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 (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 (Cmax) was up to 2.3-fold higher and area under the concentration-time curve from time 0 to infinity (AUCinf) 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 Cmax and AUCinf were 1.8- and 2.7-fold higher, respectively. In the hepatic impairment study, revefenacin Cmax and AUCinf 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 Cmax and AUCinf 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.

Conflict of interest statement

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.

© 2019 Borin et al.

Figures

Figure 1

Mean ± SD plasma concentration–time profiles for revefenacin (A) and THRX-195518 (B) in subjects with and without severe renal impairment (n=8 per group). Abbreviations: h, hours; SD, standard deviation.

Figure 2

Comparison of Cmax (A) and AUCinfa (B) for revefenacin and THRX-195518 between cohorts with normal and severely impaired renal function. Notes:aAUCinf values predicted by the population PK model. Box represents the 25th–75th percentile of the data. Whiskers indicate the 1.5x interquartile range. The solid line in the box represents the median and each dot represents an individual subject. Abbreviations: AUCinf, area under the concentration–time curve from time 0 to infinity; Cmax, maximum observed plasma concentration.

Figure 3

Scatter plots of revefenacin Cmax (A) and AUCinfa (B) versus eGFR. Cmax (C) and AUCinfa (D) versus CLcr in the renal impairment study. Notes: Open circles represent individual subject data. aAUCinf values predicted by the population PK model. The line indicates linear least-squares fit; the shaded area indicates 95% CI. Abbreviations: AUCinf, area under the concentration–time curve from time 0 to infinity; CI, confidence interval; CLcr, creatinine clearance; Cmax, maximum observed plasma concentration; eGFR, estimated glomerular filtration rate; PK, pharmacokinetic.

Figure 4

Scatter plots of THRX-195518 Cmax (A) and AUCinfa (B) versus eGFR. Cmax (C) and AUCinfa (D) versus CLcr in the renal impairment study. Notes: Open circles represent individual subject data. aAUCinf values predicted by the population PK model. The line indicates linear least-squares fit; the shaded area indicates 95% CI. Abbreviations: AUCinf, area under the concentration–time curve from time 0 to infinity; CI, confidence interval; CLcr, creatinine clearance; Cmax, maximum observed plasma concentration; eGFR, estimated glomerular filtration rate; PK, pharmacokinetic.

Figure 5

Mean ± SD plasma concentration-time profiles for revefenacin (A) and THRX-195518 (B) in subjects with and without moderate hepatic impairment (n=8 per group). Abbreviations: h, hours; SD, standard deviation.

Figure 6

Comparison of Cmax (A) and AUCinfa (B) for revefenacin and THRX-195518 between cohorts with normal and moderately impaired hepatic function. Notes: The box represents the 25th–75th percentile of the data. Whiskers indicate the 1.5x interquartile range. The solid line in the box represents the median, while each dot represents an individual subject. aAUCinf values predicted by the population PK model. Abbreviations: AUCinf, area under the concentration–time curve from time 0 to infinity; Cmax, maximum observed plasma concentration; PK, pharmacokinetic.