Mechanism of Action
Crisaborole is a phosphodiesterase 4 (PDE-4) inhibitor. PDE-4 inhibition results in increased intracellular cyclic adenosine monophosphate (cAMP) levels. While the specific mechanism(s) by which crisaborole exerts its therapeutic action is not well defined, crisaborole reduces the production of some inflammatory cytokines implicated in the pathophysiology of atopic dermatitis.
At therapeutic doses, EUCRISA ointment is not expected to prolong QTc to any clinically relevant extent. In a thorough QT/QTc study of healthy volunteers, there was no clinically important prolongation of QT/QTc interval induced by either crisaborole or its metabolites and there were no clinically significant effects on heart rate or PR or QRS intervals.
A randomized clinical study was carried out to determine the potential of EUCRISA ointment, 2%, to induce sensitization and to cause irritation by repeated topical application to normal skin of healthy volunteers (18 years of age or older) under controlled conditions. In this study, EUCRISA showed no evidence of skin sensitization potential. Some skin irritations (e.g. erythema, edema and papules) were reported.
Tmax (hrs, median (range))
Steady State Mean (SD)
3.00 (3.00 – 24.0)
The pharmacokinetics (pK) of EUCRISA were investigated in 33 pediatric patients 2 to 17 years of age with mild to moderate atopic dermatitis and a mean ± SD body surface area (BSA) involvement of 49 ± 20% (range 27% to 92%). In this study, patients applied approximately 3 mg/cm2 of EUCRISA ointment (dose range was approximately 6 g to 30 g per application) twice daily for 8 days. The lower limit of quantification for the pK assay used to detect presence of crisaborole in plasma was 0.2 ng/mL.
Plasma concentrations were quantifiable in all the patients. 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 (Table 3). 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 was 1.9.
The PK of EUCRISA were investigated in 18 subjects 3 months to less than 24 months of age. Excluding outlier values from 5 subjects the mean ± SD Cmax and AUC0-12 for crisaborole were 188 ± 100 ng/mL and 1164 ± 550 ng∙h/mL, respectively.
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.
Pharmacokinetics 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 elimination.
Special Populations and Conditions
A multicenter, open-label maximal use, systemic exposure study with a pK Phase and a non-pK Safety Phase was conducted in children and adolescents with mild to moderate AD. Based on the pK exposures, no difference was seen in pK exposures in patients between the various age cohorts (2 to <18 years old).
A separate PK study evaluated 18 subjects aged 3 months to <2 years of age. Following EUCRISA twice daily administration, large variations in plasma concentrations of crisaborole were observed, with 5 infants exhibiting more than 2-fold higher AUC compared to adults. Sampling methodology errors may have contributed to this result. When excluding values associated with potential sampling errors, results indicated comparable systemic crisaborole exposures in infants and toddlers as observed in older patients at similar treated BSA. However, an actual increase in exposure in infants and toddlers relative to older patients cannot be excluded.
PK profiles of crisaborole and its two metabolites have not been assessed in geriatric subjects.
PK profiles of crisaborole and its two metabolites have not been assessed in patients with renal impairment.
PK profiles of crisaborole and its two metabolites have not been assessed in patients with hepatic impairment.