second generation antihistamines and desloratadine in ... · highest h1-receptor affinity among...

2012-5-25 Luncheon

Hydroxyzine

Diphenhydramine

Chlorpheniramine

Terfenadine

1979

New Second-generation

Old Second-generation

First-generation

Desloratadine

2002

Levocetirizine

2002

Ebastine

1992

Fexofenadine

1995

Loratadine

1987

Cetirizine

1987

2000+ <1970 1980s 1990s

First antihistamine compound reported by Bovet (N.P. 1957) Pasteur Institute, Paris, 1930s

<1970 2000+ 1990s 1980s

Loratadine

Levocetirizine (E) Ebastine /Carebastine (M)

Desloratadine (M)

Cetirizine (M)

Fexofenadine (M) Mizolastine

Hydroxyzine Diphenhydramine Chlorpheniramine

Terfenadine

M = metabolite; E = enantiomer.

New Second-generation

Old Second-generation

First-generation

Chemical class 1st generation 2nd generation

Alkylamines Bromopheniramine, chlorpheniramine, dimethindene, pheniramine, triprolidine

acrovastine

Piperazines Buclizine, cyclizine, hydroxyzine, meclizine, oxatomide

Cetirizine, levocetirizine

Piperidines Azatadine, cyproheptadine, diphenylpyraline, ketotifen

Astemizole, bilastine, desloratadine, ebastine, fexofenadine, levocabastine, loratadine, misolastine, olopatadine, rupatadine, terfenadine

Ethanolamines Carbinoxamine, clemastine, dimenhydrinate, diphenhydramine, doxylamine, phenyltoloxamine

Ethylenediamines Antazoline, pyrilamine, tripelennamine

Phenothiazines Methdilazine, promethazine

Others Doxepin Azelastine, emedastine, epiastine

Small, liphophilic molecules that could cross BBB Not specific to H1 receptor

Chemical class

Alkylamines

Piperazines

Piperidines

Ethanolamines

Ethylenediamines

Phenothiazines

Others

1st generation antihistamine in KOREA

- chlorpheniramine; Peniramine®

- Hydroxyzine; Ucerax®

- Ketotifen; Zaditne®

Modification of 1st generation

antihistamines to eliminate S/E

More selective for peripheral H1

receptor

Some metabolites derivatives or active

enationmers of pre-existing drugs

Safer, faster acting or more potent

2nd generation AH in KOREA

- Lorataddine; CLARITYNE®

- Fexofenadine; ALLEGRA®

- Levocetirizine; XYZAL®

- Ebastine; EBASTEL®

- Olopatadine; ALLELOCK®

- Bepotastine; TALION®

- Desloratadine; AERIUS®

1)Cytochrome P450 2)P glycoprotein (PgP) 3)Organic anion transporter polypeptide (OATP) 4) Food

Small & large bowel Biliary canaliculi Kidney tubule Vascular endothel CNC, placenta, Adr gl..)

Water 300mL

GFJ 300mL

Baily DG. Br J Clin Pharmcol 2010;70(5);645-655

* Time elapsed from administration via the oral route to maximum plasma concentration; ** Based on papule and erythema testing; *** Principal active metabolite. # na, not available.

Tmax * (hours) Time to action (hours)**

Golightly LK. Drugs 2005;65(3):341-384

Highest H1-receptor affinity among second-generation antihistamines

Slow dissociation from H1-receptor Greater in vitro and in vivo antihistaminic potency than

loratadine No sedation No interaction with food Unlike loratadine, not metabolized by liver cytochrome

P450 3A4 pathway Unlike fexofenadine, no interaction with intestinal P-gp and

OATP pathways Predictable absorption and serum levels

*P-glycoprotein transporter and organic anion transporter (OATP) are major determinants of oral bioavailability.

1. Anthes et al. Eur J Pharmacol. 2002;449:229; 2. Kreutner et al. Arzneimittelforschung. 2000;50:345; 3. Anthes et al. Allergy. 2000;55:277; 4. Ring et al. Int J Dermatol. 2001;40:72; 5. Monroe et al. J Am Acad Dermatol. 2003;48:535; 6. Neoclarityn® Summary of Product Characteristics. At: http://emc.medicines.org.uk/; 7. Gupta et al. Clin Pharmacokinet. 2002;41(suppl 1):7; 8. Affrime et al. Allergy. 2000;55(suppl 63):277; 9. Banfield et al. Clin Pharmacokinet. 2002;41(suppl 1): 29; 10. Cayen et al. Allergy. 2000;55(suppl 63):1009; 11. Dresser et al. Clin Pharmacol Ther. 2002;71:11.

Anti-H1 Ki (nM) Relative Affinity

Desloratadine 0.9 194.4

Carebastine 10 17.5

Mizolastine 22 8.0

Terfenadine 40 4.4

Cetirizine 47 3.7

Ebastine 52 3.4

Loratadine 138 1.2

Fexofenadine 175 1.0

Receptor-binding affinity of histamine antagonists

on recombinant human H1 receptor

Courtesy of Prof. P. Devillier.

