Search in the Abstract Database

Abstracts Search 2019

P349 Cyclosporine has no clinically meaningful effect on pharmacokinetics (PK) of BMS-986165, an oral selective tyrosine kinase 2 (TYK2) inhibitor, in healthy subjects

A. Chimalakonda*1, J. JonesIII2, R. Dockens1, J. Throup1, S. Banerjee1, I. Girgis1

1Bristol-Myers Squibb, Princeton, USA, 2PRA Health Sciences, Blue Bell, USA

Background

Cyclosporine is a dual breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) inhibitor. Current treatment guidelines for inflammatory bowel disease include cyclosporine for steroid-refractory ulcerative colitis.1,2 BMS-986165, an oral selective TYK2 inhibitor, has demonstrated efficacy and acceptable safety in patients with moderate to severe plaque psoriasis,3 and is under investigation in moderate to severe Crohn’s disease (LATTICE; NCT03599622) among other chronic autoimmune diseases. The current study assessed the effect of cyclosporine co-administration on the PK and safety/tolerability of BMS-986165.

Methods

In this Phase 1, open-label, single-sequence drug–drug interaction study (NCT03419910), healthy male subjects aged 18–50 years with a body mass index (BMI) of 18–32 kg/m2 received a once-daily, pharmacologically relevant, oral (po) dose of BMS-986165 on Days (D) 1–5, followed by a single dose of BMS-986165 + cyclosporine 500 mg po on D6. On PK sampling days, doses were administered after an overnight fast of ≥10 h. Blood samples were collected on D5 and D6 to determine the PK of BMS-986165 and cyclosporine.

Results

Overall, 20 subjects (mean [standard deviation] age 30.3 [7.0] years, BMI 26.0 [3.2] kg/m2) were treated and evaluable for safety; 2 (10%) withdrew due to adverse events (AEs; pyrexia) before D5 PK sampling. Cyclosporine co-administration with BMS-986165 had no clinically meaningful effect on peak and total BMS-986165 exposures (16% increase in maximum concentration and 29% increase in area under the curve over 24 h; Table) or its key metabolites. Median (min, max) time to maximum concentration for BMS-986165 was 2.5 (1, 4) h on D5 and 2.5 (2, 8) h on D6. There were no serious AEs or deaths. All treatment-emergent AEs were considered mild and resolved by study end.

Table. Effect of concomitant cyclosporine administration on BMS-986165 PK in PK-evaluable subjects (n = 18).

Conclusion

Cyclosporine, a dual BCRP and P-gp inhibitor, has no clinically meaningful effect on the PK of BMS-986165. Therefore, drugs inhibiting P-gp or BCRP (eg, cyclosporine, among others), are not expected to meaningfully impact the PK of BMS-986165. BMS-986165 alone or in combination with cyclosporine was well tolerated in healthy subjects in this study.

References

1. Harbord M, et al. J Chrons Colitis. 2017.

2. Kornbluth A, et al. Am J Gastroenterol 2010.

3. Papp K, et al. N Engl J Med. 2018.