Sarecycline treatment for acne vulgaris: Rationale for weight-based dosing and limited impact of food intake on clinical efficacy.

Tetracycline-class antibiotics are frequently prescribed by dermatologists, commonly for acne vulgaris. Gastrointestinal absorption of first and second-generation tetracycline-class antibiotics, including doxycycline and minocycline, may be reduced by co-administration with food, resulting in potentially lower clinical efficacy. Development of novel compounds and formulations that are not impacted by diet could improve compliance, absorption, and effectiveness among patients. The objective of this study is to investigate weight-based dosing protocols and the impact of food intake, including high-fat meals, on the absorption, and clinical efficacy of sarecycline, a novel oral narrow-spectrum third-generation tetracycline-class antibiotic approved by the Food and Drug Administration for acne vulgaris treatment. Data from 12 clinical studies were analyzed using population pharmacokinetic modeling, exposure-response modeling and pharmacodynamics to evaluate sarecycline dosing recommendations. The extent of exposure is estimated to decrease by 21.7% following co-administration of a sarecycline tablet with a high-fat meal. Based on the PopPK-PD model, this is equivalent to a decrease in efficacy of 0.9 inflammatory lesions, which is not clinically meaningful. Sarecycline can be administered using weight-based dosing with or without food. Co-administration with high-fat food has a limited impact on clinical efficacy. The pharmacokinetics of oral sarecycline may provide added convenience and support ease of use and improved compliance for acne vulgaris patients.

Similar pharmacokinetics of three dosing regimens comprising two oral delayed-release mesalamine formulations in healthy adult volunteers: Randomised, open-label, parallel-group study.

AIMS: Mesalamine is the first-line therapy for treating mild-to-moderate ulcerative colitis. Multiple mesalamine formulations are available, with similar safety and efficacy profiles. Mesalamine is commonly administered as divided dosing, although once-daily dosing may provide benefits for patients. We evaluated the pharmacokinetics of three dosing regimens of two oral delayed-release mesalamine formulations in healthy adult volunteers. METHODS: A randomised, open-label, parallel-group study of mesalamine pharmacokinetics following Lialda 2 × 1.2 g once daily (QD) (dose A), Asacol 6 × 400 mg QD (dose B), or Asacol 2 × 400 mg three times daily (TID) (dose C) over 7 days. Assessments included 5-aminosalicylic acid (5-ASA) and N-acetyl 5-aminosalicylic acid (N-Ac-5-ASA, primary metabolite) pharmacokinetics (Ae (%), AUC0-24 and Cmax ), safety and tolerability. RESULTS: All enrolled volunteers (n = 37) completed the study. Steady state was achieved for all treatments by day 4. Ratios (95% CI) of means for steady-state AUC0-24 (dose A vs B 90.3% [39.8, 204.8], dose A vs C 123.5% [55.3, 275.7], dose B vs C 136.8% [61.3, 305.5]) and Cmax (dose A vs B 106.0% [46.4, 242.2], dose A vs C 133.0% [59.1, 299.0], dose B vs C 125.5% [55.8, 282.1]) were similar for all 5-ASA treatments. Mean urinary excretion of 5-ASA plus N-Ac-5-ASA was comparable between treatments (dose A 21.3%, dose B 20.2%, dose C 17.9%). All treatment regimens were well tolerated; no safety issues were observed. CONCLUSIONS: Plasma and urine pharmacokinetics for Asacol TID, Asacol QD, and Lialda QD are similar, suggesting similar daily systemic exposures can be obtained with either TID or QD dosing. NCT00751699.

A Single Supratherapeutic Dose of Atogepant Does Not Affect Cardiac Repolarization in Healthy Adults: Results From a Randomized, Single-Dose, Phase 1 Crossover Trial.

Atogepant is a selective, oral calcitonin gene-related peptide receptor antagonist in development for preventive treatment of migraine. This randomized, double-blind, phase 1 crossover study evaluated the cardiac repolarization effect of a single supratherapeutic (300 mg) atogepant dose vs placebo in healthy adults. Moxifloxacin 400 mg was the open-label active control. The primary end point was a change from baseline in Fridericia-corrected QT intervals (ΔQTcF). Sixty participants were randomized to atogepant 300 mg, placebo, and moxifloxacin; 59 (98.3%) completed all interventions. Assay sensitivity was confirmed: lower 90% confidence interval limit for QTcF interval change from baseline (ΔΔQTcF) for moxifloxacin was >5 millisecond vs placebo at prespecified 2-, 3-, and 4-hour time points. Following single-dose atogepant 300 mg, mean atogepant ΔΔQTcF and upper 90% confidence interval limits were lower than the 10-millisecond threshold at all time points. Atogepant mean peak plasma concentration was 3197 ng/mL, area under the concentration-time curve from time 0 to time t was 16 640 ng • h/mL, area under the concentration-time curve from time 0 to 24 hours was 16 607 ng • h/mL, and median time to peak plasma concentration was 2.1 hours. The incidence of adverse events was low; no serious adverse events or elevations of liver enzymes were reported. Overall, a single supratherapeutic dose of atogepant was safe and did not impact cardiac repolarization in healthy participants.