Anthes et al. Eur J Pharmacol. 2002;449:229.

Comparison of H1 receptor-binding affinity of antihistamines

1. Anthes et al. Biochemical characterization of desloratadine, a potent antagonist of the human histamine H1 receptor. Eur J Pharmacol. 2002;449:229-237

Carebastine, 17.5

Mizolastine, 8

Terfenadine, 4.4

Cetirizine, 3.7

Ebastine, 3.4

Loratadine, 1.2

Fexofenadine, 1

Desloratadine,

194.4

0 50 100 150 200

Rel

ativ

e af

fin

ity

Human H1-Receptor in CHO Cells:

Kinetic of Dissociation [3H] pyrilamine vs [3H] desloratadine

Pyrilamine dissociation

50% in 3.8 min

Desloratadine dissociation

37% in 6 hours

Long Duration of Action


Anthes et al. Eur J Pharmacol. 2002;449:229.

Hal

f-lif

e (

ho

urs

)

0

5

10

15

20

25

30

Desloratadine Loratadine Fexofenadine Cetirizine Levocetirizine Bepotastine

8

14

10

8

2

1. Devendra et al. Pharmacology and clinical efficacy of desloratadine as an anti-allergic and anti-inflammatory drug. Exp Opin Invest Drugs. 2001;10:547-560. 2. Desloratadine. Summary of Product Characteristics. 3. Telfast® . Summary of Product Characteristics. 4. Boots Hayfever & Allergy Relief Syrup. Summary of Product Information. 5. Xyzal® Summary of Product Characateristics. 6. Walsh et al. New Insights into the Second Generation Antihistamines. Drugs, 2001;61:207. 7. Estelle et al. Advances in H1-Antihistamines, NEJM 2004;351:2203-17 8. Katherine et al. Oral Bepotastine in allergic disorders, Drugs 2010;20(12)1579-1591

Comparison among 2nd G antihistamines 27

MEAN PLASMA CONCENTRATION OF DESLORATADINE AND

3-HYDROXYDESLORATADINE IN HEALTHY SUBJECTS

0

1

2

3

4

5

6

7

8

9

10

Day 1 Day 7 Day 14 Day 21 Day 28

Mea

n pl

asm

a co

ncen

trat

ion

(ng/

mL)

Desloratadine3-Hydroxydesloratadine

1. Mean plasma concentration of desloratadine and 3-hydroxydesloratadine in healthy subjects 2. Arrfrime et al. SCH 34117: A study evaluating the suppression of whealand flare following multiple-dose administration of desloratadine(5mg) to normal volunteers, Clinical Pharm. Study, 2000;1196:1-41


Gupta et al. Clin Pharmacokinet. 2002;41(suppl 1):7.

Open, cross-over, randomized study 18 healthy volunteers Desloratadine 7.5 mg p.o.

Fed

Fasted

De

slo

rata

din

e (n

g/m

L)

0 4 8 12 16 20 24

0

1

2

3

4

Time (hr)

50

100

150

200

1

2

3

4

0 6 12 18 24 n

g/m

L p

las

ma

Hours

With grapefruit juice Without grapefruit juice

Fexofenadine Desloratadine

ng

/mL

pla

sm

a

0 6 12 18 24

30%


Banfield et al. Clin Pharmacokinet. 2002;41(suppl 1): 29. Dresser et al. Clin Pharmacol Ther. 2002;71:11.

0 0

Potential interaction Desloratadine Levocetirizine Fexofenadine

P-gp – NR +++

Erythromycin + NR ++

Ketoconazole + NR ++

QTc interval – – –

Alcohol – + –

Food – – +*

P-gp = P-glycoprotein; NR = not reported.

*Antacid administration reduces fexofenadine bioavailability.

Neoclarityn® Summary of Product Characteristics. Available at: http://emc.medicines.org.uk/. Xyzal® Summary of Product Characteristics. Available at: http://emc.medicines.org.uk/emc/industry/default.asp?page= displaydoc.asp&documentid=7739.

Telfast® Summary of Product Information. Available at: http://raleigh.aventishosting.com/aventis_file_archive/ docs/59/doc0000026602.pdf.

Tashiro et al. Hum Psychopharmacol. 2008;23:139.

PET examination during a simulated car driving task

* Head Mount Display to watch the projected "in-car" views of the outer world.

*

1.8 2.1

0

2

4

6

8

10

Inc

ide

nc

e o

f s

om

no

len

ce

(%

)

CLARINEX® (desloratadine) US Prescribing Information. Schering Corporation.

Incidence of Somnolence

Placebo

(n=1,652)

Desloratadine

5 mg OD

(n=1,655)

Patients ≥ 12 years

1. Xyzal® Summary of Product Characteristics. At: http://emc.medicines.org.uk/emc/industry/default.asp?page=displaydoc. asp&documentid=7739.

