Methacholine challenge testing: comparative pharmacology

Figures & data

Table 1 Bronchodiltor: SAMAs

Agent	Device	Dose (µg)	End point	Time point (hours)	Dose shift (doubling concentrations)	Reference (year)
Ipratropium	pMDI	80	PD20	0.5	NQ	Woenne et al^Citation13 (1978)
Ipratropium	pMDI	80	PC20	1	5.8	Bandouvakis et al^Citation14 (1981)
Ipratropium	pMDI and DPI	80	sGaw	0.75	~4	Larsson^Citation15 (1987)
Ipratropium	pMDI	200	sGaw	0.75	4	Larsson^Citation15 (1987)
Ipratropium	DPI	200	sGaw	0.75	5	Larsson^Citation15 (1987)
Ipratropium	pMDI	40	PD20	0.33	2.3	Crimi et al^Citation11 (1992)
Ipratropium	DeVilbiss 700 Nebulizer	500	PC20	2 12 24 30	5 0 0 0	Hansel et al^Citation16 (2005)
Ipratropium	pMDI	40	PD15	1	2.7	Sposato et al^Citation12 (2008)
Ipratropium	Nasal spray	0.03% (2/nare)	PC20	0.16	<0.5	Reid et al^Citation19 (2005)
Ipratropium	pMDI	40	PC20	6 12	1 <0.5	Illamperuma et al (2009)^Citation18
Oxitropium	pMDI	200	PD15	1	4.2	Sposato et al^Citation12 (2008)

Abbreviations: SAMAs, short-acting muscarinic antagonists; pMDI, pressurized metered dose inhaler; DPI, dry powder inhaler; PD₂₀, provocation dose that results in a 20% fall in the forced expiratory volume in 1 second; PC₂₀, provocation concentration that results in a 20% fall in the forced expiratory volume in 1 second; sGaw, airway conductance; PD₁₅, dose of methacholine producing a 15% decrease in forced expiratory volume in 1 second; NQ, not quantifiable.

Table 2 Bronchodilator: long-acting muscarinic antagonists (including combination LAMA/LABA)

Agent	Device	Dose (µg)	End point	Time point (hours)	Dose shift (doubling concentrations)	Reference (year)
Tiotropium	DPI	10 40 80	PC20	2	5.0 7.1 7.9	O’Connor et al^Citation20 (1996)
Tiotropium	DPI	18	PD15	1	4.1	Sposato et al^Citation12 (2008)
Tiotropium	Respimat	5	PC20	1 24 48 72 96 168	4.2 3.1 2.7 2.3 1.9 0.84	Blais et al^Citation21 (2016)
Glycopyrronium	DPI	50	PC20	1 24 48 72 96 168	4.3 1.8 1.9 1.2 1.1 0.52	Blais et al^Citation21 (2016)
Glycopyrronium	DPI	50	PC20	1 24 48	5 2 2	Blais et al^Citation22 (2017)
Racemic glycopyrrolate	DeVilbiss 700 Nebulizer	500	PC20	2 12 24 30	4 2 1 1	Hansel et al^Citation16 (2005)
Racemic glycopyrrolate	DeVilbiss 700 Nebulizer	1000	PC20	2 12 24 30	6 4 3.5 3	Hansel et al^Citation16 (2005)
Racemic glycopyrrolate	DeVilbiss 700 Nebulizer	2000	PC20	2 12 24 30	5 3 3 2	Hansel et al^Citation16 (2005)
LAMA/LABA combination	DPI DPI	50 75	PC20	1 24	5 2	Blais et al^Citation22 (2017)
Glycopyarronium Indacaterol				48	2

Abbreviations: LAMA, long-acting muscarinic antagonists; LABA, long-acting beta antagonists; DPI, dry powder inhaler; PC₂₀, provocation concentration that results in a 20% fall in the forced expiratory volume in 1 second; PD₁₅, provocation dose that results in a 15% fall in the forced expiratory volume in 1 second.

