Fruquintinib

Fruquintinib is a small molecule kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3 with IC₅₀ values of 33, 35, and 0.5 nM, respectively. In vitro studies showed fruquintinib inhibited VEGF-mediated endothelial cell proliferation and tubular formation. In vitro and in vivo studies showed fruquintinib inhibited VEGF-induced VEGFR-2 phosphorylation. In vivo studies showed fruquintinib inhibited tumor growth in a tumor xenograft mouse model of colon cancer.

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

Cardiac Electrophysiology

A mean increase in QTc interval >20 milliseconds (ms) was not observed at the approved recommended dosage.

The fruquintinib steady-state geometric mean (% coefficient of variation [CV]) maximum concentration (C_max) is 300 ng/mL (28%) and area under the concentration-time curve for the dosing interval (AUC_0-24h) is 5880 ng∙h/mL (29%) at the recommended dosage. The fruquintinib C_max and AUC_0-24h are dose-proportional across the dosage range of 1 to 6 mg (0.2 to 1.2 times the recommended dosage). Fruquintinib steady state is achieved after 14 days with a mean AUC_0-24h accumulation of 4-fold.

Absorption

The fruquintinib median (min, max) time to C_max is approximately 2 hours (0, 26 hours).

Effect of Food

No clinically significant differences in fruquintinib pharmacokinetics were observed following administration of a high-fat meal (800 to 1000 calories, 50% fat).

Distribution

The mean (SD) apparent volume of distribution of fruquintinib is approximately 46 (13) L. Plasma protein binding of fruquintinib is approximately 95%.

Elimination

The fruquintinib mean (SD) elimination half-life is approximately 42 (11) hours and the apparent clearance is 14.8 (4.4) mL/min.

Metabolism

Fruquintinib is primarily eliminated by CYP450 and non-CYP450 (i.e., sulfation and glucuronidation) metabolism. CYP3A and to a lesser extent CYP2C8, CYP2C9, and CYP2C19 are the CYP450 enzymes involved in fruquintinib metabolism.

Excretion

Following oral administration of a 5 mg radiolabeled fruquintinib dose, approximately 60% of the dose was recovered in urine (0.5% unchanged) and 30% of the dose was recovered in feces (5% unchanged).

Specific Populations

No clinically significant differences in the pharmacokinetics of fruquintinib were observed based on age (18 to 82 years), sex, race (Asian, Black, and White), ethnicity (Hispanic/Latino vs. non-Hispanic/Latino), body weight (48 to 108 kg), mild to moderate renal impairment (CrCL 30 to 89 mL/min), mild hepatic impairment (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST).

The effect of moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN and any AST) on fruquintinib pharmacokinetics is unknown.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Strong CYP3A inducers: Fruquintinib C_max decreased by 12% and AUC_inf by 65% following concomitant use with rifampin (strong CYP3A inducer).

Moderate CYP3A inducers: Fruquintinib C_max is predicted to decrease by 4% and AUC_inf by 32% following concomitant use with efavirenz (moderate CYP3A inducer).

Other Drugs: No clinically significant differences in fruquintinib pharmacokinetics were observed when used concomitantly with itraconazole (strong CYP3A inhibitor) or rabeprazole (proton pump inhibitor; gastric acid reducing agent).

No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with fruquintinib: dabigatran etexilate (P-gp substrate), or rosuvastatin (BCRP substrate).

In Vitro Studies

Cytochrome P450 Enzymes: Fruquintinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A, or an inducer of CYP1A2, CYP2B6, CYP3A.

Transporter Systems: Fruquintinib is not a substrate of P-glycoprotein (P-gp), organic anion transporting polypeptide (OATP)1B1 or OATP1B3. Fruquintinib is not an inhibitor of OATP1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, multidrug and toxin extrusion protein (MATE)1, or MATE2-K.

In repeat dose toxicity studies in rats, daily oral administration of fruquintinib at doses ≥0.6 mg/kg (approximately 1.2 times the recommended clinical dose of 5 mg based on BSA) resulted in broken or lost teeth.