Skip to main content
SpringerLink
Log in

Drug Interactions Between Peficitinib, an Orally Administered, Once-Daily Janus Kinase Inhibitor, and Rosuvastatin in Healthy Subjects

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and objective

Peficitinib is an orally administered, once-daily Janus kinase inhibitor in development for the treatment of rheumatoid arthritis. Peficitinib and its major metabolite H2 inhibit the hepatic uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1) in vitro. This article reports a clinical study evaluating the effects of peficitinib on the pharmacokinetics of rosuvastatin, a substrate for the OATP1B1 transporter, and vice versa.

Methods

In an open-label, single-sequence clinical study, 24 healthy adults of East Asian and non-East Asian origin received a single dose of rosuvastatin 10 mg on days 1 and 10. On days 5–13, subjects received a daily dose of 150 mg peficitinib. Serial blood samples for pharmacokinetic assessment of rosuvastatin were collected up to 96 h post-dose on days 1 and 10, and for peficitinib were collected up to 24 h post-dose on days 9 and 10.

Results

Co-administration of peficitinib with rosuvastatin increased rosuvastatin area under the concentration-time curve (AUC) and maximum plasma concentration (C max) by 18 and 15%, respectively and increased peficitinib AUC and C max by 16 and 28%, respectively. In East Asian (n = 6) vs. non-East Asian subjects (n = 18), peficitinib mean AUC for a dosing interval was 45 and 21% higher, and mean C max was 67 and 34% higher, when administered alone or with rosuvastatin. Peficitinib was well tolerated with few adverse events overall.

Conclusion

In this study, once-daily oral administration of peficitinib had no clinically significant effect on the pharmacokinetics of rosuvastatin, a probe substrate for OATP1B1. Therefore, it is unlikely that peficitinib will have a clinically significant effect on the exposure of other substrates for OATP1B1.

ClinicalTrials.gov number

NCT01959399.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Takeuchi T, Tanaka Y, Iwasaki M, et al. Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015 K) monotherapy in moderate to severe rheumatoid arthritis patients in Japan: a 12-week, randomized, double-blind, placebo-controlled phase IIb study. Ann Rheum Dis. 2016;75(6):1057–64.

    Article  CAS  PubMed  Google Scholar 

  2. Papp K, Pariser D, Catlin M, et al. A phase 2a randomized, double-blind, placebo-controlled, sequential dose-escalation study to evaluate the efficacy and safety of ASP015K, a novel Janus kinase inhibitor, in patients with moderate-to-severe psoriasis. Br J Dermatol. 2015;173(3):767–76.

    Article  CAS  PubMed  Google Scholar 

  3. Genovese M, Greenwald M, Codding C, et al. A phase 2b, randomized, double-blind, parallel-group, placebo-controlled, dose-finding, multi-center study to evaluate the safety and efficacy of ASP015K in moderate-to-severe rheumatoid arthritis subjects not on concomitant methotrexate. Arthritis Rheumatol. 2014;66(S10):S1234–5.

    Google Scholar 

  4. Kivitz A, Zubrzycka-Sienkiewicz A, Guttierez-Urena S, et al. A phase 2b, randomized, double-blind, parallel-group, placebo-controlled, dose-finding, multi-center study to evaluate the safety and efficacy of ASP015 K in moderate-to-severe rheumatoid arthritis subjects who have had an inadequate response to methotrexate. Arthritis Rheumatol. 2014;66(S10):S421–2.

    Google Scholar 

  5. Zhu T, Parker B, Wojtkowski T, et al. Drug interactions between ASP015 K (ASP) and rosuvastatin (R) in Asian and non-Asian subjects [abstract no. 1-42-2000353]. Clin Pharmacol Drug Dev. 2014;3(S1):1–59.

    Article  Google Scholar 

  6. Sharma P, Butters CJ, Smith V, et al. Prediction of the in vivo OATP1B1-mediated drug-drug interaction potential of an investigational drug against a range of statins. Eur J Pharm Sci. 2012;47(1):244–55.

    Article  CAS  PubMed  Google Scholar 

  7. Allred AJ, Bowen CJ, Park JW, et al. Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers. Br J Clin Pharmacol. 2011;72(2):321–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lau YY, Huang Y, Frassetto L, Benet LZ. Effect of OATP1B1 transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther. 2007;81(2):194–204.

    Article  CAS  PubMed  Google Scholar 

  9. Menon RM, Badri PS, Wang T, et al. Drug–drug interaction profile of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol. 2015;63(1):20–9.

    Article  CAS  PubMed  Google Scholar 

  10. Prueksaritanont T, Chu X, Evers R, et al. Pitavastatin is a more sensitive and selective organic anion-transporting polypeptide 1B clinical probe than rosuvastatin. Br J Clin Pharmacol. 2014;78(3):587–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Davidson M, Ma P, Stein EA, et al. Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia. Am J Cardiol. 2002;89(3):268–75.