Table 3 Bronchodilator: SABAs

Agent	Device	Dose (µg)	End point	Time point (hours)	Dose shift (doubling concentrations)	Reference (year)
Salbutamol	MDI	200	PC20	1	1.9	Derom et al^Citation27 (1992)
Salbutamol	pMDI	200	PC20	0.5 12	3.5 0	Simons et al^Citation26 (1992)
Salbutamol	pMDI	200	PC20	0.16	4.6	Parameswaran et al^Citation23 (1999)
Salbutamol	pMDI	100 200 400	PC20	0.16	2.9 3.9 4.1	Parameswaran et al^Citation23 (1999)
Salbutamol	pMDI-HFA	100 200 400	PC20	0.16	3.1 3.9 4.5	Parameswaran et al^Citation23 (1999)
Salbutamol	pMDI	200	PC20	0.16	3.5	Jokic et al^Citation24 (2001)
Salbutamol	pMDI	200	PC20	0.16	2.4	Stewart et al^Citation25 (2012)
Salbutamol	pMDI	200	PC20	1	1.9	Derom et al^Citation27 (1992)
Salbutamol	Nebulized	2500	PC20	0.33	~3.4	Cockcroft^Citation28 (1997)
R-salbutamol	Nebulized	1250	PC20	0.33	~3.3	Cockcroft and Swystun^Citation28 (1997)
S-salbutamol	Nebulized	1250	PC20	0.33	0.9	Cockcroft^Citation28 (1997)
Salbutamol	Nebulized	2500	PC20	3	1.0	Cockcroft and Swystun^Citation28 (1997)
R-salbutamol	Nebulized	1250	PC20	3	1.2	Cockcroft and Swystun^Citation28 (1997)
S-salbutamol	Nebulized	1250	PC20	3	0	Cockcroft and Swystun^Citation28 (1997)
Salbutamol	Nebulized	200	PC20	0.5	2.8	Ramsay^Citation29 (1999)
R-salbutamol	Nebulized	100	PC20	0.5	2.9	Ramsay et al^Citation29 (1999)
S-salbutamol	Nebulized	100	PC20	0.5	0.15	Ramsay et al^Citation29 (1999)
Terbutaline	DPI	500	PD20	1	1.8	Lipworth et al^Citation36 (1998)
Terbutaline	Turbuhaler	250	PC20	1.5 3 6	1.45 0.5 −0.5	Derom et al^Citation30 (2001)
Terbutaline	Turbuhaler	500	PC20	1.5 3 6	1.67 0.75 0	Derom et al^Citation30 (2001)
Terbutaline	pMDI	250	PC20	1.5 3 6	0.99 0.13 −0.8	Derom et al^Citation30 (2001)
Terbutaline	pMDI	500	PC20	1.5 3 6	1.54 0.25 0	Derom et al^Citation30 (2001)
Terbutaline	Turbuhaler	500	PC20	0.33	2.7	O’Connor et al^Citation32 (1992)
Fenoterol	pMDI	800	PC20	1	4	Bandouvakis et al^Citation14 (1981)

Abbreviations: SABAs, short-acting beta agonists; MDI, metered dose inhaler; pMDI, pressurized metered dose inhaler; HFA, hydrofluoroalkane; DPI, dry powder inhaler; PD₂₀, provocation dose that results in a 20% fall in the forced expiratory volume in 1 second; PC₂₀, provocation concentration that results in a 20% fall in the forced expiratory volume in 1 second.

Table 4 Bronchodilator: long-acting beta agonists (LABAs)

