Effect of severe renal impairment on umeclidinium and umeclidinium/vilanterol pharmacokinetics and safety: a single-blind, nonrandomized study

Figures & data

Table 1 Patient demographics

Demographic characteristic	Healthy volunteers N=9	Severe renal impairment N=9
Age (years)
Mean (range)	49.4 (36–63)	50.4 (37–67)
Sex
Female, n (%)	3 (33)	3 (33)
Male, n (%)	6 (67)	6 (67)
Body mass index (kg/m^2)
Mean (range)	26.12 (21.1–31.9)	25.27 (18.3–31.3)
Height (cm)
Mean (range)	172.8 (161–184)	174.4 (161–182)
Weight (kg)
Mean (range)	78.03 (62.5–100.0)	77.28 (48.6–98.0)
Ethnicity, n (%)
Hispanic or Latino	0 (0)	0 (0)
Not Hispanic or Latino	9 (100)	9 (100)
Race, n (%)
White – White/Caucasian/European Heritage	9 (100)	9 (100)
Creatinine clearance (mL/min)
Mean (range)	98.94 (80.1–141.5)	22.23 (17.2–28.0)
Medical history (current), n (%)
Diabetes	0	1 (11)
Hypertension	0	8 (89)
Hyperlipidemia	0	5 (56)
Smoking history, n (%)
Never smoked	5 (56)	4 (44)
Current smoker	3 (33)	4 (44)
Former smoker	1 (11)	1 (11)

Table 2 Plasma PK parameters

Parameter	Group	N	n	n*	Geometric means	95% CI	CVb (%)
(A)
UMEC 125 μg
AUC(0–0.25h) (h.pg/mL)	Healthy	9	9	0	20.3	13.8–29.7	53.0
	Severe renal impairment	9	9	0	18.9	13.1–27.4	51.0
AUC(0–2h) (h.pg/mL)	Healthy	9	9	1	56.6	34.8–91.6	69.7
	Severe renal impairment	9	9	0	59.1	40.5–86.3	52.3
Cmax (pg/mL)	Healthy	9	9	0	127.6	84.8–191.9	57.1
	Severe renal impairment	9	9	0	113.2	75.2–170.4	57.3
tlast (h)a	Healthy	9	9	0	2.00	0.25–4.00	NA
	Severe renal impairment	9	9	0	2.00	0.50–4.00	NA
tmax (h)a	Healthy	9	9	0	0.08	0.08–0.12	NA
	Severe renal impairment	9	9	0	0.08	0.08–0.12	NA
UMEC/VI 125/25 μg
AUC(0–0.25h) (h.pg/mL)	Healthy	9	9	0	23.4	16.1–34.2	52.2
	Severe renal impairment	9	9	0	23.6	17.1–32.6	44.2
AUC(0–2h) (h.pg/mL)	Healthy	9	9	0	60.4	44.6–81.9	41.1
	Severe renal impairment	9	9	0	66.3	48.8–90.1	41.5
Cmax (pg/mL)	Healthy	9	9	0	152.4	101.1–229.7	57.4
	Severe renal impairment	9	9	0	149.2	104.2–213.5	49.3
tlast (h)a	Healthy	9	9	0	2.0	0.50–4.02	NA
	Severe renal impairment	9	9	0	2.0	0.50–4.00	NA
tmax (h)a	Healthy	9	9	0	0.08	0.08–0.12	NA
	Severe renal impairment	9	9	0	0.08	0.08–0.12	NA
Parameter	Treatment	Group comparison	Adjusted geometric means	Ratio	90% CI
(B)
AUC(0–2h) (h.pg/mL)	UMEC 125 μg	Severe renal impairment/healthy	59.1/65.8	0.90	0.64–1.26
	UMEC/VI 125/25 μg	Severe renal impairment/healthy	66.3/60.4	1.10	0.79–1.52
Cmax (pg/mL)	UMEC 125 μg	Severe renal impairment/healthy	113.2/127.6	0.89	0.58–1.35
	UMEC/VI 125/25 μg	Severe renal impairment/healthy	149.2/152.4	0.98	0.64–1.49

Notes: (A) Summary Statistics for umeclidinium parameters.

a Presented as median and range, instead of geometric mean and 95% CI, respectively. (B) Statistical analysis of umeclidinium parameters. Values of UMEC AUC_(0–2h) that were non-calculable due to nonquantifiable values were not imputed for the statistical analysis but were imputed for raw summary statistics.

