Oral contraceptive absorption unhindered by odevixibat in healthy women

The research was presented as a poster at the 2024 AASLD The Liver Meeting in San Diego, California, USA, by Florent Mazuir (Ipsen Innovation, Les Ulis, France) and co-workers.

“Although patients with PFIC [progressive familial intrahepatic cholestasis] or ALGS [Alagille syndrome] are generally diagnosed in childhood, they may continue to require treatment into adulthood,” the authors say.

They explain that as IBAT inhibition interrupts enterohepatic circulation and raises fecal excretion of bile acids (BAs), this might “impair the absorption of fat-soluble medicines” such as oral estrogen contraceptives.

To investigate, the team recruited 25 healthy women aged 18–55 years with a BMI of 18–30 kg/m². The majority of participants were White (48%) or Black (28%), and 60% were not of Hispanic or Latino ethnicity. Twenty-two of the women completed the trial.

On day 1 of the study, the women were given a single dose of oral contraceptive containing 0.03 mg of ethinyl estradiol (EE) and 0.15 mg of levonorgestrel (LVN). On days 4–9, the women were given oral odevixibat 3 mg once daily, followed by dosage with both EE/LVN and odevixibat on day 10.

Plasma samples were taken for up to 48 hours and 72 hours after dosing of EE and LVN, respectively, and for up to 2.5 hours after odevixibat dosing.

The co-primary endpoints of the study were the area under the concentration-time curve (AUC) from baseline to the last quantifiable plasma concentration and from baseline extrapolated to infinity for EE and LVN with or without odevixibat.

The AUC to the last quantifiable measurement values were comparable with and without odevixibat for both EE and LVN and the lower boundaries of the 90% confidence interval were within the no effect range of 80–125%. This was also true for the AUC extrapolated to infinity for LVN but there was a 17% reduction for EE with versus without odevixibat giving a 90% confidence interval lower boundary of 79%. However, the researchers believe that this result is not “clinically meaningful.”

Pharmacokinetic analysis indicated that there was no difference in the maximum plasma concentration of EE with or without odevixibat (71 vs 73 pg/mL) or the time to maximum EE concentration (1.5 vs 1.0 hours). The corresponding values for LVN with or without odevixibat were also similar at 3882 versus 3821 pg/mL and 1 hour each.

The terminal elimination half-life durations did not differ significantly with and without odevixibat for EE (17 vs 18 h) and LVN (39 vs 45 h).

Overall, 64% of participants experienced treatment-emergent adverse events during the study, most commonly diarrhea affecting 40% and nausea 20%. The majority of events were “mild” and resolved by the end of the study, the team says. Treatment-related adverse events occurred in 54% of patients, all of which were gastrointestinal disorders and none led to discontinuation of treatment.

“Multiple doses of odevixibat had no clinically meaningful effects on the absorption of EE or LVN in healthy female participants despite enhanced fecal excretion of BAs; this may be due to odevixibat triggering de novo synthesis of BAs,” Mazuir et al write.

While emphasizing that the research should not be extrapolated to other lipophilic drugs given alongside odevixibat, the authors believe that “[t]hese findings might help to inform clinical management of women of childbearing potential with PFIC or ALGS taking oral contraceptives.”