Pharmacokinetics and safety of olodaterol administered with the Respimat Soft Mist inhaler in subjects with impaired hepatic or renal function

Figures & data

Table 1 Demographics and baseline characteristics of all subjects in the hepatic and renal impairment studies

Trial 1222.20	Healthy subjects	Mild hepatic impairment	Moderate hepatic impairment	Trial 1222.35	Healthy subjects	Severe renal impairment
n	16	8	8	n	14	8
Sex, n (%)				Sex, n (%)
Male	12 (75)	6 (75)	6 (75)	Male	11 (78.6)	6 (75.0)
Female	4 (25)	2 (25)	2 (25)	Female	3 (21.4)	2 (25.0)
Age, years				Age, years
Mean	54.1	51.9	56.5	Mean	57.6	59.4
SD	9.6	8.9	9.4	SD	8.9	11.5
Minimum/maximum	36/70	42/70	40/67	Minimum/maximum	39/70	39/73
Height, cm				Height, cm
Mean	174.8	178.1	174.6	Mean	177.4	175.4
SD	9.3	8.3	9.3	SD	7.1	6.7
Minimum/maximum	154/188	164/190	160/183	Minimum/maximum	164/188	167/184
Weight, kg				Weight, kg
Mean	83.4	88.6	84.9	Mean	81.7	77.0
SD	13.9	17.5	18.7	SD	10.3	15.0
Minimum/maximum	54/100	53/105	60/110	Minimum/maximum	71/102	65/110

Abbreviation: SD, standard deviation.

Table 2 Pharmacokinetic parameters of olodaterol after administration of a single inhaled dose of 20 μg to subjects with mild or moderate hepatic impairment and 30 μg to healthy subjects

Parameter	Unit	Mild hepatic impairment			Moderate hepatic impairment			Healthy subjects
		n	gMean	gCV%	n	gMean	gCV%	n	gMean	gCV%
Cmax	pg·mL^−1	8	8.77	51.3	7	7.74	38.0	15	11.7	36.8
Cmax,norm	pg·mL^−1·μg^−1	8	0.439	51.3	7	0.387	38.0	15	0.391	36.8
tmaxa	hours	8	0.200	0.117–2.05	7	0.367	0.200–0.383	15	0.217	0.133–0.400
AUC0–4	pg·h·mL^−1	8	16.0	38.4	6	17.4	32.4	15	24.9	35.6
AUC0–4,norm	pg·h·mL^−1·μg^−1	8	0.802	38.4	6	0.871	32.4	15	0.829	35.6
AUC0–tz	pg·h·mL^−1	8	18.8	62.2	7	19.7	123	15	45.9	78.9
tz,plasmaa	hours	8	6.04	1.05–8.05	7	8.03	1.05–12.1	15	12.1	4.05–48.0
CLR,0–8	mL·min^−1	8	180	58.5	6	169	67.8	15	214	46.3
fe0–tz	%	8	3.31	50.4	8	2.86	76.8	16	3.61	77.4
tz,urinea	hours	8	72.0	72.0–72.0	8	72.0	8.00–72.0	16	72.0	8.00–72.0

Note:

a Median and range.

Abbreviations: gMean, geometric mean; gCV, geometric coefficient of variation; C_max, maximum observed plasma concentration; C_max,norm, C_max divided by the dose; t_max, time to C_max; AUC, area under the curve; t_z, time to last quantifiable plasma or urine concentration; CL_R, renal clearance; fe, fraction of dose excreted in the urine.

Table 3 Geometric mean ratios and 90% CIs of olodaterol pharmacokinetic parameters of hepatically or renally impaired subjects versus healthy subjects

Parameter	Unit	n	Ratio vs healthy subjects, %	Between-subject gCV%	Two-sided 90% CI
					Lower limit, %	Upper limit, %
Mild hepatic impairment
Cmax,norm	pg·mL^−1·μg^−1	8	112.2	41.1	83.6	150.7
AUC0–4,norm	pg·h·mL^−1·μg^−1	8	96.7	35.8	74.6	125.3
Moderate hepatic impairment
Cmax,norm	pg·mL^−1·μg^−1	7	99.0	41.1	72.7	134.7
AUC0–4,norm	pg·h·mL^−1·μg^−1	6	105.1	35.8	79.0	139.9
Severe renal impairment
Cmax	pg·mL^−1	7	136.6	65.5	84.1	222.0
AUC0–4	pg·h·mL^−1	7	135.2	47.5	93.7	195.0
CLR,0–8	mL·min^−1	7	20.1	59.2	12.9	31.3

Abbreviations: gCV, geometric coefficient of variation; CI, confidence interval; C_max, maximum observed plasma concentration; C_max,norm, C_max divided by the dose; AUC, area under the curve; CL_R, renal clearance.

