Selection of Nemolizumab Clinical Dosage for Atopic Dermatitis.

Nemolizumab is a monoclonal antibody directed against the interleukin-31 receptor A subunit, which is involved in the pathogenesis of pruritus and inflammation in atopic dermatitis (AD). Clinical trial results were combined with population PK (popPK) and pharmacokinetic/ pharmacodynamic (PK/PD) models to optimize nemolizumab dosing. Phase 1 and 2a clinical studies indicated that weight-based nemolizumab dosing reduced pruritus in patients with moderate-to-severe AD with good safety and tolerability even at the highest dose (3 mg/kg single dose and 2 mg/kg multiple doses). Nemolizumab PK profile was characterized by a slow absorption with peak serum concentrations reached 4.5-9.2 days post-dose, and a long terminal half-life ranging from 12.6 to 16.5 days. A change from weight-based dosing to flat dose was supported by an additional phase 2b study sponsored by Galderma. Flat dosing provides several practical advantages, including ease of preparation for self- or auto-injection and reduced chance of dosing errors. Doses of 10, 30, and 90 mg were selected based on popPK and PK/PD simulations to result in nemolizumab serum concentrations sufficient to achieve efficacy. Loading doses were administrated at the 2 lower doses in order to achieve target systemic concentrations from the first injection. The efficacy of Nemolizumab in improving cutaneous signs of inflammation and pruritus in AD and its safety profile, combined with popPK and PK/PD analyses, supported selection of the flat-dose regimen of 30 mg (with a 60 mg loading dose) given every 4 weeks subcutaneously for 16 weeks in the phase 3 ARCADIA studies sponsored by Galderma. J Drugs Dermatol. 2023;22(10):1017-1020 doi:10.36849/JDD.7437R1.

Safe Use of Adapalene 0.1 % Gel in a non-Prescription Environment.

BACKGROUND: Topical retinoids are the mainstay of acne therapy and, until 2016, were only available by prescription. The margin of safety (MOS) of adapalene for potential teratogenic effects, and its use in pregnancy were investigated as part of the OTC switch. OBJECTIVE: To determine MOS using a maximal usage trial (MUsT) and animal embryo-fetal development studies. To conduct a thorough review of safety data with respect to use of Adapalene 0.1% Gel during pregnancy. METHODS: The MUsT was multicenter, open-label pharmacokinetic study which enrolled adolescents and adult subjects with mainly severe acne vulgaris. The no observable adverse event level (NOAEL) for adapalene teratogenicity was established in rat and rabbit embryo-fetal development studies. An exhaustive review of pregnancy data from multiple safety databases was conducted. RESULTS: The calculated MOS for teratogenicity was 70 for Adapalene 0.1% Gel. For the pregnancy safety review, no pregnancy malformations were attributable to topical adapalene use. LIMITATIONS: Animal studies do not always predict effects in human development. Additionally, safety data is voluntarily reported and intrinsically incomplete. CONCLUSION: Adapalene has a large and reassuring MOS making it suitable for OTC use. No teratogenic risk was identified in a MUsT and Pregnancy Safety Review. Adapalene 0.1% Gel is a safe and effective medication for the treatment of acne in a non-prescription environment. Based on available evidence, use of adapalene during pregnancy does not pose harm to the fetus. J Drugs Dermatol. 2021;20(12):1330-1335. doi:10.36849/JDD.6527.

Kinetics of Clobetasol-17-Propionate in Psoriatic Lesional and Non-Lesional Skin Assessed by Dermal Open Flow Microperfusion with Time and Space Resolution.

