Can a monthly exenatide extended release regimen provide a therapeutic and cost benefit?

Exenatide is used to treat type 2 diabetes mellitus. The current regimen is a 2 mg extended release (ER) weekly injection. The aim of our study was to prove the efficacy of exenatide ER if administered once-monthly. The proposed monthly dose was based on an Excel simulation using pharmacokinetic parameters extracted using Plot Digitizer® (version 2.6.8) from Cirincione et al. (2017), as well as accounting for the exenatide ER formulation characteristics, in vivo and in vitro exenatide stability. A PBPK model of exenatide molecule was developed using (Simcyp® version 19) based on data from in vitro and clinical PK studies. The model was used to confirm the Excel simulation findings of the effectiveness of exenatide ER monthly in maintaining the plasma level above the minimum effective concentration (MEC). Our simulation from Excel and Simcyp® showed that the drug plasma levels of the once monthly ER dose maintained a steady state concentration (Css ) above the MEC. The simulated Excel plasma level ranged from Cmin to Cmax of 60-130ng/L, respectively. The exenatide compound was successfully modeled and used to predict the Css of the ER monthly dose. The Simcyp® simulated Css of the ER was 117 ng/L. A monthly exenatide ER dose provides a plasma level within the therapeutic range. This new proposed dose has a significant pharmacoeconomic benefit and could well improve patient adherence.

Emerging therapies for the treatment of ungual onychomycosis.

INTRODUCTION: Onychomycosis, a common fungal infection in the finger and toe nails, affects approximately 2-8% of the worldwide population. Fungal infection is more complicated in those who suffer from conditions, such as diabetes, peripheral vascular diseases and compromised immune diseases. AREA COVERED: Onychomycosis treatment has been classified on the basis of location of infection in the toes and fingers and infectious agents (dermatophytes fungi, yeast and non-dermatophyte molds). In this review, the available therapies (traditional and device based) and their limitations for the treatment of onychomycosis have been discussed. EXPERT OPINION: The success rate with topical nail products has been minimal. The main reason for this poor success rate could be attributed to the lack of complete understanding of the pathophysiology of the disease and clinical pharmacokinetic data of drugs in the infected nail apparatus.

Emerging topical onychomycosis therapies - quo vadis?

INTRODUCTION: Onychomycosis, a common chronic fungal infection affecting fingernails and toenails, globally may affect 10 - 30% of the population. This chronic disease is difficult to eradicate. The goal of developing a highly effective and safe topical treatment has not yet been reached as it depends on the type of onychomycosis and the variety of invaders. AREAS COVERED: Topical drug delivery to the nail is highly desirable in treating nail disorders. However, efficacy of topical therapies is low due to their limited permeability across the nail plate. Advances have especially been made by the development of new therapeutic options including new drug entities, new formulations and reformulations. This overview updates emerging topical treatments for onychomycosis, research progress and future perspectives. EXPERT OPINION: Development of novel effective noninvasive topical therapy for treating onychomycosis and other nail diseases such as psoriasis is long overdue. Previously there was a lack of basic knowledge about nail and its barrier properties, but with the recent increased interest in this field both from industry and academia, we hope extensive research will continue in this field to bring about successful and safe treatments for such chronic diseases.

Ability to estimate relative percutaneous penetration via a surrogate maker - trans epidermal water loss?

AIMS: This study measures the dynamic change of the trans-epidermal water loss (TEWL) rate and in vitro skin permeation data of tritiated water and [(14) C]-clonidine HCl in order to refine our knowledge in the relationship between percutaneous penetration and TEWL. MEASURES: TEWL values were measured before and during the experimental period. Single application of tritiated water and [(14) C]-clonidine HCl were dosed at the same time on dermatomed human skin samples collected from 12 donors in a flow through diffusion cell system. Radioactivity of absorbed dose: stratum corneum, epidermis, dermis, receptor fluid collected every 4 hours, as well as removable dose residue was counted to determine accountability, percent dose, µg equivalent, and flux rate. These data were further combined with TEWL values to analyze their possible relationship. RESULTS: Results showed that baseline TEWL values correlated with the thickness of dermatomed skin (r=-0.44, P=0.007), and with tritiated water fluxes (r=0.34, P=0.04) and [(14) C]-clonidine HCl (r=0.36; P=0.03). The fluxes of tritiated water and [(14) C]-clonidine HCl were correlated (r=0.67, P<0.001). When TEWL and permeation data were compared, the pattern of tritiated water expressed as a percent dose permeated in receptor fluid resembled the TEWL pattern. CONCLUSION: The methodology described provides evidences of the correlation of TEWL and skin integrity and skin permeation and further demonstrates to be a rapid alternative to tritiated water permeation for measuring skin barrier functions in vitro. To develop TEWL measurement as a possible predictive model to assess in vitro percutaneous absorption, however more chemicals with various physical-chemical properties need to be examined, and the relationships to TEWL and tritiated water flux better defined.

Correlation of transepidermal water loss with skin barrier properties in vitro: comparison of three evaporimeters.

AIM: This study investigates the relationship between transepidermal water loss (TEWL) and skin permeability to tritiated water as a rapid assessment of the integrity of the barrier properties of skin as part of in vitro skin permeation studies. METHODS: TEWL values before and during the experimental period were measured using three evaporimeters (A, B, and C) representing different measuring principles and technologies. Single application of tritiated water was dosed on dermatomed human skin samples in a flow-through diffusion cell system. Radioactivity of the absorbed dose and the removable dose residues was counted to determine percent dose and flux rate. These data were further combined with TEWL values to analyze the correlation. RESULTS: Evaporimeter C, a closed chamber-condenser technology, had higher measurement capacity than other instruments, evaporimeter A, an open chamber, and evaporimeter B, a closed chamber (P<0.001). The baseline TEWL value correlated with tritiated water flux (r=0.34, P=0.04). The pattern of tritiated water expressed as percent dose permeated into receptor fluid was similar to that of TEWL values. CONCLUSION: These data indicate that TEWL can be ascribed to be a measure of skin water barrier function. Further work should be conducted to interpret the significance of measuring TEWL by evaporimetry.

Transungual drug delivery: current status.

Topical therapy is highly desirable in treating nail disorders due to its localized effects, which results in minimal adverse systemic events and possibly improved adherence. However, the effectiveness of topical therapies is limited by minimal drug permeability through the nail plate. Current research on nail permeation that focuses on altering the nail plate barrier by means of chemical treatments, penetration enhancers as well as physical and mechanical methods is reviewed. A new method of nail sampling is examined. Finally limitations of current ungual drug permeability studies are briefly discussed.