Figure 1 Geometric mean plasma concentration–time profiles after single inhaled administration of 20 μg olodaterol in subjects with mild (

) and moderate (

) hepatic impairment and 30 μg olodaterol in healthy subjects (

).

Notes: Geometric mean data are shown at sampling time points where at least three subjects had quantifiable olodaterol plasma concentrations. Dashed line: lower limit of quantitation of the bioanalytical assay for olodaterol.

Table 4 Pharmacokinetic parameters of olodaterol after administration of a single inhaled dose of 30 μg to subjects with severe renal impairment and healthy subjects

Parameter	Unit	Severe renal impairment			Healthy subjects
		n	gMean	gCV%	n	gMean	gCV%
Cmax	pg·mL^−1	7	11.1	96.3	13	8.15	48.0
tmaxa	hours	7	0.383	0.233–0.717	13	0.233	0.133–1.08
AUC0–4	pg·h·mL^−1	7	23.4	65.4	13	17.3	36.8
AUC0–tz	pg·h·mL^−1	7	37.5	159	13	27.6	104
tz,plasmaa	hours	7	12.1	2.05–24.1	13	6.08	2.07–48.1
CLR,0–8	mL·min^−1	7	35.9	48.4	13	179	64.2
fe0–tz	%	8	0.411	161	14	2.31	107
tz,urinea	hours	8	48.0	12.0–72.0	14	72.0	24.0–72.0

Note:

a Median and range.

Abbreviations: gMean, geometric mean; gCV, geometric coefficient of variation; C_max, maximum observed plasma concentration; t_max, time to C_max; AUC, area under the curve; t_z, time to last quantifiable plasma or urine concentration; CL_R, renal clearance; fe, fraction of dose excreted in the urine.

Figure 2 Geometric mean plasma concentration–time profiles after single inhaled administration of 30 μg olodaterol in subjects with severe renal impairment (

) and healthy subjects (

).

Notes: Geometric mean data are shown at sampling time points where at least three subjects had quantifiable olodaterol plasma concentrations. Dashed line: lower limit of quantitation of the bioanalytical assay for olodaterol.

Figure 3 Time course of serum potassium concentrations by subject group (mean ± SD).

Notes: (A) Hepatic impairment study: mild hepatic impairment (

), moderate hepatic impairment (

), healthy subjects (

). (B) Renal impairment study: severe renal impairment (

), healthy subjects (

).
Abbreviation: SD, standard deviation.

Table S1 Pharmacokinetic parameters of olodaterol after administration of a single inhaled dose of 20 μg to subjects with moderate hepatic impairment

Parameter	Unit	Subject 19 included			Subject 19 excluded
		n	gMean	gCV%	n	gMean	gCV%
Cmax	pg·mL^−1	8	8.58	47.2	7	7.74	38.0
Cmax,norm	pg·mL^−1·μg^−1	8	0.429	47.2	7	0.387	38.0
tmaxa	hours	8	0.367	0.200–0.383	7	0.367	0.200–0.383
AUC0–4	pg·h·mL^−1	7	19.7	45.9	6	17.4	32.4
AUC0–4,norm	pg·h·mL^−1·μg^−1	7	0.987	45.9	6	0.871	32.4
AUC0–tz	pg·h·mL^−1	8	26.3	182	7	19.7	123
tz,plasmaa	hours	8	10.0	1.05–47.9	7	8.03	1.05–12.1

Note:

a Median and range.

Abbreviations: gMean, geometric mean; gCV, geometric coefficient of variation; C_max, maximum observed plasma concentration; C_max,norm, C_max divided by the dose; t_max, time to C_max; AUC, area under the curve; t_z, time to last quantifiable plasma concentration.

Table S2 Geometric mean ratios and 90% CIs of olodaterol pharmacokinetic parameters in subjects with moderate hepatic impairment versus healthy subjects

Parameter	Unit	n	Ratio vs healthy subjects, %	Between-subject gCV%	Two-sided 90% CI
					Lower limit, %	Upper limit, %
Subject 19 included
Cmax,norm	pg·mL^−1·μg^−1	8	109.8	43.3	80.6	149.5
AUC0–4,norm	pg·h·mL^−1·μg^−1	7	119.0	38.8	88.9	159.3
Subject 19 excluded
Cmax,norm	pg·mL^−1·μg^−1	7	99.0	41.1	72.7	134.7
AUC0–4,norm	pg·h·mL^−1·μg^−1	6	105.1	35.8	79.0	139.9

Abbreviations: CI, confidence interval; gCV, geometric coefficient of variation; C_max, maximum observed plasma concentration; C_max,norm, C_max divided by the dose; AUC, area under the curve.