Pharmacokinetics and safety of revefenacin in subjects with impaired renal or hepatic function

Abstract

Purpose

Revefenacin, a long-acting muscarinic antagonist for nebulization, has been shown to improve lung function in patients with chronic obstructive pulmonary disease. Here we report pharmacokinetic (PK) and safety results from two multicenter, open-label, single-dose trials evaluating revefenacin in subjects with severe renal impairment (NCT2578082) and moderate hepatic impairment (NCT2581592).

Subjects and methods

The renal impairment trial enrolled subjects with normal renal function and severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m²). The hepatic impairment trial enrolled subjects with normal hepatic function and moderate hepatic impairment (Child-Pugh class B). Subjects received a single 175-µg dose of revefenacin through nebulization. PK plasma samples and urine collections were obtained at multiple time points for 5 days following treatment; all subjects were monitored for adverse events.

Results

In the renal impairment study, the maximum observed plasma revefenacin concentration (C_max) was up to 2.3-fold higher and area under the concentration–time curve from time 0 to infinity (AUC_inf) was up to 2.4-fold higher in subjects with severe renal impairment compared with those with normal renal function. For THRX-195518, the major metabolite of revefenacin, the corresponding changes in C_max and AUC_inf were 1.8- and 2.7-fold higher, respectively. In the hepatic impairment study, revefenacin C_max and AUC_inf were 1.03- and 1.18-fold higher, respectively, in subjects with moderate hepatic impairment compared with those with normal hepatic function. The corresponding changes in THRX-195518 C_max and AUC_inf were 1.5- and 2.8-fold higher, respectively.

Conclusion

Systemic exposure to revefenacin increased modestly in subjects with severe renal impairment but was similar between subjects with moderate hepatic impairment and normal hepatic function. The increase in plasma exposure to THRX-195518 in subjects with severe renal or moderate hepatic impairment is unlikely to be of clinical consequence given its low antimuscarinic potency, low systemic levels after inhaled revefenacin administration, and favorable safety profile.

Keywords:

• liver disease
• kidney disease
• chronic obstructive pulmonary disease
• long-acting muscarinic antagonist
• LAMA
• revefenacin

Acknowledgment

This study was funded by Theravance Biopharma R&D, Inc. (George Town, Cayman Islands). Mylan Inc. (Canonsburg, PA, USA) and Theravance Biopharma US, Inc. (South San Francisco, CA, USA) funded medical writing support. The authors would like to thank Thomas C Marbury (Orlando Clinical Research Center, Orlando, FL, USA) and William B Smith (New Orleans Center for Clinical Research, Knoxville, TN, USA) for their support in the conduct of the trials. The authors acknowledge Lisa Baker, PhD, and Ritu Pathak, PhD, for medical writing and Paula Stuckart for editorial assistance in the preparation of the manuscript (Ashfield Healthcare Communications, Middletown, CT, USA).

Abbreviations

AE, adverse event; Ae_0–96h, cumulative amount excreted in the urine from time 0–96 hrs post dose; ANOVA, analysis of variance; AUC, area under the concentration–time curve; AUC_inf, AUC from time 0 to infinity; AUC_t, from time 0 to time of last quantifiable concentration; CI, confidence interval; CLcr, creatinine clearance; CL_r, renal clearance; C_max, maximum observed plasma concentration; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; fe_0–96h, cumulative fraction of dose excreted in urine from 0 to 96 hrs post dose; GCP, Good Clinical Practice; ICH, International Council on Harmonisation; IV, intravenous; LLOQ, lower limit of quantification; LS, least-squares; MDRD, Modification of Diet in Renal Disease; t_1/2, terminal elimination half-life; MR_AUC, metabolite-to-parent ratio based on AUC_t; MR_Cmax, metabolite-to-parent ratio based on C_max; PK, pharmacokinetic; QTcF, QT interval corrected for heart rate; SD, standard deviation; T_max, time to reach C_max; TEAE, treatment-emergent AE.

Data sharing statement

Theravance Biopharma (and its affiliates) will not be sharing individual de-identified participant data or other relevant study documents.

Author contributions

All authors provided significant contributions to the conception and/or design of the work or the acquisition, analysis, or interpretation of data for the work, drafted the work or revised it critically for important intellectual content, provided final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

MTB is a consultant for Theravance Biopharma US, Inc. AL and DLB are employees of Theravance Biopharma US, Inc. CNB and SP were employees of Theravance Biopharma US, Inc. at the time this study was conducted. The authors report no other conflicts of interest in this work.