Agent	Device	Dose (µg)	End point	Time point (hours)	Dose shift (doubling concentrations)	Reference (year)
Salmeterol	pMDI	25	PC20	0.5 12	~3 ~3	Simons et al^Citation26 (1992)
Salmeterol	pMDI	50	PC20	0.5 12	~4 ~4	Simons et al^Citation26 (1992)
Salmeterol	pMDI	50 100	PC20	1	1.9 2.7	Derom et al^Citation27 (1992)
Salmeterol	pMDI	50	PD20	1	~4	Verbene et al^Citation33 (1993)
Salmeterol	pMDI (with chamber)	50	PC20	1	3.3	Cheung et al^Citation34 (1992)
Salmeterol	pMDI	50	PC20	1	3.3	Bhagat et al^Citation35 (1992)
Formoterol	DPI	6 12 24	PD20	1	2.5 2.7 3.3	Lipworth et al^Citation36 (1998)
Formoterol	DPI	12	PC20	0.16	~2	Davis et al^Citation37 (2003)
Formoterol	pMDI	12	PC20	0.5 8	3.8 1.2	Lipworth et al^Citation31 (2005)
Formoterol	DPI	12	PC20	1	2.6	Prabhakaran et al^Citation5 (2011)
Formoterol	DPI	24	PC20	1	3.8	Prabhakaran et al^Citation5 (2011)
Indacaterol	DPI	75	PC20	1 24 48	1.5 1 1	Blais et al^Citation22 (2017)
Olodaterol	Respimat	2	PC20	0.5 4 8 24 32	2.1 2.0 1.9 1.2 1.2	O’Byrne et al^Citation38 (2009)
Olodaterol	Respimat	5	PC20	0.5 4 8 24 32	2.6 2.4 2.5 1.7 1.8	O’Byrne et al^Citation38 (2009)
Olodaterol	Respimat	10	PC20	0.5 4 8 24 32	3.6 3.6 3.3 2.5 2.1	O’Byrne et al^Citation38 (2009)
Olodaterol	Respimat	20	PC20	0.5 4 8 24 32	4.2 4.2 4.2 3.0 2.7	O’Byrne et al^Citation38 (2009)

Abbreviations: pMDI, pressurized metered dose inhaler; DPI, dry powder inhaler; PD₂₀, provocation dose that results in a 20% fall in the forced expiratory volume in 1 second; PC₂₀, provocation concentration that results in a 20% fall in the forced expiratory volume in 1 second.

Table 5 Controllers: inhaled corticosteroid, leukotriene receptor antagonist, theophylline, and ICS/LABA combination therapies

Inhaled corticosteroid
Agent	Device	Dose	End point	Time point	Dose shift (doubling concentrations)	Reference (year)
Budesonide	DPI	400 µg bid	PC20	4 weeks	~1	Bel et al^Citation39 (1991)
Budesonide (children)	MDI (with spacer)	800 µg (single dose)	PD20	5 hours	0.1	Van Essen-Zandvliet et al^Citation43 (1993)
Budesonide	DPI	800 µg bid	PC20	12 weeks	~1.4	Booms et al^Citation46 (1997)
Fluticasone	HFA pMDI	500 µg/day × 4 weeks	PC20	24 hours post-last dose	2.0	Lee et al^Citation47 (2004)
Budesonide	DPI	200 µg/day × 8 weeks	PC20	8 weeks	0.79	Kraan et al^Citation44 (1988)
Beclomethasone diproprionate	MDI+spacer	Variable	PD20	1 year	1.1	Oga et al^Citation48 (2001)
Ciclesonide	HFA pMDI	400 µg/day × 4 weeks	PC20	24 hours post-last dose	0.67	Lee et al^Citation47 (2004)
Leukotriene receptor antagonists
Montelukast	Tablet	20 mg (single dose)	PC15	3 hours	~0	Crimi et al^Citation51 (2003)
Montelukast	Tablet	10 mg (single dose)	PC20	1 hours	~0.4	Davis and Cockcroft^Citation50 (2005)
Pranlukast	Tablet	225 mg bid × 1 week	PC20	3–4 hours post-last dose	0.68	Fujimura et al^Citation52 (1993)
Theophylline
Theophylline	IV	5 mg/L (Plasma concentration) 10 15	PC20	1 hour	0.36 0.74 0.61	Koeter et al^Citation42 (1989)
Theophylline	Tablet	250 mg/day median dose	PC20	2 months	1.7	Page et al (1998)^Citation41
ICS/LABA combination treatments
Fluticasone + formoterol	pMDI	125 + 5 bid	PD20	6 weeks	3.4	Cortese et al^Citation59 (2016)
Fluticasone + formoterol	pMDI	125 bid + 12 prn	PD20	6 weeks	1.8	Cortese et al^Citation59 (2016)
Fluticasone + formoterol	pMDI	250 bid + 12 prn	PD20	6 weeks	2.7	Cortese et al^Citation59 (2016)

Abbreviations: ICS, inhaled corticosteroids; LABA, long-acting beta agonists; MDI, metered dose inhaler; pMDI, pressurized metered dose inhaler; DPI, dry powder inhaler; HFA, hydrofluoroalkane; bid, twice a day; IV, intravenous; prn, as needed; PD₂₀, provocation dose that results in a 20% fall in the forced expiratory volume in 1 second; PC₂₀, provocation concentration that results in a 20% fall in the forced expiratory volume in 1 second; PC₁₅, provocation concentration that results in a 15% fall in the forced expiratory volume in 1 second.

