3A Inducers and P-gp Inducers: Taletrectinib C_max decreased by 42% and AUC by 86% following concomitant administration of rifampin (strong CYP3A and P-gp inducer) 600 mg daily.

Moderate CYP3A Inducers: Concomitant use with a moderate CYP3A inducer (efavirenz) is predicted to reduce taletrectinib AUC by 66% and its C_max by 40%.

Proton Pump Inhibitors (PPIs): Taletrectinib displays a pH-dependent aqueous solubility. Taletrectinib C_max decreased by 65% and AUC by 40% following concomitant administration of omeprazole (PPI) 40 mg daily.

P-gp substrates: No clinically significant difference in the exposure of digoxin (P-gp substrate) was observed when used concomitantly with taletrectinib.

In vitro Studies

CYP450 Enzymes: Taletrectinib inhibits CYP2C8, CYP2D6, and CYP3A. Taletrectinib induces CYP1A2 and CYP3A4.

Transporter Systems: Taletrectinib is a P-gp substrate. Taletrectinib inhibits P-gp, BCRP, OATP1B1, MATE1 and MATE2-K.