Ziritaxestat Drug-Drug Interaction with Oral Contraceptives: Role of SULT1E1 Inhibition

Clin Pharmacol Ther. 2022 Jun 17. doi: 10.1002/cpt.2689. Online ahead of print.ABSTRACTIn vitro signals indicate that ziritaxestat is a weak cytochrome P450 (CYP) 3A4 inhibitor and inducer. Therefore, potential drug-drug interactions (DDIs) with oral contraceptives were examined at a time when ziritaxestat was under development for treatment of fibrotic diseases. This open-label, crossover (fixed sequence) DDI study enrolled healthy, non-pregnant females aged 18-65 years (n=15) who were using highly effective contraception such as a non-hormonal intrauterine device, bilateral tubal occlusion or sexual abstinence. A single dose of oral contraceptive (0.03 mg ethinyl estradiol [EE] and 3 mg drospirenone [DRSP]) was administered on Days 1, 8, and 18, and ziritaxestat 600 mg once daily was administered from Days 8 to 23. Coadministration resulted in a 2.8-fold and 2.4-fold increase in EE Cmax and AUC0-inf , respectively (Day 18 vs Day 1). DRSP Cmax and AUC0-inf increased by 1.1-fold and 1.2-fold, respectively. DRSP is a CYP3A4 substrate, meaning increased EE exposure with ziritaxestat was not due to CYP3A4 inhibition. Ziritaxestat inhibition of EE glucuronidation and sulfation was quantified by LC-MS/MS in Day 1 and Day 18 plasma samples after EE conjugate hydrolysis. The ratio of EE AUClast with/without hydrolysis by arylsulfatase was substantially lower on Day 18 versus Day 1, suggesting ziritaxestat is a potent inhibitor of sulfation; EE glucuronidation was largely unaffected ...
Source: Clinical Pharmacology and Therapeutics - Category: Drugs & Pharmacology Authors: Source Type: research