Table 6 Anti-H1 histamines

Agent	Route of administration	Dose	End point	Time point (hours)	Dose shift (doubling concentrations)	Reference (year)
Clemastine	Nebulized	1 mg	sGaw	0.5	nsd	Nogradyand Bevan^Citation54 (1978)
Clemastine	Tablet	1 mg	PC20	4	0.82	Wood-Baker and Holgate^Citation56 (1993)
Cetirizine	Tablet	20 mg	PC20	2 weeks	~0	Finnerty et al^Citation55 (1990)
Cetirizine	Tablet	10 mg	PC20	2	~0	Cockcroft et al^Citation58 (2015)
Cetirizine	Tablet	10 mg	PC20	2	0.26	Wood-Baker and Holgate^Citation56 (1993)
Diphenhydramine	Tablet	50 mg	PC20	2	~0	Cockcroft et al^Citation58 (2015)
Brompheniramine	Tablet	4 mg	PC20	4	0.59	Wood-Baker and Holgate^Citation56 (1993)
Loratadine	Tablet	10 mg qd × 3 days	PC20	3	~0	Town and Holgate^Citation57 (1990)
Loratadine	Tablet	20 mg qd × 3 days	PC20	3	~0	Town and Holgate^Citation57 (1990)
Chlorpheniramine	Inhaled	5 mg in 3mL saline	PD20	0.5	–0.35	Woenne et al^Citation13 (1978)
Chlorpheniramine	Tablet	4 mg	PC20	2	0.85	Wood-Baker and Holgate^Citation56 (1993)
Terfenadine	Tablet	60 mg	PC20	2	0.09	Wood-Baker and Holgate^Citation56 (1993)
Cyproheptadine	Tablet	4 mg	PC20	4	0.45	Wood-Baker and Holgate^Citation56 (1993)
Astemizole	Tablet	10 mg	PC20	2	0.55	Wood-Baker and Holgate^Citation56 (1993)
Desloratadine	Tablet	5 mg	PC20	2	~0	Cockcroft et al^Citation58 (2015)

Abbreviations: qd, every day; PD₂₀, provocation dose that results in a 20% fall in the forced expiratory volume in 1 second; PC₂₀, provocation concentration that results in a 20% fall in the forced expiratory volume in 1 second; sGaw, airway conductance; nsd, not significantly different.

Table 7 Recommended washout intervals prior to MCT

Drug type	Example	Washout interval
Muscarinic antagonists	SAMA (eg, ipratropium)	12 hours
	LAMA (eg, tiotropium)	7 days
Beta agonists	SABA (eg, salbutamol)	6 hours
	LABA (eg, salmeterol)	24 hours
	uLABA (eg, olodaterol)	48 hours
Xanthines	Theophylline	Not necessary
Inhaled glucocorticosteroid	Single dose (eg, budesonide)	Not necessary
	Stable dose (eg, budesonide)	Unknown
Leukotriene receptor antagonists	Single dose or up to 1 week (eg, montelukast)	Not necessary
	Stable dose	Unknown
Antihistamines	(eg, diphenhydramine, desloratadine)	Not necessary
Combination therapies (limited or no data)	ICS/LABA (eg, fluticasone/formoterol)	24 hours
	ICS/uLABA (eg, fluticasone/vilanterol)	48 hours
	LAMA/LABA (eg, glycopyrronioum/indacaterol)	7 days

Abbreviations: MCT, methacholine challenge test; SAMA, short-acting muscarinic antagonist; LAMA, long-acting muscarinic antagonist; SABA, short-acting beta agonists; LABA, long-acting beta agonists; uLABA, ultra-long-acting beta agonists; ICS, inhaled corticosteroids.

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