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

Abstract

In 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, nonpregnant women aged 18-65 years (n = 15) who were using highly effective contraception, such as a nonhormonal 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. Co-administration resulted in a 2.8-fold and 2.4-fold increase in EE maximum plasma concentration (C max ) and area under the plasma drug concentration-time curve from time zero to infinity (AUC 0-inf ), respectively (day 18 vs. day 1). DRSP C max and AUC 0-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 liquid chromatography with tandem mass spectrometry in day 1 and day 18 plasma samples after EE conjugate hydrolysis. The ratio of EE AUC from time of administration up to the time of the last quantifiable concentration (AUC last ) with/without hydrolysis by arylsulfatase was substantially lower on day 18 vs. day 1, suggesting ziritaxestat is a potent inhibitor of sulfation; EE glucuronidation was largely unaffected by ziritaxestat. In vitro assessment confirmed ziritaxestat is a potent inhibitor of sulfotransferase family 1E member 1 (half-maximal inhibitory concentration < 0.8 μM). These findings highlight the importance of assessing enzymes other than CYP3A4 when investigating potential DDIs with oral contraceptives.

Combined Oral Contraceptives As Victims of Drug Interactions

“…In addition, in that study, UGT1A1 polymorphism did not have a clear impact on the effect of faldaprevir on raltegravir AUC. (2.19, 2.60) (Helmer et al, 2022) No effect on DRSP (Helmer et al, 2022) n/a n/a n/a = not available; qd = once daily; bid = twice daily b Rufinamide at 400 mg bid dose was a weak inducer of CYP3A, as indicated by its effect on AUC (reduced by 36%) of triazolam, a sensitive substrate of CYP3A (NDA 21911).…”

“…An article published in the 1980s suggests that ascorbic acid (vitamin C) and paracetamol (acetaminophen) increased plasma levels of EE possibly by competing for sulfation in the gut (Back et al, 1981). The impact of SULT1E1 inhibition on EE exposure is perhaps best demonstrated by a recent clinical DDI study of ziritaxestat with an EE/DRSP containing COC (Helmer et al, 2022). In this study, co-administration with ziritaxestat at 600 mg once daily for 18 days resulted in about 2.8-fold and 2.4-fold increase in EE C max and AUC, respectively, but no significant changes on DRSP exposure, indicating that ziritaxestat did not potently inhibit CYP3A.…”

“…One aspect that could be considered is to incorporate measurement of EE conjugates in DDI studies. As exemplified by the recently published work by Helmer et al describing the DDI between ziritaxestat and a EE-containing COC, changes in the plasma concentrations of glucuronide and sulfate conjugates of EE were measured to deconvolute the interacting mechanism (i.e., inhibition of sulfation pathway instead of glucuronidation by ziritaxestat (Helmer et al, 2022)). In the study evaluating the effect of etoricoxib (Schwartz et al, 2009), sulfate conjugate of EE was also measured providing direct evidence that sulfation of EE was inhibited.…”

Attempting to Unmask the Inhibition of Sulfotransferase 1E1 in 17α‐Ethinyl Estradiol Drug Interactions

“…This means that one needs to consider all 3 enzymes when attempting to understand EE DDI 1 . As an example, Helmer et al reported that ziritaxestat (autotaxin inhibitor) significantly impacts the pharmacokinetic (PK) profile of EE 2 . The inhibition of CYP3A4 was ruled out, as the DDI with drospirenone, a sensitive CYP3A4 substrate, was weaker (Table 1).…”

“… b See Table S1 for the estimation of SULT1E1 percentage inhibition in vivo (gut and liver not differentiated), based on the 2.5‐fold decrease in the ratio of measured plasma EE 3‐ O ‐sulfate AUC GMR/parent EE AUC GMR (etoricoxib) and the 5.6‐fold decrease in EE AUCR following arylsulfatase hydrolysis (ziritaxestat) 2,5 …”