Crisaborole

Crisaborole is an anti-inflammatory benzoxaborole phosphodiesterase-4 (PDE4) inhibitor that suppresses secretion of certain cytokines, such as tumour necrosis factor-α (TNF-α), interleukins (IL-2, IL-4, IL-5), and interferon gamma (IFNγ), and improves skin barrier function as measured by transepidermal water loss (TEWL). Crisaborole applied on atopic dermatitis lesions of patients reduces expression of atopic inflammation associated chemokines including CCL17, CCL18, and CCL22.

Cardiac Electrophysiology

At therapeutic doses, crisaborole ointment is not expected to prolong QTc to any clinically relevant extent.

Absorption

The pharmacokinetics (PK) of crisaborole were investigated in 33 paediatric subjects 2 to 17 years of age with mild to moderate atopic dermatitis and a mean ± SD BSA involvement of 49 ± 20% (range 27% to 92%). In this study, subjects applied approximately 3 mg/cm² of crisaborole ointment (dose range was approximately 6 g to 30 g per application) twice daily for 8 days. Plasma concentrations were quantifiable in all subjects. The mean ± SD maximum plasma concentration (C_max) and area under the concentration time curve from 0 to 12 hours post dose (AUC_0-12) 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 AUC_0-12 between Day 8 and Day 1, the mean accumulation factor for crisaborole was 1.9. Systemic exposure (C_max and AUC_0-12) of crisaborole and its main metabolites increased with increasing % BSA treated.

The studies were performed with a different formulation of crisaborole which contained butylhydroxytoluene (BHT). In vitro permeation testing (IVPT) was performed in intact skin to support therapeutic equivalence between the BHT-containing and the no-added BHT formulations. Although the results were inconclusive and highly variable, a possible slight increase in permeation is not expected to influence the benefit-risk profile of the product in patients with up to 40% BSA affected to a clinically relevant extent.

Distribution

Based on an in vitro study, crisaborole is 97% bound to human plasma proteins.

Biotransformation and elimination

Crisaborole is substantially metabolised into inactive metabolites. The main metabolite 5-(4-cyanophenoxy)-2-hydroxyl benzylalcohol (metabolite 1), is formed via multiple CYP enzymes including CYP3A4, 1A2 and hydrolysis; this metabolite is further metabolised into downstream metabolites, among which 5-(4-cyanophenoxy)-2-hydroxyl benzoic acid (metabolite 2), formed via oxidation, is also a main 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 AUC_0-12 between Day 8 and Day 1, the mean accumulation factors for metabolites 1 and 2 were 1.7 and 6.3, respectively. The mean ± SD C_max and AUC_0-12 for metabolite 2 on Day 8 were 1850 ± 1830 ng/mL and 18200 ± 18100 ng*h/mL, respectively. Renal excretion of metabolites is the major route of elimination. Approximately 25% of the radiolabelled dose was absorbed and predominantly excreted in the urine.

Drug interactions

Potential for crisaborole to influence the PK of other medicinal products

In vitro studies using human liver microsomes indicated that under the conditions of clinical use, crisaborole and metabolite 1 are not expected to inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, and 3A4.

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 interaction potential.

In vitro studies indicate that under the condition of clinical use, crisaborole and metabolites 1 and 2 are not expected to induce CYP enzymes.

Based on in vitro data, crisaborole is metabolised to some extent (<30%) via CYP3A4 and CYP1A2. Concomitant administration of crisaborole and potent CYP3A4 or CYP1A2 inhibitors may result in increases in crisaborole systemic exposure.

In vitro studies showed that crisaborole and metabolite 1 did not inhibit the activities of uridine diphosphate (UDP)-glucuronosyltransferase (UGT) 1A1, 1A4, 1A6, 1A9, 2B7, and 2B15. Metabolite 2 did not inhibit UGT1A4, 1A6, 2B7, and 2B15. Metabolite 2 showed weak inhibition of UGT1A1; however, no clinically significant drug interactions are expected between crisaborole (and its metabolites) and UGT1A1 substrates at therapeutic concentrations. Metabolite 2 showed moderate inhibition of UGT1A9 and may result in a moderate increase of the concentrations of sensitive UGT1A9 substrates, such as propofol. A clinically relevant interaction between metabolite 2 and propofol is not anticipated due to the posology and method of administration of propofol (intravenous infusion or injection with titration to clinical effect for anaesthesia or sedation). Drug interaction studies with sensitive UGT1A9 substrates have not been conducted.

In vitro studies indicate that under the condition of clinical use, crisaborole and metabolites 1 and 2 are not expected to cause clinically significant interactions with substrates of transporters such as P-glycoprotein, breast cancer resistance protein (BCRP) and organic anionic or cationic transporters.

Preclinical data from studies conducted in vitro or in vivo by the oral and dermal routes of administration reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, juvenile toxicity, or toxicity to reproduction and development.

A drug-related increased incidence of benign granular cell tumours in the uterus with cervix and vagina (combined) was noted in crisaborole-treated female rats at oral doses approximately 2 times the mean human systemic exposure in maximum use conditions. The clinical relevance of this finding is unknown, however given the tumour type and benign status in a single species and single sex, the relevance to humans is considered to be low.