PURPOSE: To evaluate the kinetics of topically applied clobetasol-17-propionate (CP-17) in lesional and non-lesional psoriatic skin when released from a commercially available low-strength cream using in vivo dermal open-flow microperfusion (dOFM). METHODS: Twelve patients received Dermovate® cream (CP-17, 0.05%) on small lesional and non-lesional skin test sites for 14 days, once daily. On day 1 and 14, dOFM samples were continuously taken in the dermis for 24 h post-dose and analyzed by LC-MS/MS. Probe depths were assessed by 50 MHz ultrasound scanning. RESULTS: Mixed-effects modelling identified skin condition, treatment duration and probe-depth as kinetics determining variables. The time- and depth-resolved intradermal data revealed (i) slower penetration of CP-17 into lesional than into non-lesional skin, (ii) normalized (faster) skin penetration after repeated dosing, and (iii) no CP-17 accumulation within the dermis independently of the skin condition. CONCLUSIONS: Intradermal investigation of a highly lipophilic drug released from low-strength cream was successfully performed by using dOFM and timely and spatially, i.e., probe-depth dependent, resolved kinetic data were delivered. These data support the assumption that the thickened psoriatic stratum corneum might act as trap compartment which lowers the skin penetration rate for lipophilic topical drugs.

Current challenges in bioequivalence, quality, and novel assessment technologies for topical products.

This paper summarises the proceedings of a recent workshop which brought together pharmaceutical scientists and dermatologists from academia, industry and regulatory agencies to discuss current regulatory issues and industry practices for establishing therapeutic bioequivalence (BE) of dermatologic topical products. The methods currently available for assessment of BE were reviewed as well as alternatives and the advantages and disadvantages of each method were considered. Guidance on quality and performance of topical products was reviewed and a framework to categorise existing and alternative methods for evaluation of BE was discussed. The outcome of the workshop emphasized both a need for greater attention to quality, possibly, via a Quality-By-Design (QBD) approach and a need to develop a "whole toolkit" approach towards the problem of determination of rate and extent in the assessment of topical bioavailability. The discussion on the BE and clinical equivalence of topical products revealed considerable concerns about the variability present in the current methodologies utilized by the industry and regulatory agencies. It was proposed that academicians, researchers, the pharmaceutical industry and regulators work together to evaluate and validate alternative methods that are based on both the underlying science and are adapted to the drug product itself instead of single "universal" method.

Validation of PqsD as an anti-biofilm target in Pseudomonas aeruginosa by development of small-molecule inhibitors.

2-Heptyl-4-hydroxyquinoline (HHQ) and Pseudomonas quinolone signal (PQS) are involved in the regulation of virulence factor production and biofilm formation in Pseudomonas aeruginosa. PqsD is a key enzyme in the biosynthesis of these signal molecules. Using a ligand-based approach, we have identified the first class of PqsD inhibitors. Simplification and rigidization led to fragments with high ligand efficiencies. These small molecules repress HHQ and PQS production and biofilm formation in P. aeruginosa. This validates PqsD as a target for the development of anti-infectives.

Clinical Pharmacology and Safety of Trifarotene, a First-in-Class RARγ-Selective Topical Retinoid.

Trifarotene is a new drug with retinoic acid receptor activity and selectivity for retinoic acid receptor-γ. The reported studies aimed at assessing the clinical pharmacology and safety of trifarotene. The clinical pharmacology of topical trifarotene up to 100 µg/g was extensively investigated through 2 maximal usage pharmacokinetic trials (MUsT) conducted in adult (≥18 years) and pediatric patients (9-17 years) with moderate to severe acne and two studies conducted in healthy volunteers: 1 thorough QTC study and 1 drug-drug interaction study with concomitantly administered oral levonorgestrel (0.15 mg)/ethinyl estradiol (0.03 mg). Safety assessments included adverse event reporting and assessment of erythema, scaling, dryness, and stinging/burning using a scale from 0 = none to 4 = severe, as well as the evaluation of the systemic safety of trifarotene through routine laboratory testing. Systemic absorption of trifarotene was generally unquantifiable in the target population, especially when applied at 50 µg/g. QTC investigations did not show any risk of cardiovascular health issues; trifarotene did not reduce the systemic exposure to oral contraceptives such as levonorgestrel/ethinyl estradiol. Safety analyses did not show local or systemic safety concerns with trifarotene up 100 µg/g, a dose twice as high as the intended market dose. Results showed that trifarotene 50 µg/g cream is well tolerated and safe, even when applied under maximized conditions in adults and pediatric acne patients presenting with severe acne. Daily use of trifarotene 50 µg/g cream was not associated with cardiovascular effects and did not result in drug-drug interaction in women of childbearing potential using oral contraception.

