Mechanism Of Action
Crisaborole is a phosphodiesterase 4 (PDE-4) inhibitor.
PDE-4 inhibition results in increased intracellular cyclic adenosine
monophosphate (cAMP) levels. The specific mechanism(s) by which crisaborole
exerts its therapeutic action for the treatment of atopic dermatitis is not well
At therapeutic doses, EUCRISA ointment is not expected to
prolong QTc to any clinically relevant extent.
The pharmacokinetics (PK) of EUCRISA were investigated in
33 pediatric subjects 2 to 17 years of age with mild to moderate atopic dermatitis and a mean ± SD body surface area involvement of 49 ± 20% (range 27%
to 92%). In this study, subjects applied approximately 3 mg/cm² of EUCRISA
ointment (dose range was approximately 6 g to 30 g per application) twice daily
for 8 days.
Plasma concentrations were quantifiable in all the
subjects. The mean ± SD maximum plasma concentration (Cmax) and area under the
concentration time curve from 0 to 12 hours post dose (AUC0-12) for crisaborole
on Day 8 were 127 ± 196 ng/mL and 949 ± 1240 ng*h/mL, respectively. Systemic
concentrations of crisaborole were at steady state by Day 8. Based on the
ratios of AUC0-12 between Day 8 and Day 1, the mean accumulation factor for crisaborole
Based on an in vitro study, crisaborole is 97% bound to
human plasma proteins.
Crisaborole is substantially metabolized into inactive
metabolites. The major metabolite 5-(4-cyanophenoxy)-2-hydroxyl benzylalcohol
(metabolite 1), is formed via hydrolysis; this metabolite is further
metabolized into downstream metabolites, among which 5-(4- cyanophenoxy)-2-hydroxyl
benzoic acid (metabolite 2), formed via oxidation, is also a major metabolite.
PK of metabolites 1 and 2 were assessed in the PK study
described above and the systemic concentrations were at or near steady state by
Day 8. Based on the ratios of AUC0-12 between Day 8 and Day 1, the mean
accumulation factors for metabolites 1 and 2 were 1.7 and 6.3, respectively.
Renal excretion of metabolites is the major route of
Drug Interaction Studies
In vitro studies using human liver microsomes indicated
that under the conditions of clinical use, crisaborole and metabolite 1 are not
expected to inhibit cytochrome P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and
In vitro human liver microsomes studies for metabolite 2
showed that it did not inhibit activities of CYP2C19, 2D6, and 3A4; was a weak
inhibitor of CYP1A2 and 2B6; and a moderate inhibitor of CYP2C8 and 2C9. The
most sensitive enzyme, CYP2C9, was further investigated in a clinical trial
using warfarin as a CYP2C9 substrate. The results of this study showed no drug
In vitro studies in human hepatocytes showed that under
the conditions of clinical use, crisaborole and metabolites 1 and 2 are not
expected to induce CYP enzymes.
Two multicenter, randomized, double-blind,
parallel-group, vehicle-controlled trials (Trials 1 and 2) treated a total of
1522 subjects 2 to 79 years of age (86.3% of subjects were 2 to 17 years of
age) with a 5% to 95% treatable body surface area. At baseline, 38.5% of the subjects
had an Investigator's Static Global Assessment [ISGA] score of 2 (mild), and
61.5% had an ISGA score of 3 (moderate), in the overall assessment of atopic
dermatitis (erythema, induration/papulation, and oozing/crusting) on a severity
scale of 0 to 4.
In both trials, subjects were randomized 2:1 to receive
EUCRISA or vehicle applied twice daily for 28 days. The primary efficacy
endpoint was the proportion of subjects at Day 29 who achieved success, defined
as an ISGA grade of Clear (score of 0) or Almost Clear (score of 1) with a
2-grade or greater improvement from baseline, comparing EUCRISA-treated subjects
to vehicle-treated subjects.
Efficacy results from the two trials are summarized in
Table 2: Primary Efficacy Outcomes in Subjects with
Mild to Moderate Atopic Dermatitis at Day 29
|Success in ISGAa
|a Defined as an ISGA score of Clear (0) or
Almost Clear (1) with a 2-grade or greater improvement from baseline.
The success rates over time are presented in Figure 1.
Figure 1: Success in ISGAa Over Time in
Subjects with Mild to Moderate Atopic Dermatitis