Effects of rifampin on the pharmacokinetics and pharmacodynamics of milvexian, a potent, selective, oral small molecule factor XIa inhibitor

• Published in: Scientific reports Vol. 12; no. 1; pp. 22239 - 8
• Main Authors: Perera, Vidya, Wang, Zhaoqing, Lubin, Susan, Christopher, Lisa J., Chen, Wei, Xu, Sophia, Seiffert, Dietmar, DeSouza, Mary, Murthy, Bindu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.12.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/436; 692/699/75; Area Under Curve; Coagulation factors; Cytochrome P-450 CYP3A - metabolism; Cytochrome P450; Drug Interactions; Factor XIa - metabolism; Healthy Volunteers; Humanities and Social Sciences; Humans; multidisciplinary; Organic anion transporting polypeptide; P-Glycoprotein; Pharmacodynamics; Pharmacokinetics; Protein transport; Rifampin; Rifampin - pharmacology; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-25936-2

Milvexian (BMS-986177/JNJ-70033093) is a potent, oral small molecule that inhibits the active form of factor XI with high affinity and selectivity. This study assessed the single-dose pharmacokinetic and pharmacodynamic properties of milvexian co-administered with rifampin, an organic anion transport protein (OATP) inhibitor and potent cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp) inducer. In this open-label, nonrandomized, single-sequence study, healthy participants ( N  = 16) received single doses of milvexian on Day 1 (100 mg), milvexian and rifampin (600 mg) on Day 4, rifampin on Days 5–11, milvexian and rifampin on Day 12, and rifampin on Days 13–14. Pharmacokinetic data were summarized using descriptive statistics. Administration of milvexian, alone or in combination with rifampin, was generally safe and well tolerated. Single-dose co-administration of rifampin and milvexian demonstrated no meaningful changes in milvexian exposure versus milvexian alone (C max , 110%; AUC [0–T] , 102%; AUC [INF] , 101%). After multiple doses of rifampin and milvexian, peak and total milvexian exposure substantially decreased versus milvexian alone (C max , 22%; AUC [0–T] , 15%; AUC [INF] , 15%). Results were consistent with preclinical data, indicating that milvexian is a substrate for CYP3A4/5 and P-gp but not OATP. The implications of these results on the need for dose adjustment of milvexian will be further elucidated following the completion of phase 2 and 3 trials. Trial registration The study was registered with ClinicalTrials.gov (NCT02959060; submitted 7/11/2016, first posted 8/11/2016).