2. Bachert et al. J Allergy Clin Immunol. 2004;114:838.

Placebo (n=771)

Levocetirizine1 5 mg once daily

(n=935)

Placebo (n=273)

Levocetirizine2 5 mg once daily

(n=278)

1.41.8

5.2

6.8

0

2

4

6

8

Inci

de

nce

of

som

no

len

ce

(%)

Incidence of Somnolence

*At clinically recommended doses in product labels.

Source: Summaries of Product Characteristics. At: http://emc.medicines.org.uk.

Agent

Desloratadine

Levocetirizine

Fexofenadine

Loratadine

Cetirizine

Ebastine

Mizolastine

Reported Increase in Somnolence vs Placebo*

No

Yes

No

No

Yes

Yes

Yes

Bousquet J et al. Allergy 2009

N=276, Control= 271, intermittent AR, 15 d TX

Bousquet J et al. Int Arch Allergy Immunol 2010;153:395–402

N=360, Control= 356, persistent AR, 85 d TX

-1.35

-1.66

-0.95

-1.39

-1.8

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

Day 29 Day 85

Mea

n c

han

ge in

RQ

LQ s

core

improves quality of life of patients with PER

-4

-3

-2

-1

0

Desloratadine (n=355) Baseline score:

9.63

Placebo (n=351)

Mea

n c

han

ge f

rom

bas

elin

e

aver

aged

ove

r D

ays

1-2

9 (

po

ints

)

9.55

Primary Endpoint Results: Aerius® significantly relieves the symptoms of PER1

desloratadine

Placebo

Bousquet J et al. Int Arch Allergy Immunol 2010;153:395–402

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

Mea

n c

han

ge f

rom

bas

elin

e

Primary Efficacy Variable: Reduction in AM/PM Nasal Congestion Score in SAR

Day 2 Day 3 Day 4 Day 2-15

* * * *

Desloratadine 5 mg (n=172)

Placebo (n=174)

*P<0.05 vs placebo.

Nayak and Schenkel. Allergy. 2001;56:1077.

0 Day 7 Day 14 Day 21 Day 28

0

* **

***

Desloratadine 5 mg OD AM (n=293)

Placebo (n=291)

-0.2

-0.4

-0.6

-0.8

-1.0

-1.2

*P=0.015 vs placebo; **P=0.004 vs placebo; ***P=0.009 vs placebo.

Holmberg. ACAAI. 2005

Morning (AM) Nasal Congestion Score in PER

Horak F et al. J Allergy Clin Immunol. 2002;109:956-61.

*P = 0.005 †P = 0.01 ‡P = 0.001

compared with placebo

15

Allergen Exposure Time (min)

0

0.6

1.2

1.6

1.8

1.4

1

0.8

0.4

0.2

45 75 105 135 165 195 225 255 285 315 345

†

*

* † * † † †

†

* †

†

*

†

*

† *

‡

‡ ‡ ‡ ‡

‡

Less Congestion

Desloratadine Placebo

Me

an C

han

ge f

rom

Bas

elin

e in

N

asal

Ob

stru

ctio

n S

core

s SAR, N=47, 7d Tx 10d Wash-out 6Hr Ag challenge Nasal airflow, SAR Sx

Bousquet et al. Allergy. 2008;63(suppl. 88):633-634. Abstract 1759

Desloratadine 5 mg

Placebo

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

in In

terf

ere

nc

e S

co

res

*

-0.25

-0.05

*

Sleep Interference (AM Diary Score)

-0.42

-0.13

Interference with Daily Activities (PM Diary Score)

Day 1 Day 2

Baseline:

0

-0.40

-0.30

-0.20

-0.10

1.72 1.66 1.37 1.38

-0.50 4-point scale (0=none, 3=severe). *P<0.05 vs placebo.

Placebo

MTL 10mg

MTL 20mg

LRT 10mg

MTL 10mg + LRT 10mg

Better

No change

Worse

Percentage of patient %

10

20

30

40

50

60

70

Meltzer EO et al. J Allergy Clin Immunol. 2000; 105:917-22.

• Combination treatment with Montelukast and loratadine could provide an additional benefit to AR symptom control

Have strong histamine H1 receptor antagonism

Not have anti-cholinergic action

Not have impaired performaance

Not have cardiotoxicity

Have anti-inflammatory actions which can be demonstrated in vivo,

in humans at therapeutic doses

Have sufficient-high “Benefit-to-risk ratio”

Not be affected by extensive drug metabolism and transport

mechanism

Not have drug-to-drug & drug-to food interaction

COGNA: Consensus group On New-Generation Antihistamine (2003)


Slow dissociation from H1-receptor Greater in vitro2 and in vivo antihistaminic potency

than loratadine No sedation No interaction with food Unlike loratadine, not metabolized by liver cytochrome

P450 3A4 pathway Unlike fexofenadine, no interaction with intestinal P-gp

and OATP pathways

Predictable absorption and serum levels

second generation antihistamines and desloratadine in ... · highest h1-receptor affinity among...

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