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Background: Branebrutinib (BMS-986195) is a highly potent and selective irreversible small-molecule covalent inhibitor of Bruton’s tyrosine kinase (BTK), 1 a non-receptor tyrosine kinase involved in the pathophysiology of immune-mediated diseases. Branebrutinib has the potential to be best in its class, as it achieves ~100% BTK occupancy in humans, sustained over a 24-hour dosing interval at low doses (≤ 10 mg once daily [QD]) despite its short half-life (≤ 2 hours),2 and demonstrates potent efficacy in murine models of immune-mediated diseases.1 Branebrutinib is under clinical study in multiple autoimmune inflammatory disorders such as RA, systemic lupus erythematosus, primary Sjögren’s syndrome, and atopic dermatitis. In vitro drug-drug interaction (DDI) studies with branebrutinib predicted pharmacokinetic DDI potential with substrates of cytochrome P450 (CYP)3A4 and the breast cancer resistant protein drug transporter.
Objectives: To assess the DDI potential of branebrutinib when co-administered with potential concomitant medications and probe substrates of major drug-metabolizing enzymes (DMEs) and drug transporters.
Methods: DDI risk with branebrutinib was assessed in 3 single-sequence, cross-over clinical studies in healthy participants. In the first 2-part study, MTX was administered alone or with steady-state (SS) branebrutinib (10 mg QD) in part 1; in part 2, caffeine, montelukast, flurbiprofen, omeprazole, midazolam, digoxin, and pravastatin were taken with or without SS branebrutinib (9 mg QD). In the second study, rosuvastatin was taken alone or with SS branebrutinib (9 mg QD). In cycle 1 of the third study, the oral contraceptive (OC) loestrin (1.5 mg norethindrone/30 μg ethinyl estradiol) was taken alone; in cycle 2, SS branebrutinib (9 mg QD) was taken alone or with the OC.
Results: Weak DDI with montelukast (CYP2C8) was observed, leading to a mild increase in montelukast exposure (max concentration [C
max
], 56%; area under the curve [AUC], 27%). A mild increase in digoxin exposure (P-glycoprotein [P-gp] substrates; C
max
, 57%; AUC, 21%) was also observed. There was no potential DDI with MTX (
Results from clinical DDI studies of branebrutinib
| Adjusted geometric mean ratios with (test) and without (reference) branebrutinib | |||
|---|---|---|---|
| Concomitant medication or probe substrate | DME or drug transporter tested | C max ratio (90% CI) | AUC ratio (90% CI) |
| Digoxin (0.25 mg) | P-gp | 1.57 (1.36–1.80) | 1.21 (1.11–1.32) |
| MTX (7.5 mg) | BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MRP2, MRP4 | 1.00 (0.92–1.09) | 0.94 (0.90–0.99) |
| Pravastatin (40 mg) | OATP1B1, OATP1B3 | 1.25 (1.00–1.57) | 1.06 (0.90–1.25) |
| Rosuvastatin (10 mg) | BCRP, OATP1B1, OATP1B3 | 0.81 (0.71–0.93) | 0.96 (0.88–1.04) |
| Montelukast (10 mg) | CYP2C8 | 1.56 (1.24–1.95) | 1.27 (1.10–1.47) |
| Caffeine (200 mg) | CYP1A2 | 0.98 (0.94–1.01) | 1.16 (1.08–1.24) |
| Flurbiprofen (50 mg) | CYP2C9 | 1.06 (0.97–1.16) | 1.12 (1.09–1.15) |
| Omeprazole (50 mg) | CYP2C19 | 1.05 (0.85–1.30) | 0.97 (0.84–1.13) |
| Midazolam (5 mg) | CYP3A4 | 0.95 (0.82–1.11) | 1.00 (0.84–1.19) |
| Ethinyl estradiol (30 μg) | CYP3A, CYP2C9, UGAT1A1, SULT1E1 | 1.16 (1.09–1.23) | 1.17 (1.12–1.22) |
| Norethindrone (1.5 mg) | CYP3A4, CYP2C19 | 1.10 (1.04–1.15) | 1.06 (1.01–1.12) |
BCRP, breast cancer resistant protein; MRP, multidrug resistance-associated protein; OAT, organic anion transporting polypeptide; SULT, estrogen sulfotransferase; UGAT, uridine diphosphate glucuronosyltransferase.
Conclusion: In all 3 studies, co-administration of SS branebrutinib was generally well tolerated. The only potentially significant DDIs with substrates of major DMEs or transporters were mild increases in montelukast (CYP2C8) and digoxin (P-gp) exposures.
REFERENCES:
[1]Watterson SH, et al. J Med Chem 2019;62:3228–50.
[2]Catlett IM, et al. Br J Clin Pharmacol 2020;86:1849–59.
Acknowledgements: This study was sponsored by Bristol Myers Squibb. Editorial assistance was provided by Candice Judith Dcosta, MSc, of Caudex, and was funded by Bristol Myers Squibb.
Disclosure of Interests: Aberra Fura Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Ihab Girgis Shareholder of: Bristol Myers Squibb, Johnson & Johnson, Employee of: Bristol Myers Squibb, Johnson & Johnson, CSL Behring, Miroslawa Nowak Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Leon Carayannopoulos Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Celgene, Merck Sharp & Dohme, Dennis Grasela Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Wenying Li Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Bindu Murthy Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Urvi Aras Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb