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An Open Label, Phase 1, Randomized, Seven-treatment, Seven-period, Crossover Study to Assess the Relative Bioavailability, pH Effect, Food Effect, and Dose Proportionality of CC-292, a Potent and Orally Available Bruton’s Tyrosine Kinase Inhibitor

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective

CC-292 is a potent, selective, orally administered small molecule inhibitor of Bruton’s tyrosine kinase (BTK). To support the clinical investigation of CC-292, a randomized, seven-treatment, seven-period, crossover study was conducted to assess the relative bioavailability, pH effect, food effect, and dose-proportionality of two formulated tablets of CC-292.

Methods

Healthy subjects (n = 24) were enrolled in the study and randomly assigned into different treatment sequences. Blood samples were collected at pre-specified time points to measure the drug concentrations in plasma. Statistical analyses were performed to compare the pharmacokinetics of CC-292 under different conditions.

Results

The relative bioavailability of the newly developed formulation [spray-dried dispersion (SDD)] to the reference formulation (P22) was 1.24. When a single dose of CC-292 SDD tablet was administered under fed conditions, the area under the plasma concentration–time curve from time zero to infinity (AUC∞) increased by 10.9% and the maximum plasma drug concentration Cmax) decreased by 19.4% compared to when CC-292 was administered under fasted conditions. When a single dose of CC-292 SDD tablet was administered after multiple doses of omeprazole, the area under the plasma concentration–time curve from time zero to infinity (AUC∞) decreased by 36.8% and the maximum plasma drug concentration Cmax) decreased by 48.1% compared to when CC-292 was administered alone. Over a dose range of 100–300 mg (SDD formulation), CC-292 exhibited more than dose-proportional increases of drug exposures.

Conclusions

CC-292 was well tolerated when administered to healthy subjects as single oral doses under all conditions. Food intake had no clinically relevant impact on CC-292 pharmacokinetics compared to fasted conditions. Therefore, CC-292 can be administered with or without food. Co-administration of CC-292 with multiple doses of omeprazole (40 mg) decreased the pharmacokinetic exposure of CC-292. However, the effect was not clinically relevant.

Clinical Trials Registration

NCT02433457

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Acknowledgements

The authors thank all study participants, their families and clinical study team members.

Author information

Authors and Affiliations

  1. Clinical Pharmacology and Pharmacometrics, Bristol Myers Squibb, 556 Morris Ave, Summit, NJ, 07901, USA

    Yiming Cheng, Simon Zhou & Yan Li

  2. Global Biometrics and Data Sciences, Bristol Myers Squibb, Berkeley Heights, NJ, USA

    Liangang Liu

  3. Non-Clinical Research and Development, Bristol Myers Squibb, Princeton, NJ, USA

    Yongjun Xue

Authors
  1. Yiming Cheng
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  4. Simon Zhou
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Corresponding author

Correspondence to Yan Li.

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Funding

This work was sponsored and funded by Bristol Myers Squibb.

Competing Interests

Y.C., L.L., Y.X., S.Z. and Y.L. are employees and hold equity ownership in Bristol Myers Squibb.

Consent for Publication

Not applicable.

Ethics Approval

The study was conducted in accordance with the applicable United States (US) Code of Federal Regulations (CFR) governing the Protection of Human Subjects (21 CFR 50, 1980), Financial Disclosure by Clinical Investigators (21 CFR 54, 1998), Institutional Review Board (IRB) (21 CFR 56, 1981), the Investigational New Drug Application (21 CFR 312, 1987), and Applications for Food and Drug Administration Approval to Market a New Drug (21 CFR 314, 1985). As such, these sections of US Title 21 CFR, along with the applicable International Conference on Harmonisation Guidelines (ICH, E6, 1997), are commonly known as Good Clinical Practice (GCP), which are consistent with the Declaration of Helsinki (World Medical Association, 2008). The study was approved by the Schulman Associates Independent Review Board (Cincinnati, Ohio, USA).

Consent to Participate

The investigator obtained written informed consent from the subjects prior to any study-related procedures.

Code Availability

Not applicable.

Availability of Data and Material

The datasets are available from the corresponding author upon request.

Authors' Contributions

Y.L. and L.L. contributed to conception and design; Y.L. and Y.X. contributed to acquisition of data; Y.C., L.L., S.Z. and Y.L. contributed to analysis; Y.C., S.Z. and Y.L. drafted and revised the article. All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agreed to be accountable for all aspects of the work.

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Cheng, Y., Liu, L., Xue, Y. et al. An Open Label, Phase 1, Randomized, Seven-treatment, Seven-period, Crossover Study to Assess the Relative Bioavailability, pH Effect, Food Effect, and Dose Proportionality of CC-292, a Potent and Orally Available Bruton’s Tyrosine Kinase Inhibitor. Eur J Drug Metab Pharmacokinet 47, 579–592 (2022). https://doi.org/10.1007/s13318-022-00776-7

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