Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
Cardiac Electrophysiology

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

Pharmacokinetic Properties

12.3 Pharmacokinetics
Absorption
The PK of STAQUIS 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 (BSA) involvement of 49 ± 20% (range 27% to 92%). In this study, subjects applied approximately 3 mg/cm2 of STAQUIS 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 was 1.9.

The PK of STAQUIS were investigated in 13 subjects 4 months to less than 24 months of age. The mean ± SD Cmax and AUC0-12 for crisaborole were 188 ± 100 ng/mL and 1164 ± 550 ng∙h/mL, respectively.

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

Elimination
Metabolism
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.

Excretion
Renal excretion of metabolites is the major route of elimination.

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 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 in human hepatocytes showed that under the conditions of clinical use, crisaborole and metabolites 1 and 2 are not expected to induce CYP enzymes.

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.

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 P-glycoprotein and organic anionic or cationic transporters. Crisaborole and metabolite 1 are not expected to inhibit breast cancer resistance protein (BCRP); metabolite 2 is expected to inhibit BCRP at therapeutic concentrations.