Retinoic acid-related orphan receptor gamma t (RORγt). Bevurogant (BI 730357) is a RORγt antagonist. [1]

Assessing drug-drug interactions for new investigational compounds typically requires multiple trials, each evaluating different drugs with distinct transporter specificities. However, employing a cocktail of drugs that target various transporters allows a single study to simultaneously assess the pharmacokinetics of each component, thereby reducing the number of clinical DDI trials needed during drug development. This study aimed to evaluate the impact of steady-state BI 730357 (bevurogant) on the pharmacokinetics of a validated and optimized four-component transporter cocktail. This Phase I trial employed an open-label, non-randomized, two-period, fixed-sequence design. Healthy subjects aged 18 to 55 years with a body mass index between 18.5 and 29.9 kg/m² received a transporter cocktail (0.25 mg digoxin, 1 mg furosemide, 10 mg metformin hydrochloride, and 10 mg rosuvastatin) either alone or together with BI 730357. During the reference period (Period 1), the cocktail was administered 90 minutes after breakfast. Following a washout period, during the test period (Period 2), subjects received BI 730357 twice daily for 13 days, with the transporter cocktail given on day 1. Primary endpoints included the area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC₀-∞) and the maximum observed plasma concentration (Cmax). The secondary endpoint was the AUC from time zero to the last quantifiable time point (AUC₀-tz). At steady state, BI 730357 increased digoxin exposure by 48% to 94%, had minimal impact on metformin (‑2% to ‑9%), and slightly increased furosemide (12% to 18%) and rosuvastatin (19% to 39%) exposure. Consequently, no clinically meaningful inhibition of the transporters OCT2, MATE-1, MATE-2K, OAT1, OAT3, OATP1B1, or OATP1B3 was observed. While the pharmacokinetic parameters of the endogenous biomarkers coproporphyrin I and III (probes for OATP1B1/1B3) remained within bioequivalence limits, the PK parameters of rosuvastatin (AUC₀-∞, Cmax, AUC₀-tz) exceeded these boundaries, suggesting potential inhibition of breast cancer resistance protein. BI 730357 was found to be safe and well tolerated. This trial confirms that the transporter cocktail containing digoxin, furosemide, metformin, and rosuvastatin is a useful and tolerable tool for assessing drug-transporter interactions in vivo. [1]

Bevurogant (BI 730357) is primarily metabolized by CYP3A4 in vivo. Coadministration with itraconazole (a strong CYP3A4 inhibitor) increased BI 730357 exposure by approximately 9-fold. [1]
In this study, Bevurogant was administered orally at 300 mg twice daily for 13 days under fed conditions (30 minutes after a standardized breakfast and dinner). This regimen was designed to achieve an exposure of 44,079 ng/mL•h (AUCτ,ss) and a Cmax,ss of 2,201 ng/mL based on population PK modeling, ensuring that the predicted Cmax,ss for drug interaction (959 ng/mL) was reached and accounting for a positive food effect observed previously. [1]
Steady state of Bevurogant was reached within 7 days of dosing. On Day 7 (one day prior to transporter cocktail administration in period 2), the geometric mean Cpre,ss was 1,135 ng/mL (range 597-2,628), AUCτ,ss was 15,724 ng/mL•h (range 8,688-27,396), and Cmax,ss was 1,690 ng/mL (range 954-2,788). [1]

Bevurogant (BI 730357) at steady-state administration of 300 mg twice daily for 13 days was safe and well tolerated in healthy subjects. [1]
Adverse events (AEs) reported were either mild or moderate in severity and resolved without treatment. No serious AEs, AEs of special interest, or trial discontinuations due to AEs were reported. [1]
For Bevurogant alone, 2 subjects reported drug-related AEs: food aversion (n=1, 6.7%) and pain in extremity (n=1, 6.7%). For BI 730357 plus transporter cocktail, 2 subjects reported drug-related AEs: headache (n=2, 13.3%), parosmia (n=1, 6.7%), and malaise (n=1, 6.7%). [1]

[1]. Choi H, et al. The Effect of BI 730357 (Retinoic Acid-Related Orphan Receptor Gamma t Antagonist, Bevurogant) on the Pharmacokinetics of a Transporter Probe Cocktail, Including Digoxin, Furosemide, Metformin, and Rosuvastatin: An Open-Label, Non-randomized, 2-Period Fixed-Sequence Trial in Healthy Subjects. Clin Pharmacol Drug Dev. 2024 Feb;13(2):197-207.

[2]. Compounds as modulators of ror gamma. US20150291607A1.

Bevurogant (BI 730357) at steady-state administration of 300 mg twice daily for 13 days was safe and well tolerated in healthy subjects. [1]
Adverse events (AEs) reported were either mild or moderate in severity and resolved without treatment. No serious AEs, AEs of special interest, or trial discontinuations due to AEs were reported. [1]
For Bevurogant alone, 2 subjects reported drug-related AEs: food aversion (n=1, 6.7%) and pain in extremity (n=1, 6.7%). For BI 730357 plus transporter cocktail, 2 subjects reported drug-related AEs: headache (n=2, 13.3%), parosmia (n=1, 6.7%), and malaise (n=1, 6.7%). [1]

C26H28N8O3S

532.6173

532.2

C, 58.63; H, 5.30; N, 21.04; O, 9.01; S, 6.02

1817773-66-2

118440466

White to light yellow solid powder

1.1

1

9

8

38

1030

1

S(C([H])([H])[H])(C1=C([H])N=C(C([H])=C1[H])C([H])([H])N([H])C1C(N(C2C(=C([H])N=C(C3=C(C([H])([H])[H])N=C([H])N=C3C3([H])C([H])([H])C3([H])[H])N=2)N=1)[C@@]([H])(C([H])([H])[H])C1([H])C([H])([H])C1([H])[H])=O)(=O)=O

HVVHIBHBDCYLDI-HNNXBMFYSA-N

InChI=1S/C26H28N8O3S/c1-14-21(22(17-6-7-17)31-13-30-14)23-29-12-20-25(33-23)34(15(2)16-4-5-16)26(35)24(32-20)28-10-18-8-9-19(11-27-18)38(3,36)37/h8-9,11-13,15-17H,4-7,10H2,1-3H3,(H,28,32)/t15-/m0/s1

8-[(1S)-1-cyclopropylethyl]-2-(4-cyclopropyl-6-methylpyrimidin-5-yl)-6-[(5-methylsulfonylpyridin-2-yl)methylamino]pteridin-7-one

Bevurogant; BI 730357； 1817773-66-2; BI-730357； Bevurogant [INN]; BI730357； 1874HVK11I; 7(8H)-Pteridinone, 8-((1S)-1-cyclopropylethyl)-2-(4-cyclopropyl-6-methyl-5-pyrimidinyl)-6-(((5-(methylsulfonyl)-2-pyridinyl)methyl)amino)-;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 250 mg/mL (469.4 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (3.91 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (3.91 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)