Chemical formula: C₁₅H₁₇FN₂O₃ Molecular mass: 292.122 g/mol PubChem compound: 71464713
Acoramidis is a selective stabilizer of transthyretin (TTR). Acoramidis binds TTR at thyroxine binding sites and slows dissociation of the TTR tetramer into its constituent monomers, the rate-limiting step in amyloidogenesis.
Changes in serum TTR level or in vitro TTR stabilization assays were utilized as pharmacodynamic markers of TTR stabilization. Increases in mean serum TTR levels were observed by Day 28 in ATTR-CM patients treated with acoramidis. Near-complete in vitro TTR stabilization was observed as early as Day 28 and through completion of a 30-month study of patients with ATTR-CM (wild-type and variant) treated with the recommended dosage.
Acoramidis may decrease serum concentrations of free thyroxine without an accompanying change in thyroid stimulating hormone (TSH). A reduction in free thyroxine values has been observed with transthyretin stabilizers probably due to reduced thyroxine binding to or displacement from transthyretin (TTR).
In a clinical study of acoramidis in patients with ATTR-CM, at Month 30, the increase in N-terminal prohormone of brain natriuretic peptide [NT-proBNP] and troponin I was lower with acoramidis versus placebo. The increase in NT-proBNP at Month 30 for acoramidis was about half that of placebo.
At approximately 1.2 times the steady state peak plasma concentrations (Cmax) at the recommended dose, acoramidis does not prolong the QTc interval to any clinically relevant extent.
The systemic exposures (Cmax and AUC) increase in a less than dose proportional manner following single and multiple doses of acoramidis. Over the dose range from 89 mg twice daily to 712 mg twice daily, AUC increases only 130%. Acoramidis steady state is achieved by 4 days with approximately 1.3-fold accumulation at the approved recommended dosage. At steady state, a dose of 712 mg twice daily results in a mean (SD) Cmax of 13700 (6090) ng/mL and AUC0-12h of 47200 (10300) ng.h/mL.
The time to Cmax of acoramidis (Tmax) is approximately 1 hour following oral administration.
No clinically significant differences in acoramidis pharmacokinetics were observed following administration of a high-fat meal (800-1000 total calories, ≥ 50% fat).
The apparent steady-state volume of distribution for acoramidis is 654 liters. Acoramidis is 96% bound to human plasma proteins in vitro. Acoramidis primarily binds to TTR.
The effective half-life of acoramidis is approximately 6 hours with a steady state apparent clearance of 16 L/hr.
Acoramidis is primarily metabolized by glucuronidation via UGT1A9, UGT1A1 and UGT2B7. Acoramidis-β-D-glucuronide (Acoramidis-AG) is the predominant metabolite of acoramidis (8% of total circulating drug related moieties).
Acoramidis-AG is approximately ⅓ as pharmacologically active compared with acoramidis, has a low potential for covalent binding, and does not contribute to pharmacological activity.
After a single oral dose of radiolabeled acoramidis 712 mg to healthy adult subjects, approximately 32% of the dose radioactivity was recovered in feces (15% unchanged), and approximately 68% was recovered in urine (<10% unchanged).
No clinically significant differences in the pharmacokinetics of acoramidis were observed based on age, race/ethnicity (including Japanese and non-Japanese), sex, or renal impairment. The effect of hepatic impairment (Child Pugh A, B, or C) on acoramidis pharmacokinetics is unknown.
Following the administration of acoramidis (712 mg, BID) in a clinical study in healthy adult volunteers, there was not a clinically significant increase in exposure to the organic anion transporter-1 (OAT1) substrate (adefovir) and to OAT3 substrate (oseltamivir carboxylate). Concomitant diuretic use in patients does not affect steady-state plasma acoramidis concentrations.
Cytochrome P450 Enzymes:
Acoramidis is a time-dependent inhibitor of CYP2C9, but does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, or CYP3A4/5. Acoramidis does not induce CYP1A2, CYP2B6, or CYP3A4.
UDP-Glucuronosyl Transferase (UGT):
Acoramidis is a substrate of multiple UGT enzymes including UGT1A9, UGT1A1, and UGT2B7.
Transporter Systems:
Acoramidis is a substrate for OAT1 and breast cancer resistance protein (BCRP). Acoramidis inhibits OAT1 and OAT3, but does not inhibit MATE1, OCT1, OCT2, OATP1B1, OATP1B3, MATE2-K, BCRP, P-gp, or BSEP.
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