second generation antihistamines and desloratadine in ... · highest h1-receptor affinity among...
TRANSCRIPT
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
Courtesy of Prof. P. Devillier.
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
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.
Courtesy of Prof. P. Devillier.
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%
Courtesy of Prof. P. Devillier.
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.
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.
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)
Highest H1-receptor affinity among second-generation antihistamines
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