Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults.

BACKGROUND: Additional topical treatments for atopic dermatitis (AD) are needed that provide relief while minimizing risks. OBJECTIVE: We sought to assess the efficacy and safety of crisaborole ointment, a phosphodiesterase 4 inhibitor, in two phase III AD studies (AD-301: NCT02118766; AD-302: NCT02118792). METHODS: Two identically designed, vehicle-controlled, double-blind studies enrolled and randomly assigned (2:1, crisaborole:vehicle) patients aged 2 years or older with an Investigator's Static Global Assessment (ISGA) score of mild or moderate for twice-daily application for 28 days. The primary end point was ISGA score at day 29 of clear (0)/almost clear (1) with 2-grade or greater improvement from baseline. Additional analyses included time to success in ISGA score, percentage of patients achieving clear/almost clear, reduction in severity of AD signs, and time to improvement in pruritus. RESULTS: More crisaborole- than vehicle-treated patients achieved ISGA score success (clear/almost clear with ≥2-grade improvement; AD-301: 32.8% vs 25.4%, P = .038; AD-302: 31.4% vs 18.0%, P < .001), with a greater percentage with clear/almost clear (51.7% vs 40.6%, P = .005; 48.5% vs 29.7%, P < .001). Crisaborole-treated patients achieved success in ISGA score and improvement in pruritus earlier than those treated with vehicle (both P ≤ .001). Treatment-related adverse events were infrequent and mild to moderate in severity. LIMITATIONS: Short study duration was a limitation. CONCLUSIONS: Crisaborole demonstrated a favorable safety profile and improvement in all measures of efficacy, including overall disease severity, pruritus, and other signs of AD.

Clinical pharmacokinetics of gabapentin after administration of gabapentin enacarbil extended-release tablets in patients with varying degrees of renal function using data from an open-label, single-dose pharmacokinetic study.

BACKGROUND: Gabapentin enacarbil, a transported acyloxyalkylcarbamate prodrug of gabapentin, provides predictable and dose-proportional gabapentin exposure (AUC). Gabapentin is cleared via renal excretion, and its elimination is proportional to creatinine clearance (CrCL); CrCL can, therefore, be used as a predictor of gabapentin renal clearance. Gabapentin produced from hydrolysis of gabapentin enacarbil is also eliminated via the renal clearance pathway. It was, therefore, anticipated that the pharmacokinetics of gabapentin derived from gabapentin enacarbil would also be affected by renal function. OBJECTIVE: The objective of this study was to describe a population pharmacokinetic analysis of gabapentin enacarbil in patients with varying degrees of renal function, using data from an open-label study of gabapentin enacarbil in patients with renal impairment (XenoPort, Inc. protocol XP066), to determine whether dosage adjustments are necessary in patients with renal impairment. METHODS: Men and women >18 years of age with a body mass index ≤34 kg/m(2) and who were, in general, healthy with the exception of renal impairment were enrolled All patients received a single 600-mg gabapentin enacarbil extended-release tablet under fed conditions. After dosing, plasma, urine, and dialysate samples were analyzed. Safety profile evaluations included adverse events, vital signs, ECGs, and laboratory values. Pharmacokinetic data were compared with those from Phase I-III studies in subjects with normal renal function to evaluate the relationship between gabapentin oral clearance (CL/F) and CrCL. RESULTS: Fifteen patients (11 men and 4 women) were enrolled. One patient had moderate renal impairment (CrCL 30-59 mL/min), 7 patients had severe renal impairment (CrCL <30 mL/min), and 7 patients had end-stage renal disease (CrCL <15 mL/min). Ten patients were white, 4 were African American, and 1 was American Indian or Alaskan Native. Their mean (range) age was 55 (28-76) years, weight was 85.6 (62-134) kg, and body mass index was 28.3 (22-34) kg/m(2). Mean maximum plasma gabapentin concentration was 5.77 µg/mL in patients with moderate and severe renal impairment, and 5.59 µg/mL in patients with end-stage renal disease who were undergoing hemodialysis. Based on the population pharmacokinetic analysis, gabapentin CL/F after administration of gabapentin enacarbil was proportionally related to CrCL, with an approximately 1.6-fold decrease in CL/F for every 2-fold decrease in CrCL. The most frequent adverse event was dizziness (4 of 15 patients). Other adverse events that were assessed as possibly or probably related to treatment were defecation urgency, extremity pain, feeling of relaxation, and muscle weakness; each occurred in 1 patient only. All events were mild or moderate and resolved without sequelae. CONCLUSIONS: The data suggest that dosage adjustment for gabapentin enacarbil is necessary in patients with impaired renal function. Gabapentin enacarbil, 600 mg, seemed to be well tolerated in this small selected population.

Clinical pharmacokinetic drug interaction studies of gabapentin enacarbil, a novel transported prodrug of gabapentin, with naproxen and cimetidine.

AIM: Gabapentin enacarbil, a transported prodrug of gabapentin, provides sustained, dose-proportional exposure to gabapentin. Unlike gabapentin, the prodrug is absorbed throughout the intestinal tract by high-capacity nutrient transporters, including mono-carboxylate transporter-1 (MCT-1). Once absorbed, gabapentin enacarbil is rapidly hydrolyzed to gabapentin, which is subsequently excreted by renal elimination via organic cation transporters (OCT2). To examine the potential for drug-drug interactions at these two transporters, the pharmacokinetics of gabapentin enacarbil were evaluated in healthy adults after administration alone or in combination with either naproxen (an MCT-1 substrate) or cimetidine (an OCT2 substrate). METHODS: Subjects (n= 12 in each study) received doses of study drug until steady state was achieved; 1200 mg gabapentin enacarbil each day, followed by either naproxen (500 mg twice daily) or cimetidine (400 mg four times daily) followed by the combination. RESULTS: When gabapentin enacarbil was co-administered with naproxen, gabapentin C(ss,max) increased by, on average, 8% and AUC by, on average, 13%. When gabapentin enacarbil was co-administered with cimetidine, gabapentin AUC(ss) increased by 24% and renal clearance of gabapentin decreased. Co-administration with gabapentin enacarbil did not affect naproxen or cimetidine exposure. Gabapentin enacarbil was generally well tolerated. CONCLUSIONS: No gabapentin enacarbil dose adjustment is needed with co-administration of naproxen or cimetidine.