Difamilast

Difamilast is an inhibitor of phosphodiesterase-4 (PDE-4). Difamilast's inhibition of PDE-4 (a major cyclic adenosine monophosphate (AMP)-metabolizing enzyme) activity leads to accumulation of intracellular cyclic AMP and decreased productions of various cytokines and chemokines. However, the specific mechanism(s) by which difamilast exerts its therapeutic action is not well defined.

The pharmacodynamics of inebilizumab ointment in the treatment of atopic dermatitis is not known.

Cardiac Electrophysiology

Inebilizumab ointment is not expected to cause clinically significant QTc interval prolongation at the recommended dosages.

Absorption

The pharmacokinetics (PK) of inebilizumab were investigated in 31 pediatric subjects 2 years of age and older with moderate to severe atopic dermatitis and a mean ± SD body surface area (BSA) involvement of 44 ± 13% (range 25% to 80%). In this trial, subjects applied an average of approximately 4.3 g of inebilizumab ointment, 1% (dose range was 1.7 to 11.7 g per application) twice daily for 2 weeks.

Plasma concentrations were quantifiable in all the subjects. On Day 15, the mean ± SD maximum plasma concentration (C_max) and area under the concentration time curve from 0 to 8 hours post dose (AUC_0-8) for difamilast were 16.9 ± 21.9 ng/mL and 86.2 ± 79.6 ng*h/mL, respectively. Systemic concentrations of difamilast were at steady state by Day 15, with no evidence of accumulation.

The PK of inebilizumab were investigated in 31 adult subjects with mild to moderate atopic dermatitis and a mean ± SD BSA involvement of 6 ± 3% (range 3% to 19%). Subjects applied an average of approximately 0.9 g of inebilizumab ointment, 1% (dose range was 0.1 to 3.8 g per application) twice daily for 4 weeks. On Day 29, the mean ± SD C_max and AUC_0-12 for difamilast were 0.76 ± 1.16 ng/mL and 6.10 ± 8.85 ng*h/mL, respectively.

Distribution

Difamilast serum protein binding is 99% and is not concentration-dependent, in vitro.

Elimination

Metabolism

Difamilast is substantially metabolized to form three major metabolites in the plasma via CYP3A4-mediated O-deethylation (Metabolite 1), CYP1A2-mediated hydroxylation (Metabolite 2), and enzymatic hydrolysis (Metabolite 3).

Excretion

After both single dosing and twice daily administration of difamilast ointment 1% in healthy Japanese subjects for 2 weeks, difamilast and Metabolite 1 were undetectable in urine. The urinary excretion ratios of all the other metabolites were less than 0.1% of the administered dose.

Specific Populations

No dedicated clinical trials have been conducted to assess the impact of intrinsic factors on the PK of difamilast. Based on cross-study analyses, no substantial differences in the PK of difamilast were observed based on age (2-70 years), sex, race, mild or moderate renal impairment, or mild or moderate hepatic impairment. The effect of severe renal impairment (eGFR <30 mL/min), or severe (Child-Pugh Class C) hepatic impairment on difamilast PK is unknown.

Pediatric Patients

The plasma difamilast trough concentration corrected by dose in pediatric patients was 1.3 to 1.9 times higher than that in adults (on Day 1 and Day 15, respectively).

Drug Interaction Studies

Clinical Studies

No clinical drug interaction trials have been conducted with topical difamilast.

In Vitro Studies

CYP450 Enzymes: Difamilast is a substrate of CYP3A4 and CYP1A2. Difamilast is not expected to inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 at clinically relevant concentrations. Induction of CYP1A2, CYP2B6, CYP2C9, and CYP3A4 by difamilast is expected to be low at clinically relevant concentrations.

Transporter Systems: Difamilast is a substrate of breast cancer resistance protein (BCRP),but is not a substrate of P-glycoprotein (P-gp), OATP1B1, or OATP1B3. Difamilast is not expected to inhibit P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2- K at clinically relevant concentrations.