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

Figures & data

Table 1 Baseline demographics and clinical characteristics

Characteristic	Renal impairment study		Hepatic impairment study
	Severe renal impairment (n=8)	Normal renal function (n=8)	Moderate hepatic impairment (n=8)	Normal hepatic function (n=8)
Age, years
Mean (SD)	60.6 (13.95)	59.4 (10.61)	56.6 (6.63)	56.9 (5.11)
Range	29–70	36–69	48–65	51–66
Male sex, n (%)	5 (62.5)	5 (62.5)	7 (87.5)	7 (87.5)
Race, n (%)
White	8 (100)	8 (100)	7 (87.5)	7 (87.5)
Black/African American	0 (0)	0 (0)	1 (12.5)	1 (12.5)
Weight, kg, mean (SD)	93.1 (17.21)	92.2 (12.55)	101.8 (12.03)	98.7 (16.47)
Height, cm, mean (SD)	167.4 (11.38)	173.0 (12.31)	175.2 (4.50)	175.8 (9.95)
BMI, kg/m^2, mean (SD)	32.9 (3.54)	31.0 (5.26)	33.1 (3.34)	31.8 (3.85)
eGFR, mL/min/1.73 m^2, mean (SD)	21.7 (5.04)	73.5 (12.25)	NC	NC
CLcr, mL/min, mean (SD)^a	34.6 (7.94)	103.2 (25.73)	NC	NC

Notes: ^aSummary statistics for baseline CLcr were calculated using the Cockcroft-Gault equation. For two subjects in the normal renal function group, the calculated Cockcroft-Gault CLcr results were <90 mL/min. With prior sponsor approval, eligibility for these two subjects was determined using a 24 hr urine collection.

Abbreviations: BMI, body mass index; CLcr, creatinine clearance; eGFR, estimated glomerular filtration rate; NC, not calculated; SD, standard deviation.

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.

Table 2 Plasma and urine PK parameters (arithmetic mean [SD]) for revefenacin and THRX-195518 in renal impairment study

	Revefenacin		THRX-195518
Parameter	Severe renal impairment (n=8)	Normal renal function (n=8)	Severe renal impairment (n=8)	Normal renal function (n=8)
Plasma
Cmax, ng/mL	0.267 (0.161)	0.196 (0.201)^a	0.0689 (0.0410)	0.0404 (0.0310)^b,c
Tmax, h^d	0.250 (0.250–0.250)	0.250 (0.250–0.250)	0.500 (0.250–0.533)	0.250 (0.250–0.500)^b
AUCt, ng·h/mL	0.336 (0.201)	0.211 (0.205)^e	0.139 (0.0930)	0.0701 (0.0808)^f
AUCinf, ng·h/mL^g	0.354 (0.199)	0.220 (0.193)^h	0.258 (0.131)	0.126 (0.120)^i
t1/2, h	35.3 (22.4)^b	29.7 (4.15)^j	6.69 (2.14)^j	NC^k
MRAUC^l	NA	NA	0.451 (0.405)	0.301 (0.280)^f
MRCmax	NA	NA	0.317 (0.267)	0.286 (0.218)^b,m
Urine
Ae0–96h, µg	0.112 (0.0909)	0.350 (0.364)	0.0376 (0.0411)	0.0984 (0.120)
fe0–96h, %	0.0638 (0.0519)	0.200 (0.208)	NC	NC
CLr, L/h	0.272 (0.190)	1.70 (1.06)^j	NR^n	NR^n

Notes: ^aMean (SD) C_max, excluding two subjects with low plasma revefenacin and THRX-195518 concentrations, was 0.259 (0.194) ng/mL. ^bn=7. ^cMean (SD) C_max, excluding two subjects with low plasma revefenacin and THRX-195518 concentrations, was 0.0461 (0.0297) ng/mL. ^dMedian (minimum, maximum) is presented. ^eMean (SD) AUC_t, excluding two subjects, was 0.280 (0.189) ng·h/mL. ^fn=6. ^gAUC_inf values predicted by the population PK model. ^hMean (SD) AUC_inf, excluding two subjects, was 0.289 (0.172) ng·h/mL. ⁱMean (SD) AUC_inf, excluding two subjects, was 0.162 (0.118) ng·h/mL. ^jn=5. ^kOnly two subjects had values of 0.608 and 1.69 hrs, respectively. ^lMR_AUC calculated using AUC_t, since AUC_inf was not calculable or reportable for most subjects for THRX-195518. ^mMean (SD) MR_Cmax, excluding two subjects, was 0.246 (0.210) ng/mL. ⁿCL_r not reported because available n was ≤2 in each group.

Abbreviations: AUC, area under the concentration–time curve; AUC_inf, AUC from time 0–infinity; AUC_t, AUC from time 0 to time of last quantifiable concentration; Ae_0–96h, cumulative amount excreted in the urine from time 0–96 hrs post-dose; CL_r, renal clearance; C_max, maximum observed plasma concentration; fe_0–96h, cumulative fraction of dose excreted in urine from 0 to 96 hrs post-dose; h, hours; MR_AUC, metabolite-to-parent ratio based on AUC_t; MR_Cmax, metabolite-to-parent ratio based on C_max; NA, not applicable; NC, not calculated; NR, not reported; PK, pharmacokinetic; SD, standard deviation; t_1/2, terminal elimination half-life; T_max, time to reach C_max.

