(M1230-02-10) No Clinically Meaningful Pharmacokinetic Drug-Drug Interaction Between Berotralstat and the Progestin Oral Contraceptive Desogestrel

Purpose: Hereditary angioedema (HAE) is a genetic disorder characterized by recurrent episodes of swelling of the skin, pharynx, larynx, gastrointestinal tract, genitals, and extremities. Berotralstat (ORLADEYO®) is a first-line, once-daily (QD) oral long-term prophylactic therapy for HAE patients ≥ 12 years old. Women with HAE often prefer progestin-only oral contraceptives (OCs) to combination OCs since estrogen can worsen HAE symptoms. Desogestrel is a commonly used progestin-only OC (eg., Cerazette 0.075 mg desogestrel) in the EU and is the only oral progesterone OC considered highly effective because it inhibits ovulation. Desogestrel is metabolized primarily by cytochrome P450 (CYP) 2C9 to its active metabolite etonogestrel. Berotralstat, as a weak inhibitor of CYP2C9, could decrease the efficacy of desogestrel-only OCs. This study aimed to determine the effect of berotralstat on the pharmacokinetics (PK) of etonogestrel following coadministration of Apri® (0.15 mg desogestrel and 0.03 mg ethinyl estradiol).

Methods: This single-center, open-label study was designed to evaluate the effect of berotralstat on the PK of desogestrel and its active metabolite etonogestrel. Single doses of Apri were administered on Days 1 and 16. Berotralstat (150 mg QD) was administered on Days 7 through 17. Serial blood samples for PK analysis for etonogestrel were collected through 72 hours after the Apri dose on Day 1 (without berotralstat) and Day 16 (with berotralstat). Blood samples for the analysis of berotralstat concentrations were collected pre-dose and 4 hours post-dose on Days 7 and 16. Etonogestrel PK parameters were calculated using noncompartmental analysis. Steady-state etonogestrel exposures with and without concomitant berotralstat were predicted using population PK modeling.

Results: Twenty-two healthy female subjects completed the study and were included in the PK analysis. The mean (SD) subject age was 33.8 (7.30) years (range 20 to 45 years), all subjects were of Hispanic ethnicity and most subjects were white (90.9%). Following 10 days (from Day 7 to Day 16) of berotralstat administration, the arithmetic mean plasma berotralstat concentrations were consistent with steady-state berotralstat exposures observed in other studies. Following administration of Apri with or without berotralstat, desogestrel was rapidly converted into etonogestrel with median etonogestrel Tmax ranging from 1 to 4 hours post-dose. Single-dose geometric mean plasma etonogestrel Cmax was similar when Apri was administered with or without berotralstat; however, geometric mean etonogestrel AUC0-last and AUC0-24 increased following administration with berotralstat (Table 1). The lower limit of quantification of the etonogestrel bioanalytical assay precluded proper characterization of the terminal half-life of etonogestrel needed to estimate AUCinf which was then replaced by AUC0-24 for the drug interaction assessment. Due to the increase in etonogestrel exposures, population PK modeling and steady-state simulations were conducted. A two-compartment linear PK model best described the PK of etonogestrel with a decreased elimination rate when administered with berotralstat. Simulations demonstrated that berotralstat coadministration resulted in increased steady-state etonogestrel exposures.

Conclusion: With the increased exposure of etonogestrel, the efficacy of desogestrel as a contraceptive is not expected to be reduced when coadministered with berotralstat. The predicted steady-state etonogestrel exposure following administration of 0.075 mg desogestrel remains below that seen with desogestrel-estrogen combined products (0.15 mg desogestrel and 0.03 mg ethinyl estradiol). Based on these results, no dose adjustment is needed for concomitant use of desogestrel and berotralstat.


Table 1. Observed and Simulated Etonogestrel Pharmacokinetic Parameters in the Presence and Absence of Berotralstat after Single-Dose (Observed) or Steady-State (Simulated) Administration