Atrasentan

Atrasentan is an ET_A receptor antagonist (Ki = 0.034 nM) with >1800-fold selectivity for the ET_A receptor compared to the endothelin type B receptor (Ki = 63.3 nM). Endothelin (ET)-1 is thought to contribute to the pathogenesis of IgAN via the ET_AR.

Dose-response information is not available. At the recommended dose regimen, no statistically significant exposure-response (E-R) relationship was identified between atrasentan exposure and the percentage reduction from baseline in UPCR at Week 36 over the observed atrasentan exposure range. Increased atrasentan exposure was associated with an increased incidence of anemia, but no association was observed between atrasentan exposure and hypotension or peripheral edema.

Cardiac Electrophysiology

At exposures 40% higher than the clinical exposure at the maximum recommended dose, clinically significant QTc interval prolongation was not observed.

Atrasentan area under the time concentration curve (AUC) is dose proportional across the 0.35 mg to 30 mg (0.47 to 40 times the approved recommended dosage) dose range. Atrasentan steady state plasma concentrations are reached within 7 days with 2- to 3-fold accumulation.

Absorption

Atrasentan time to peak plasma concentration (T_max) is approximately 0.5 hour.

Effect of Food

No clinically significant differences in atrasentan pharmacokinetics were observed following administration with a high-fat meal (800 to 1000 Kcal, >50% fat) in healthy subjects.

Distribution

Atrasentan steady-state apparent (oral) volume of distribution (Vd/F) is 1180 L. Atrasentan is >99% bound to human plasma proteins, in vitro.

Elimination

Atrasentan effective half-life is approximately 24 to 41 hours with an apparent (oral) clearance (CL/F) of 19 L/h.

Metabolism

Atrasentan is extensively metabolized by CYP3A and multiple uridine 5'-diphospho-glucuronosyltransferases (UGTs) with approximately half via CYP3A and the remaining half via glucuronidation by multiple UGTs.

Excretion

After a single dose of radiolabeled atrasentan 10 mg to healthy subjects, approximately 86% of the dose was recovered in feces (5.5% as parent atrasentan). Renal excretion was minimal, with < 4% recovered in urine (negligible amounts of parent atrasentan).

Specific Populations

No clinically significant differences in the pharmacokinetics of atrasentan were observed based on age (19 to 77 years), sex, race, mild to severe renal impairment (eGFR 15 to 90 mL/min/1.73 m², estimated by CKD-EPI), or mild to moderate hepatic impairment (Child-Pugh class A or B). The effect of severe hepatic impairment (Child-Pugh class C) or end-stage renal disease (eGFR <15 mL/min/1.73 m²) on atrasentan pharmacokinetics is unknown.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Strong and moderate CYP3A inducers: Atrasentan C_trough decreased by 90% following coadministration of a single dose of 10 mg atrasentan with rifampin (strong CYP3A inducer).

OATP1B1/1B3 inhibitors: Atrasentan C_max was 4.3 times as high and AUC was 3.8 times as high following coadministration of a single dose of 0.75 mg atrasentan with cyclosporine (OATP1B1/1B3 inhibitor).

Strong CYP3A inhibitors: Atrasentan AUC increased by 90% following coadministration of a single dose of 10 mg atrasentan with ketoconazole (strong CYP3A inhibitor).

Other Drugs: No clinically significant differences in the pharmacokinetics of midazolam (CYP3A4 substrate), losartan (CYP2C9 and CYP3A4 substrate) or fexofenadine (P-gp substrate) were observed or expected when used concomitantly with atrasentan.

In Vitro Studies

CYP450 Enzymes: Atrasentan is a CYP3A substrate. Atrasentan inhibits in vitro CYP3A, CYP2B6, CYP2C8 and CYP2C9 and induces CYP3A and CYP2B6, but is not expected to cause clinically significant interactions with these CYP450 enzymes in the liver. Atrasentan does not inhibit CYP1A2, CYP2C19, or CYP2D6 and is not an inducer of CYP1A2.

Transporter Systems: Atrasentan is a substrate of P-gp and OATP1B1/1B3 but not a substrate of BCRP, MRP2/4, NTCP, OCT1, or OATP2B1. Atrasentan inhibits P-gp, OATP1B1, and OATP1B3, but not expected to cause clinically significant interactions. Atrasentan does not inhibit MRP, NTCP, OCT, OAT1, MATE1, or MATE2K.