Intranasal Corticosteroids: Topical Potency, Systemic Activity and Therapeutic Index

Figures & data

Table 1 INCS Physicochemical, Pharmacokinetic and Pharmacological Characteristics

INCS^a	RRA^b	Log P^c	Therapeutic Dose^d, µg/day	Dose Volume, µL/day	Bioavailability^e, %	CL, L/h	Plasma AUC^f for 20% Cortisol Suppression, pg/mL*h	Dose for 20% Cortisol Suppression, µg/day	TI^g
FF	2989^Citation12	4.17^Citation12	110^Citation62,Citation63	200^Citation63	0.50^Citation62	65^Citation12	848	11,095	101
FP	1775^Citation12	3.89^Citation12	200^Citation64	400 [mg]^Citation64	0.51^Citation34	69^Citation12	1332	18,020	90
MF	2100^Citation12	4.73^Citation12	200^Citation65	400 [mg]^Citation65	0.46^Citation32,Citation38	54^Citation12	1126	13,215	66
CIC^h	1200^Citation12	3.00^Citation12	200^Citation66	280^Citation66	7.4^Citation73,i	228^Citation12	2158	6650	33
TAA	233^Citation12	1.85^Citation12	220^Citation67	120	46^Citation38	37^Citation12	8935	713	3.2
FLU	190^Citation12	1.36^Citation12	464/400^Citation68	800 [mg]^Citation68	50^Citation68	58^Citation12	10,953	1271	2.7
BUD	935^Citation12	2.32^Citation12	256^Citation69	200^Citation70	31^Citation38	84^Citation12	2206	562	2.2
BDP^h	1345^Citation12	3.27^Citation12	336^Citation71	800 [mg]^Citation71	44^Citation35,Citation38	120^Citation12	2179	594	1.8
DEX	100^Citation72	1.68	400		75	17	6750	154	0.4

Notes: ^aAll in ANS formulation except CIC, which uses a MDI; ^bRelative to DEX where DEX affinity = 100; ^cValues (lipophilicity) are defined as the log10 of the octanol/water partition coefficient; ^dTherapeutic doses for AR for adults and children (≥12) unless further specified (for BDP >12; FLU ≥14); ^eF, absolute bioavailability via nasal route (nose and gut absorption) determined in healthy subjects; ^fPlasma AUC (F dose/CL) is the estimated daily dose that would result in 20% cortisol suppression;¹² gDose for 20% cortisol suppression/therapeutic dose; ^hValues are for the active metabolites BMP and des-CIC; ⁱValue calculated based on Weiswasser et al J Allergy Clin Immunol. 2008,⁷³ using the clearance and relative to value for oral inhalation.

Abbreviations: ANS, aqueous nasal spray; AR, allergic rhinitis; AUC, area under the curve; BDP, beclomethasone dipropionate; BMP, beclomethasone 17-monopropionate; BUD, budesonide; CIC, ciclesonide; CL, plasma clearance; Des-CIC, desisobutyryl ciclesonide; DEX, dexamethasone; FF, fluticasone furoate; FLU, flunisolide; FP, fluticasone propionate; INCS, intranasal corticosteroid; MDI, metered-dose inhaler; MF, mometasone furoate; RRA, relative receptor affinity; TAA, triamcinolone acetonide; TI, therapeutic index.

Figure 1 Relationship between relative glucocorticoid receptor binding affinity and therapeutic daily doses of intranasal corticosteroids (r = 0.833).^{12,32,34,35,38,62}

Abbreviations: BDP, beclomethasone dipropionate; BUD, budesonide; CIC, ciclesonide; DEX, dexamethasone; FF, fluticasone furoate; FLU, flunisolide; FP, fluticasone propionate; INCS, intranasal corticosteroid; MF, mometasone furoate; TAA, triamcinolone acetonide.

Figure 2 Relationship between relative glucocorticoid receptor binding affinity and human nasal tissue concentration (tissue binding) of intranasal corticosteroids.^{12,32,34,35,38,62}

Notes: Data from Esmailpour et al¹⁷ are plotted as ■ symbols (r² = 0.989); data plotted as ● symbols are values predicted from Esmailpour et al data.¹⁷

Abbreviations: BDP, beclomethasone dipropionate; BUD, budesonide; CIC, ciclesonide; DEX, dexamethasone; FF, fluticasone furoate; FLU, flunisolide; FP, fluticasone propionate; MF, mometasone furoate; TAA, triamcinolone acetonide.

Figure 3 Relationship between relative glucocorticoid receptor binding affinity and the therapeutic index for various intranasal corticosteroids.^{12,32,34,35,38,62}

Notes: The therapeutic index is defined here as the ratio of the dose that causes measurable systemic activity (defined as dose for cortisol suppression) divided by the therapeutic dose.

Abbreviations: BDP, beclomethasone dipropionate; BUD, budesonide; CIC, ciclesonide; DEX, dexamethasone; FF, fluticasone furoate; FLU, flunisolide; FP, fluticasone propionate; MF, mometasone furoate; TAA, triamcinolone acetonide.

Figure 4 Relationship between systemic bioavailability and the therapeutic index for various intranasal corticosteroids.^{12,32,34,35,38,62}

Notes: The therapeutic index is defined here as the ratio of the dose that causes measurable systemic activity (defined as dose for cortisol suppression) divided by the therapeutic dose.

Abbreviations: BDP, beclomethasone dipropionate; BUD, budesonide; CIC, ciclesonide; DEX, dexamethasone; FF, fluticasone furoate; FLU, flunisolide; FP, fluticasone propionate; MF, mometasone furoate; TAA, triamcinolone acetonide.

Figure 5 Model-predicted changes in annual growth velocity for a range of doses of intranasal corticosteroids above and below the standard pediatric therapeutic doses. Reprinted from Clin Ther, 26(11), Daley-Yates PT, Richards DH. Relationship between systemic corticosteroid exposure and growth velocity: development and validation of a pharmacokinetic/pharmacodynamic model, 1905–1919, Copyright (2004), with permission from Elsevier.³⁷

Notes: The dotted lines indicate clinical equivalence limits of ±0.8 cm/y.

Abbreviations: BDP, beclomethasone dipropionate; BUD, budesonide; FP, fluticasone propionate; GV, growth velocity; MF, mometasone furoate; TAA, triamcinolone acetonide.

Figure 6 Model-predicted changes in annual growth velocity for combined inhaled and intranasal corticosteroid regimens. Adapted from Clin Ther, 26(11), Daley-Yates PT, Richards DH. Relationship between systemic corticosteroid exposure and growth velocity: development and validation of a pharmacokinetic/pharmacodynamic model, 1905–1919, Copyright (2004), with permission from Elsevier.³⁷

Abbreviations: BDP, beclomethasone dipropionate; BUD, budesonide; FP, fluticasone propionate; ICS, inhaled corticosteroids; INCS, intranasal corticosteroid; MF, mometasone furoate; TAA, triamcinolone acetonide.

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