Fixed-Combination Gels of Adapalene and Benzoyl Peroxide Provide Optimal Percutaneous Absorption Compared to Monad Formulations of These Compounds: Results from Two In Vitro Studies.

INTRODUCTION: Adapalene 0.1%/benzoyl peroxide 2.5% (0.1% A/BPO) and adapalene 0.3%/BPO 2.5% (0.3% A/BPO) gels are fixed-combination options for the topical treatment of acne. However, the active compounds of these combinations are also available as monads, to be used in association or as monotherapy. These two in vitro studies determined the effect of different treatment regimens on the percutaneous absorption of adapalene (0.1% and 0.3%) gels and BPO 2.5% gel in ex vivo human skin. METHODS: In vitro percutaneous absorption studies were conducted using full-thickness human skin from six donors. Treatment regimens included the application of 0.1% A/BPO, 0.3% A/BPO, or four free-combination regimens of the monads. Skin samples were incubated for 24 h. Concentrations of adapalene and BPO equivalent (BPO-eq) (i.e. benzoic acid after chemical transformation of BPO) were measured using high-performance liquid chromatography. Comparison of regimens was performed using a bioequivalence criterion (estimated ratio bewteen 0.8 and 1.25). RESULTS: The fixed combination 0.3% A/BPO regimen demonstrated more than three times higher absorption of adapalene versus the fixed-combination 0.1% A/BPO. Based on the bioequivalence acceptance criterion, all four free-combination regimens were different from 0.1% A/BPO and 0.3% A/BPO, with higher adapalene release delivered by the fixed combinations versus the free combinations. For BPO-eq, the results showed that the free-combination regimens where adapalene 0.1% was applied first were different from 0.1% A/BPO, with lower BPO-eq release delivered by these regimens compared to the fixed combination. The regimen adapalene 0.3% for 10 h followed by BPO 2.5% delivered lower BPO-eq release compared to the fixed combination. CONCLUSION: The fixed-combination A/BPO gels provide optimal percutaneous absorption of the active compounds compared to free combinations of adapalene 0.1%, adapalene 0.3%, and BPO 2.5%. The higher concentration of adapalene in the 0.3% A/BPO gel and the resulting higher absorption may explain higher clinical efficacy.

Human galectin-8 isoforms and cancer.

Galectins are animal lectins that can specifically bind beta-galactosides. Thirteen galectins have already been described. This review focuses on a specific member of this family: galectin-8. This galectin was discovered in prostate cancer cells eight years ago and has been studied extensively in the last few years. The galectin-8 gene ( LGALS8) encodes numerous mRNAs by alternate splicing and the presence of three unusual polyadenylation signals. These mRNAs encode six different isoforms of galectin-8: three belong to the tandem-repeat galectin group (with two CRDs linked by a hinge peptide) and three to the prototype group (with one CRD). Various studies showed that galectin-8 is widely expressed in tumor tissues as well as in normal tissues. The level of galectin-8 expression may correlate with the malignancy of human colon cancers and the degree of differentiation of lung squamous cell carcinomas and neuro-endocrine tumors. Recently, the differences in galectin-8 expression levels between normal and tumor tissues have been used as a guide for the selection of strategies for the prevention and treatment of lung squamous cell carcinoma. These experiments are still under investigation, but demonstrate the potential of galectin-8 research to enhance our understanding of, and possibly prevent, the process of neoplastic transformation.