Table Of ContentTacrolimus Ointment
Springer-Verlag Berlin Heidelberg GmbH
T. RUZICKA • S. REITAMO (EDS.)
Tacrolimus Ointment
AT opicallmmunomodulator for Atopic Dermatitis
Springer
ISBN 978-3-662-10211-4 ISBN 978-3-662-10209-1 (eBook)
DOI 10.1007/978-3-662-10209-1
Library of Congress Cataloging-in-Publication Data
Tacrolimus ointment : a topical immunomodulator for atopic dermatitis I
[edited by] T. Ruzicka, S. Reitamo
p.;cm.
Includes bibliographical references and index.
1. Atopic dermatitis-Chemotherapy. 2. FK-506 (Drug). I. Ruzicka, Thomas. II. Reitamo, Sakari.
[DNLM: 1. Dermatitis, Atopic-therapy. 2. Tacrolimus-therapeutic use. 3. Ointments-therapeutic
use. WR 160 Tl19 2003]
RL243.T33 2003
616.5'21-dcZl
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Originally published by Springer-Verlag Berlin Heidelberg New York in 2004
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lntrodudion
T. Ruzicka, T. Assmann and S. Reitamo
The introduction of glucocorticosteroids in the 1950s has revolutionised the manage
ment of acute and chronic inflammatory skin disorders. These compounds have
maintained their leading role in dermatotherapy for several decades. They still
represent the principal option of treatment for atopic eczema (atopic dermatitis), a
prototype of a common chronic relapsing inflammatory skin disease which is seen
with increasing frequency both in children and adults. In developed countries, the
prevalence of the disease amounts to more than 10% of the general population in
infants. However, continuous application of topical glucocorticosteroids can in
duce a great number of unwanted side effects. The most relevant side effects are the
induction of cutaneous atrophy, particularly on sensitive skin sites such as face, neck,
and intertriginous areas, and of contact allergy, rosacea-like dermatitis, and striae.
Further problems include poor long-term management and even therapeutic re
sistance. In paediatric patients, adrenal insufficiency and growth retardation may
be related to prolonged application of potent topical glucocorticosteroids.
The development of a new generation of topical glucocorticosteroids in order to
diminish the risk of side effects has improved the benefit/risk ratio. However, the lack
of acceptance (so-called corticophobia) with reduced patient compliance remains a
problem in daily clinical practice.
Consequently, there has been an enormous need for alternative anti-inflamma
tory agents in the treatment of inflammatory skin disease, which stimulated the
search for and the development of new topical, non-steroidal drugs. The search had
been initiated by the observation of potent anti-inflammatory effects of systemically
administered cyclosporin. The topical application of cyclosporin, however, failed
to provide beneficial effects due to its low penetration into inflamed skin. Another
compound of this class of immunomodulatory macrolactams, tacrolimus, has been
shown to exert similar anti-inflammatory effects on systemic administration as
cyclosporin, but the drug has also proven to be topically effective in the therapy
of inflammatory skin disease, particularly in atopic eczema. Tacrolimus acts via in
hibition of the calcineurin-mediated transcription of proinflammatory cytokine
genes, such as interleukin-2, and interferes early and directly with the induction of
cutaneous immune responses. Thus, these targeted mechanisms of action elucidate
that topical tacrolimus appears much more specific than any of the topical gluco
corticosteroid compounds.
In several multicentre, randomised, double-blind clinical trials, carried out
around the turn of the millennium, topical tacrolimus was demonstrated to be an
effective and safe drug in the management of atopic eczema both in children and in
adults. The clinical development plan for tacrolimus ointment (Protopic) has been
the most extensive ever for a new drug in dermatology. The studies, which included
more than 13 ooo patients in North America, Japan, and Europe, showed that tacro
limus ointment is not only effective in short-term treatment for several weeks, but
also over periods of more than one year. Recently, tacrolimus ointment has been
approved for the treatment of moderate to severe atopic eczema in Japan, North
America, and many European countries. Current trials are evaluating the safety
profile and efficacy of tacrolimus ointment in long-term treatment of 2 to 5 years.
Long-term safety data of patients followed for up to four years show that tacrolimus
ointment lacks systemic side effects and that frequencies of serious adverse events
such as malignancies are consistent with expected rates in the general population.
The most striking advantage of tacrolimus ointment over topical glucocortico
steroids is that the cutaneous collagen synthesis remains unaffected, and the risk
of skin atrophy is not imminent. These findings enable the drug to be used as a
long-term treatment, even on thinner sites of inflamed skin such as face and neck,
which are frequently affected in atopic eczema. Thus, the non-compliance seen with
topical glucocorticosteroids may not represent a problem in the treatment of atopic
eczema with tacrolimus ointment, because this topical immunomodulator is likely
to exert a profound impact on the manner in which dermatologists and patients treat
and manage the disease.
A number of recent publications has demonstrated that tacrolimus ointment is
also effective in the management of a variety of other inflammatory skin disorders,
and may represent an alternative therapeutic option in other diseases than atopic
eczema. Of course, these initial observations have to be confirmed by larger trials
comparing topical tacrolimus to current standard treatment.
This book summarises the historical, pharmacokinetic and pharmacodynamic
aspects of the use of topical tacrolimus in dermatology. It gives insight into the broad
clinical experience of treatment with tacrolimus ointment, particularly in atopic
eczema, and also provides an overview of putative future indications. Finally, it may
serve as a tool to change the dermatologist's views on and approach to anti-inflam
matory treatment.
