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

Marie T Borin; Arthur Lo; Chris N Barnes; Srikanth Pendyala; David L Bourdet

doi:10.2147/COPD.S203709

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

Int J Chron Obstruct Pulmon Dis. 2019 Oct 8:14:2305-2318. doi: 10.2147/COPD.S203709. eCollection 2019.

Authors

Marie T Borin¹, Arthur Lo², Chris N Barnes³, Srikanth Pendyala⁴, David L Bourdet²

Affiliations

¹ Department of Clinical and Translational Pharmacology, Theravance Biopharma US, Inc., South San Francisco, CA, USA.
² Department of Drug Metabolism and Pharmacokinetics, Theravance Biopharma US, Inc., South San Francisco, CA, USA.
³ Department of Biostatistics, Theravance Biopharma US, Inc., South San Francisco, CA, USA.
⁴ Department of Clinical Development, Inflammation and Immunology, Theravance Biopharma US, Inc., South San Francisco, CA, USA.

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 (NCT02578082) and moderate hepatic impairment (NCT02581592).

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: LAMA; chronic obstructive pulmonary disease; kidney disease; liver disease; long-acting muscarinic antagonist; revefenacin.

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Benzamides / adverse effects*
Benzamides / pharmacokinetics*
Carbamates / adverse effects*
Carbamates / pharmacokinetics*
Female
Hepatic Insufficiency / metabolism*
Humans
Male
Middle Aged
Multicenter Studies as Topic
Muscarinic Antagonists / adverse effects*
Muscarinic Antagonists / pharmacokinetics*
Renal Insufficiency / metabolism*
Severity of Illness Index
Young Adult

Substances

Benzamides
Carbamates
Muscarinic Antagonists
revefenacin

Associated data

ClinicalTrials.gov/NCT02578082
ClinicalTrials.gov/NCT02581592