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Maximal Use Pharmacokinetic
Trial Design for Topical
Dermatological Products
By
Doanh (Donny) Tran, PhD, RPh
Division of Clinical Pharmacology 3
US FDA/CDER/OTS/OCP 1
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Disclaimer
The opinions and views expressed in this
presentation are my own and do not reflect US
Food and Drug Administration policy or official
guidance.
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Outline
• Topical dermatological products
• The skin barrier and dermatological
diseases
• Maximal use pharmacokinetic (PK) trial
design
• Application of systemic PK data
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Topical dermatological products
• Topically applied products
– Intended for local action
– May have unintended systemic absorption
– Variety of dosage forms: cream, lotion, ointment,
gel, foam, etc.
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The skin barrier
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Altered skin barrier
Atopic dermatitis
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7 Atopic dermatitis
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Severe acne vulgaris
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9 Mild and severe papulopustular rosacea
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10 Chronic plaque psoriasis
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Potential for systemic absorption
Luliconazole cream for tinea pedis and tinea cruris.
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Reference: Clinical Pharmacology and Biopharmaceutics review.
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204153Orig1s000ClinPharmR.pdf
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Potential for systemic absorption
Tavaborole topical solution, 5% for onychomycosis
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Reference: Clinical Pharmacology and Biopharmaceutics review.
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204427Orig1s000ClinPharmR.pdf
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Regulatory requirement
• Code of Federal Regulations (21 CFR 320.21)
– Evidence measuring the in vivo bioavailability of
the drug product that is the subject of the
application, or
– Information to permit FDA to waive the
submission of evidence measuring the in vivo
bioavailability
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Determinants of Topical Bioavailability
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Maximal use PK trial
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A maximal use pharmacokinetic (PK) trial is conducted by obtaining adequate
number of PK samples following administration of your to-be-marketed
formulation. This trial should be conducted in a suitable number of subjects with
the dermatological disease of interest at the upper range of severity as
anticipated in both your clinical trials and proposed labeling. Such a trial would
attempt to maximize the potential for drug absorption to occur by incorporation of
the following design elements:
• Frequency of dosing
• Duration of dosing
• Use of highest proposed strength
• Total involved surface area to be treated at one time
• Amount applied per square centimeter
• Method of application/site preparation
Steps should be taken to ensure that the target patient population (age, gender, race,
etc.) is properly represented in the maximal use PK trial.
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Therapeutic Innovation & Regulatory Science
2015, Vol. 49(1) 108-115
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Healthy versus diseased skin
17
Diseased skin has compromised barrier properties which could affect the amount
of drug absorbed through the skin
Atopic dermatitis Healthy skin
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Change in disease states affects drug absorption
18 Reference: Adapted from raw data in NDA 204153 - Clinical Pharmacology and Biopharmaceutics review.
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204153Orig1s000ClinPharmR.pdf
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Total involved surface area
19
• Example: For acne
indication, drug should be
applied to the entire face,
shoulders, upper chest and
upper back in order to
capture the worst case
Severe acne vulgaris
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Study duration
• Effects of improvement in skin barrier with
treatment
• Duration should be sufficient to reach steady
state but not too long that the skin is healed
and reduces drug absorption
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Study duration
• Topical corticosteroid formulation X
– Drug was applied for either 15 days or 29 days to
subjects with plaque psoriasis
– HPA axis suppression was seen at Day 15 (about
20%) but not seen at Day 29
– Likely reason is due improvement in skin
conditions (i.e., skin barrier function) with the
longer treatment duration
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• Higher systemic drug concentrations in pediatric subjects
might be observed due to larger surface area to body weight
ratio and/or ontogenic differences in physiological processes
affecting ADME
Pediatric subjects
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Drug X
Age Group
Cmax
(ng/mL)
(%CV)
AUC
(ng*h/mL)
(%CV)
<12 months 230 (50) 670 (43)
1 to <2 years 150 (49) 410 (37)
2 to <3 years 160 (48) 600 (51)
3 to 17 years 50 (45) 190 (39)
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Pediatric subjects • HPA axis suppression rate for Diprolene AF Cream,
0.05% in subjects with atopic dermatitis
• Rates appear higher with lower age
– Caveat: not statistically significant, not all cases show this
trend
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Age Group 3mo-1yr
n=4
2yr-5yr
n=16
6yr-8yr
n=28
9yr-12yr
n=12
# suppressed 2 6 9 2
% 50 38 32 17
Adapted from presentation by Denise Cook, MD at the Joint Meeting of the Dermatologic and
Ophthalmic Drugs Advisory Committee and the Nonprescription Drugs Advisory Committee
on March 24, 20015
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Method of application and site preparation
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• Debridement procedure
removes dead tissue from the
surface and thus may alter
drug absorption
• Occluded conditions might
alter drug absorption
compared to non-occluded
conditions
Debridement
for diabetic
foot ulcer
Occluded
application
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Impact of excipient change on drug bioavailability
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• Surfactant system was
changed in the
formulation
• The bioavailability (BA)
of clindamycin increased
by ~ 1.6 fold while that of
tretinoin remained
unchanged
Reference: NDA 50803- Clinical Pharmacology and Biopharmaceutics review.
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/050803Orig1s000ClinPharmR.pdf
Formulation
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Formulation
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• To-be-marketed formulation should be used
• In case when there is a change in the
excipient system, an additional maximal use
PK trial may be needed
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• Amount applied in the maximal use PK trial should be recorded
and compared with that used in the Phase 3 safety and efficacy
trials and proposed for clinical use
Amount applied
27
Apply pea size
Apply thin
layer
Apply enough to
saturate hair and scalp
Apply golf ball size
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Impact of Maximal Use PK Trial
• Systemic safety evaluation
– Comparing the systemic exposure to animal toxicity
threshold data
– Correlating systemic levels to systemic safety
signals
– Comparing to data from other formulation or route
of administration to assess relative risk
– Comparing to data from in vitro enzyme
inhibition/induction studies to assess risk for drug
interactions 28
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Impact of Maximal Use PK Trial
• Support waiver for Pharm/Tox studies when
submitting a 505(b)(2) NDA application
• Support establishment of a clinical bridge when
submitting a 505(b)(2) NDA application
• Support waiver of TQT trial if systemic
exposures are low (e.g., Cmax below 1nM)
• HPA axis suppression for topical corticosteroids – Requires empirical data currently
– Potential for exposure-response in future?
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Other considerations
• Maximal use PK trial design is flexible
– Discuss with FDA if there are unique
circumstances
• May be used in conjunction with other
techniques
– Microdialysis to assess local concentrations
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Summary
• Topical drug products can lead to systemic
absorption and adverse effects
• Systemic bioavailability assessment should be
conducted under maximal use conditions
• Study design should be discussed with the
FDA
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Acknowledgements
• CAPT. E. Dennis Bashaw, Pharm. D. – Director,
Division of Clinical Pharmacology – 3
• Chinmay Shukla, Ph.D. – Senior Reviewer,
Dermatology and Dental Clinical Pharmacology
Team
Email: [email protected] 32