    Article  CAS  PubMed  Google Scholar 

  12. Davidson MH, Abate N, Ballantyne CM, et al. Ezetimibe/simvastatin compared with atorvastatin or rosuvastatin in lowering to specified levels both LDL-C and each of five other emerging risk factors for coronary heart disease: non-HDL-cholesterol, TC/HDL-C, apolipoprotein B, apo-B/apo-A-I, or C-reactive protein. J Clin Lipidol. 2008;2(6):436–46.

    Article  PubMed  Google Scholar 

  13. Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol. 2003;92(2):152–60.

    Article  CAS  PubMed  Google Scholar 

  14. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006;295(13):1556–65.

    Article  CAS  PubMed  Google Scholar 

  15. Simonson SG, Raza A, Martin PD, et al. Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine. Clin Pharmacol Ther. 2004;76(2):167–77.

    Article  CAS  PubMed  Google Scholar 

  16. Kulmatycki K, Hanna I, Meyers D, et al. Evaluation of a potential transporter-mediated drug interaction between rosuvastatin and pradigastat, a novel DGAT-1 inhibitor. Int J Clin Pharmacol Ther. 2015;53(5):345–55.

    Article  CAS  PubMed  Google Scholar 

  17. Li R, Barton HA, Maurer TS. Toward prospective prediction of pharmacokinetics in OATP1B1 genetic variant populations. CPT Pharmacomet Syst Pharmacol. 2014;3:e151.

    Article  CAS  Google Scholar 

  18. Ebner T, Ishiguro N, Taub ME. The use of transporter probe drug cocktails for the assessment of transporter-based drug-drug interactions in a clinical setting: proposal of a four component transporter cocktail. J Pharm Sci. 2015;104(9):3220–8.

    Article  CAS  PubMed  Google Scholar 

  19. Lee E, Ryan S, Birmingham B, et al. Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment. Clin Pharmacol Ther. 2005;78(4):330–41.

    Article  CAS  PubMed  Google Scholar 

  20. Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011;63(1):157–81.

    Article  CAS  PubMed  Google Scholar 

  21. Zhu T, Sawamoto T, Valluri U, et al. Pharmacokinetics, safety, and tolerability of ASP015K, a novel janus kinase inhibitor, in healthy volunteers. Ann Rheum Dis. 2013;72(Suppl 3):A898–9.

    Google Scholar 

  22. MedDRA. Introductory guide MedDRA v14.0. 2011. http://www.meddra.org/sites/default/files/guidance/file/intguide_14_0_english.pdf. [Accessed 17 Jan 2016].

  23. Choi JH, Lee MG, Cho JY, et al. Influence of OATP1B1 genotype on the pharmacokinetics of rosuvastatin in Koreans. Clin Pharmacol Ther. 2008;83(2):251–7.

    Article  CAS  PubMed  Google Scholar 

  24. Smith NF, Figg WD, Sparreboom A. Role of the liver-specific transporters OATP1B1 and OATP1B3 in governing drug elimination. Exp Opin Drug Metab Toxicol. 2005;1(3):429–45.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Medical writing support was provided by Matthew Reynolds and Victoria Jones of Choice Healthcare Solutions and funded by Astellas Pharma Inc. We acknowledge all other investigators for their participation in this trial.

Author information

Authors and Affiliations

  1. Clinical Pharmacology and Exploratory Development, Astellas Pharma Global Development Inc., 1 Astellas Way, Northbrook, IL, 60062, USA

    Tong Zhu, Barbara Parker, Tomasz Wojtkowski, Jay P. Garg & James Keirns

  2. Astellas Pharma Inc., Tokyo, Japan

    Tetsuya Nishimura

  3. Astellas Research Institute of America LLC, Skokie, IL, USA

    Ogert Fisniku

  4. California Clinical Trials, PAREXEL International, Glendale, CA, USA

    David Han

Authors
  1. Tong Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Barbara Parker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomasz Wojtkowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tetsuya Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jay P. Garg
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ogert Fisniku
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. James Keirns
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tong Zhu.

Ethics declarations

Funding

This study was funded by Astellas Pharma Inc.

Conflict of interest

Tong Zhu, Tomasz Wojtkowski, Tetsuya Nishimura, and James Keirns are employees of Astellas Pharma Inc. Barbara Parker, Jay Garg, and Ogert Fisniku were employees of Astellas Pharma Inc. during the study. David Han is an employee of PAREXEL International, contracted by Astellas Pharma Inc. to conduct the clinical assessments throughout this study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 13 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, T., Parker, B., Wojtkowski, T. et al. Drug Interactions Between Peficitinib, an Orally Administered, Once-Daily Janus Kinase Inhibitor, and Rosuvastatin in Healthy Subjects. Clin Pharmacokinet 56, 747–757 (2017). https://doi.org/10.1007/s40262-016-0474-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-016-0474-4

Keywords

Search

Navigation