Abbreviations: AUC, area under the curve; CI, confidence interval; C_max, maximum observed plasma concentration; CVb, between-subject coefficient of variation; n*, number imputed; NA, not applicable; PK, pharmacokinetic; t_last, time to last quantifiable concentration; t_max, time to C_max; UMEC, umeclidinium; VI, vilanterol; N, number of patients included in the study population; n, number of patients included in the assessment.

Table 3 Urine PK parameters

Parameter	Group	N	n	Geometric means	95% CI	CVb (%)
(A)
UMEC 125 μg
Ae(0–24h)(ng)	Healthy	9	9	1,553	998–2,415	62.6
	Severe renal impairment	9	9	178	100–319	87.4
CLr (L/h)	Healthy	9	2	13.041	0.838–202.849	31.3
	Severe renal impairment	9	3	0.881	0.229–3.380	58.4
Fe(0–24h)a (%)	Healthy	9	9	1.4337	0.4938–3.1294	NA
	Severe renal impairment	9	9	0.1878	0.0686–0.5362	NA
t1/2 (h)	Healthy	9	5	9.66	4.44–20.99	69.2
	Severe renal impairment	9	7	8.03	6.49–9.94	23.3
UMEC/VI 125/25 μg
Ae(0–24h)(ng)	Healthy	9	9	1,627	1,186–2,232	42.9
	Severe renal impairment	9	9	184	104–326	86.1
CLr (L/h)	Healthy	9	1	12.917	ND^b	ND
	Severe renal impairment	9	3	0.722	0.0529–9.8348	142.2
Fe(0–24h)a (%)	Healthy	9	9	1.3936	0.5357–2.4370	NA
	Severe renal impairment	9	9	0.1891	0.0492–0.5031	NA
t1/2 (h)	Healthy	9	3	11.34	7.58–16.97	16.3
	Severe renal impairment	9	8	9.22	6.54–12.99	42.9
Parameter	Treatment	Group comparison	Adjusted geometric means	Ratio	90% CI
(B)
Ae(0–24h)(ng)	UMEC 125 μg	Severe renal impairment/Healthy	178/1,553	0.12	0.07–0.19
	UMEC/VI 125/25 μg	Severe renal impairment/Healthy	184/1,627	0.11	0.07–0.19

Notes: (A) Summary statistics for umeclidinium parameters.

a Arithmetic mean value (range). (B) Statistical analysis of umeclidinium parameters.

Abbreviations: Ae_(0–24h), amount excreted over 24 hours; CI, confidence interval; CLr, renal clearance of treatment; CVb, between-subject coefficient of variation; Fe_(0–24h), amount excreted over 24 hours as percentage of inhaled dose; NA, not applicable; ND, not determined due to insufficient sample size; PK, pharmacokinetic; t_1/2, terminal phase half-life; UMEC, umeclidinium; VI, vilanterol; N, number of patients included in the study population; n, number of patients included in the assessment.

Table 4 Plasma PK parameters

Parameter	Group	N	n	Geometric means	95% CI	CVb (%)
(A)
AUC(0–1h) (h.pg/mL)	Healthy	9	9	28.7	20.6–40.00	45.3
	Severe renal impairment	9	9	34.8	25.9–46.6	39.6
Cmax (pg/mL)	Healthy	9	9	74.8	53.1–105.4	46.9
	Severe renal impairment	9	9	77.1	56.9–104.7	41.3
tlast (h)a	Healthy	9	9	1.00	0.50–2.00	NA
	Severe renal impairment	9	9	1.00	1.0–4.00	NA
tmax (h)a	Healthy	9	9	0.08	0.08–0.12	NA
	Severe renal impairment	9	9	0.12	0.08–0.25	NA
Parameter	Treatment	Group comparison	Adjusted geometric means	Ratio	90% CI
(B)
AUC(0–1h) (h.pg/mL)	UMEC/VI 125/25 μg	Severe renal impairment/Healthy	34.8/28.7	1.21	0.87–1.70
Cmax (pg/mL)	UMEC/VI 125/25 μg	Severe renal impairment/Healthy	77.1/74.8	1.03	0.73–1.46

Notes: (A) Summary statistics for vilanterol parameters.

a Presented as median and range. (B) Statistical analysis of vilanterol parameters.

Abbreviations: AUC, area under the curve; CI, confidence interval; C_max, maximum observed plasma concentration; CVb, between-subject coefficient of variation; NA, not applicable; PK, pharmacokinetic; t_last, time to last quantifiable concentration; t_max, time to C_max; UMEC, umeclidinium; VI, vilanterol; h, hour; N, number of patients included in the study population; n, number of patients included in the assessment.