Bioavailability and swallowability of an age-appropriate, delayed-release mesalamine formulation in healthy volunteers.

Objective: Delayed-release mesalamine 400 mg capsules containing four 100 mg tablets have been developed for children with ulcerative colitis who have difficulty swallowing. Bioavailability of the mesalamine capsules was compared with existing mesalamine tablets in healthy adults, and the effect of food on bioavailability from mesalamine capsules was determined. Tablet swallowability in healthy children was evaluated. Methods: In the open-label, replicate-treatment, single-dose, crossover, comparative bioavailability study, healthy adult volunteers were randomized to one of four treatment sequences to receive mesalamine 400 mg tablets (fasted) twice, mesalamine 400 mg capsules (fasted) twice, and a mesalamine 400 mg capsule (with food) once, with ≥7 days between treatments. Pharmacokinetic (PK) parameters were calculated and analyzed using the reference-scaled average bioequivalence procedure. In the open-label, single-dose swallowability study, healthy children aged 5-11 years were asked to swallow eight placebo tablets identical to those contained in two mesalamine capsules. Results: In the bioavailability study (n=160), mesalamine capsules and tablets in fasted volunteers exhibited similarly delayed absorption and were shown to be bioequivalent; statistical parameters calculated from PK values met the criteria for bioequivalence. A slight increase in mesalamine bioavailability was observed with food administration, but the delayed-release performance of the capsules was not affected. Overall safety profiles between capsules and tablets were similar. In the swallowability study (n=60), the majority of children swallowed eight placebo tablets, with slight variability between age groups. Conclusion: Evaluation of PK parameters confirmed mesalamine capsules are bioequivalent to mesalamine tablets. Mesalamine capsules were well tolerated, can be administered with or without food, and are an age-appropriate product for children.

Safety and Tolerability of Sarecycline for the Treatment of Acne Vulgaris: Results from a Phase III, Multicenter, Open-Label Study and a Phase I Phototoxicity Study.

Objective: We sought to evaluate the safety, tolerability, and patterns of use for the once-daily oral, narrow-spectrum antibiotic sarecycline in patients with moderate-to-severe acne vulgaris during a 40-week Phase III, multicenter, open-label extension study. Participants: Patients aged nine years or older with moderate-to-severe acne who completed one of two prior Phase III, double-blind, placebo-controlled, 12-week trials in which they received sarecycline 1.5mg/kg/day or placebo were included. Measurements: The primary assessment was the safety of sarecycline 1.5mg/kg/day for 40 weeks as indicated by adverse events (AEs), vital signs, electrocardiograms, clinical laboratory tests, and physical examinations. Patterns of sarecycline use were a secondary assessment. Results: The safety population included 483 patients; 354 patients (73.3%) completed the study. The most common reasons for premature discontinuation were withdrawal by the patient (14.5%), lost to follow-up (7.9%), and AEs (2.5%). The most common treatment-emergent AEs (TEAEs) were nasopharyngitis (3.7%), upper-respiratory-tract infection (3.3%), headache (2.9%), and nausea (2.1%). Clinical laboratory evaluations suggested no clinically meaningful differences between the treatment sequences. Rates of TEAEs commonly associated with other tetracycline antibiotics include dizziness (0.4%) and sunburn (0.2%), and for gastrointestinal TEAEs, nausea (2.1%), vomiting (1.9%), and diarrhea (1.0%). Also reported herein are the results of a Phase I phototoxicity study. Conclusion: Patients aged nine years or older with moderate-to-severe acne vulgaris who received sarecycline once daily for up to 40 weeks showed low rates of TEAEs, with nasopharyngitis, upper-respiratory-tract infection, headache, and nausea being the only TEAEs reported by 2% or more of patients. No clinically meaningful safety findings were noted. ClinicalTrials.gov Registration: NCT02413346.