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Open Access Highly Accessed Research article

Changes in serum creatinine in patients with active rheumatoid arthritis treated with tofacitinib: results from clinical trials

John D Isaacs1, Andrea Zuckerman2, Sriram Krishnaswami2, Chudy Nduaka2*, Shuping Lan2, Matthew M Hutmacher3, Mary G Boy2, Ken Kowalski3, Sujatha Menon2 and Richard Riese2

Author Affiliations

1 The National Institute for Health Research and Newcastle Biomedical Research Centre based at Newcastle Hospitals Foundation Trust and Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK

2 Pfizer Inc, 558 Eastern Point Road, Groton, CT 06340, USA

3 Ann Arbor Pharmacometrics Group (A2PG), 110 Miller Avenue, Ann Arbor, MI 48104, USA

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Arthritis Research & Therapy 2014, 16:R158  doi:10.1186/ar4673

Published: 25 July 2014

Abstract

Introduction

Small increases in mean serum creatinine (SCr) were observed in studies of rheumatoid arthritis patients during tofacitinib treatment. These SCr changes were investigated and potential mechanisms explored.

Methods

SCr values and renal adverse event data were pooled from five Phase 3 and two long-term extension (LTE) studies. Dose-response relationships and association with inflammation (C-reactive protein (CRP)) were explored using Phase 2 data and confirmed with Phase 3 data.

Results

In Phase 3, least squares mean SCr differences from placebo at Month 3 were 0.02 and 0.04 mg/dl for tofacitinib 5 and 10 mg twice daily (BID) (P <0.05), respectively. During Months 0 to 3, confirmed SCr ≥33% increases over baseline were reported in 17 (1.4%; 5 mg BID) and 23 (1.9%; 10 mg BID) patients. Generally, elevations plateaued and remained within normal limits throughout Phase 3 and LTE studies. Exposure-response modeling demonstrated small, reversible effects of tofacitinib on mean SCr, and significant (P <0.05) effects of CRP on model parameters. Phase 3 data confirmed that patients with higher baseline CRP or greater CRP decreases following tofacitinib treatment had the largest increases in SCr. Across Phase 3 and LTE studies, 22 tofacitinib-treated patients had clinical acute renal failure (ARF), predominantly in the setting of concurrent serious illness.

Conclusions

Tofacitinib treatment was associated with small, reversible mean increases in SCr that plateaued early. The mechanism behind these SCr changes remains unknown, but may involve effects of tofacitinib on inflammation. ARF occurred infrequently, was associated with concurrent serious illness, and was unrelated to prior SCr increases.