Table of Contents
Atopic Dermatitis
Epidemiology of Atopic Dermatitis 3
T.L. DIEPGEN
Introduction 3
The Prevalence of AD Yesterday and Today 4
Definition and Validation of AD 7
Age of Onset and Concomitant Atopy 10
Genetic Susceptibility ll
East/West Differences and Migration Studies 13
Environmental Factors and Lifestyle 14
Immunology and Infections 16
Future Public Health Implications of Increasing Atopic Dermatitis 18
References 19
The Pathogenesis of the Atopic Eczema/Dermatitis Syndrome 23
N. NOVAK, T. BIEBER
Introduction 23
Genetic Factors 24
Candidate Genes Related to IgE Synthesis 26
Candidate Genes Related to the High Affinity Receptor for IgE FcERl 26
Chemokines and Other Candidate Genes 27
Immunological Mechanisms Involved in AEDS 27
The Skin Immune System 27
Evidence for a Pathophysiological Role of Keratinocytes in AEDS 28
The Role of Infectious Agents 29
Autoallergens 30
Neuroimmunological Factors Influencing the Skin 30
Phosphodiesterase Activity 31
Omega-6 Fatty Acids 31
VII
Table of Contents
Cellular Mechanisms 32
IgE-Mediated Type IV Reactions of the Skin 32
Atopic Dermatitis 35
The Role of IgE-The Allergic and Non-Allergic Forms of AEDS 36
The Atopy Patch Test as a New Diagnostic Tool 38
Conclusion and Future Perspectives 39
References 39
Detecting, Diagnosing and Grading Atopic Dermatitis 47
}.M. HANIFIN
Introduction 47
Criteria for Research Populations 47
Screening Tools for Atopic Dermatitis 50
Screening with Questionnaires 51
Clinical Examination 53
Seeking Optimal Diagnostic Criteria 54
Quantitating Eczematous Disease 56
References 59
Current Treatment of Atopic Dermatitis 63
J.D.Bos
Introduction 63
Diagnosis of Atopic Dermatitis: Knowing Whether It Is Atopy
(Atopic Dermatitis) or Not (Atopiform Dermatitis) Is Essential
for Its Management 65
Atopic Dermatitis: A Common Disease with a Serious Impact
on the Quality of Life 65
Genetics of Atopy and Its Role in the Management of Atopic Dermatitis 66
General Measures in the Management of Atopic Dermatitis 67
Prevention 68
Information 68
Allergen Avoidance and Elimination of Triggering Factors 68
Emollients 69
Topical Antimicrobials and Antiseptics 69
Treatment Failure 69
Specific Therapies in the Management of Atopic Dermatitis 70
Topical Therapies Including Corticosteroids 70
Systemic Antihistamines 71
Systemic Antibiotics 72
Systemic Immunomodulators 72
VIII
Table of Contents
Phototherapy and Photochemotherapy 72
Hospitalisation and Day-Care Centres 73
Treatment of Complications 73
Alternative Treatments in the Management of Atopic Dermatitis 74
New Approaches Needed in Atopic Dermatitis Management 75
Impending Innovative Therapies in the Management of Atopic Dermatitis 75
References 76
Development of Tacrolimus Ointment
Development of Tacrolimus Ointment 81
~GOTO,H.NAKAGAWA
Discovery and Isolation of Tacrolimus 81
Preclinical Studies 86
In Vitro Immunomodulatory Effects 86
Antimicrobial Activity 87
In Vivo Immunomodulatory Effects 87
Molecular Immunology 89
Clinical Applications 90
Transplantation Medicine 90
Treatment of Dermatological Diseases 91
Experimental Approaches 92
Atopic Dermatitis 95
References 98
Pharmacokinetics ofTaaolimus Ointment: Clinical Relevance 99
N.A. UNDRE
Introduction 99
Pharmacokinetics 100
Physicochemical Properties 101
Systemic Pharmacokinetics 101
Dermal Pharmacokinetics - In Vitro Models 103
In Vitro Metabolism of Tacrolimus by Human Skin 105
Pharmacokinetics ofTacrolimus-Topical Application 105
Pharmacokinetics - Healthy Adult Subjects 105
Pharmacokinetics-Patients with Atopic Dermatitis 106
Potential for Interaction with Other Medications 110
References 110
IX
Table of Contents
Tacrolimus as an lmmunomodulator 111
T. ASSMANN, B. HoMEY, T. RuzicKA
Mode of Action ofTacrolimus Ointment 112
Biochemical Mechanisms of Action Studied in T Cells 112
Further In Vitro and Ex Vivo Findings 113
In Vivo Studies in Animals 118
Differentiation of Topical Tacrolimus from Topical Glucocorticosteroids 120
General Mode of Action of Glucocorticosteroids in Skin 120
Comparison of In Vivo Effects ofTacrolimus and Glucocorticosteroids 121
Effects on Collagen Synthesis and Skin Atrophy 122
Conclusion 123
References 125
Clinical Experience with Tacrolimus Ointment in Atopic Dermatitis
Clinical Experience in Adults 129
S. REITAMO
Introduction 129
Early Clinical Development 131
Drug Concentration Studies 131
Pharmacokinetics 132
The Tacrolimus Ointment Clinical Trials Programme 133
Clinical Efficacy of Topical Tacrolimus 135
Efficacy Assessments 135
Comparison with Vehicle 137
Efficacy in Patients with Limited Disease 141
Comparison with Corticosteroids 141
Long-Term Comparison of Tacrolimus Ointment and Corticosteroids 144
Selection of Drug Concentration and Administration 144
Long-Term Efficacy 145
Safety and Tolerability 147
General Tolerability and Treatment Discontinuations 148
Local Adverse Events 148
Non-Application-Site Adverse Events 150
Effects ofTacrolimus Ointment on Laboratory Values 151
Comparison with Topical Corticosteroids 151
Long-Term Safety and Tolerability 154
Quality of Life and Cost-Effectiveness 157
Summary 158
References 159
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