Figure 2 Comparison of C_max (A) and AUC_inf^a (B) for revefenacin and THRX-195518 between cohorts with normal and severely impaired renal function.

Notes: ^aAUC_inf 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: AUC_inf, area under the concentration–time curve from time 0 to infinity; C_max, maximum observed plasma concentration.

Figure 3 Scatter plots of revefenacin C_max (A) and AUC_inf^a (B) versus eGFR. C_max (C) and AUC_inf^a (D) versus CLcr in the renal impairment study.

Notes: Open circles represent individual subject data. ^aAUC_inf values predicted by the population PK model. The line indicates linear least-squares fit; the shaded area indicates 95% CI.
Abbreviations: AUC_inf, area under the concentration–time curve from time 0 to infinity; CI, confidence interval; CLcr, creatinine clearance; C_max, maximum observed plasma concentration; eGFR, estimated glomerular filtration rate; PK, pharmacokinetic.

Figure 4 Scatter plots of THRX-195518 C_max (A) and AUC_inf^a (B) versus eGFR. C_max (C) and AUC_inf^a (D) versus CLcr in the renal impairment study.

Notes: Open circles represent individual subject data. ^aAUC_inf values predicted by the population PK model. The line indicates linear least-squares fit; the shaded area indicates 95% CI.
Abbreviations: AUC_inf, area under the concentration–time curve from time 0 to infinity; CI, confidence interval; CLcr, creatinine clearance; C_max, maximum observed plasma concentration; eGFR, estimated glomerular filtration rate; PK, pharmacokinetic.

Table 3 Plasma and urine PK parameters (arithmetic mean [SD]) for revefenacin and THRX-195518 in hepatic impairment study

Parameter	Revefenacin		THRX-195518
	Moderate hepatic impairment (n=8)	Normal hepatic function (n=8)	Moderate hepatic impairment (n=8)	Normal hepatic function (n=8)
Plasma
Cmax, ng/mL	0.236 (0.144)	0.229 (0.124)	0.0894 (0.0625)	0.0528 (0.0199)
Tmax, h^a	0.250 (0.0833–0.500)	0.250 (0.250–0.250)	0.500 (0.250–0.500)	0.500 (0.250–0.500)
AUCt, ng·h/mL	0.280 (0.176)	0.263 (0.133)	0.455 (0.252)	0.105 (0.0735)
AUCinf, ng·h/mL^b	0.308 (0.166)	0.262 (0.120)	0.563 (0.238)	0.201 (0.0974)
t1/2, h	29.8 (7.75)^c	30.3 (14.1)^d	23.6 (14.4)^c	10.8 (12.5)^e
MRAUC^f	NA	NA	1.82 (0.693)	0.502 (0.363)
MRCmax	NA	NA	0.412 (0.170)	0.293 (0.146)
Urine
Ae0–96h, µg	1.04 (0.520)^d	0.438 (0.375)^g	1.45 (0.765)^d	0.175 (0.163)
fe0–96h, %	0.593 (0.297)^d	0.250 (0.214)^g	NC	NC
CLr, L/h	3.58 (1.80)^h	1.44 (1.05)^g	NR^i	NR^j

Notes: ^aMedian (minimum, maximum) is presented. ^bAUC_inf values predicted by the population PK model. ^cn=6. ^dn=7. ^en=4. ^fMRAUC calculated using AUCt, since AUCinf was not calculable or reportable for most subjects for THRX-195518. ^gIncludes two subjects who had no drug detected in urine. ^hn=5. ⁱCL_r not reported because available n was ≤2 in each group, minimum and maximum values are 1.05 and 2.81. ^jNot calculated as n=0.

Abbreviations: AUC, area under the concentration–time curve; AUC_inf, AUC from time 0–infinity; AUC_t, AUC from time 0 to time of last quantifiable concentration; Ae_0–96h, cumulative amount excreted in the urine from time 0–96 hrs post-dose; CL_r, renal clearance; C_max, maximum observed plasma concentration; fe_0–96h, cumulative fraction of dose excreted in urine from 0 to 96 hrs post-dose; h, hours; MR_AUC, metabolite-to-parent ratio based on AUC_t; MR_Cmax, metabolite-to-parent ratio based on C_max; NA, not applicable; NC, not calculated; NR, not reported; PK, pharmacokinetic; SD, standard deviation; t_1/2, terminal elimination half-life; T_max, time to reach C_max.

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 C_max (A) and AUC_inf^a (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. ^aAUC_inf values predicted by the population PK model.
Abbreviations: AUC_inf, area under the concentration–time curve from time 0 to infinity; C_max, maximum observed plasma concentration; PK, pharmacokinetic.