Reactive Oxygen Species-Responsive Polymer Nanoparticles to Improve the Treatment of Inflammatory Skin Diseases.

To improve the quality of life for people living with chronic inflammatory skin diseases, we propose a new treatment strategy by exploring a stimuli-responsive drug delivery system. Formulations designed by exploiting smart materials can be programmed to perform a specific action upon exposure to disease-related stimuli. For instance, increased levels of reactive oxygen species (ROS), especially the accumulation of hydrogen peroxide, can be utilized to differentiate between healthy and inflamed tissues. In this concept-proofing study, the polymer poly(1,4 phenyleneacetone dimethylene thioketal) (PPADT) was investigated for its ROS-responsive properties and potential to treat inflammatory skin diseases. PPADT nanoparticles were formulated by oil-in-water emulsification followed by solvent evaporation and characterized by size, zeta-potential, and release kinetic profiles. Release profiles revealed that the PPADT nanoparticles were sensitive toward elevated levels of ROS in an ROS-stimulus concentration (0.1-10 mM) and time-dependent manner (flare-up mimicked). The safety assessment proved that the PPADT polymer and the monomers generated by oxidation do not show any sign of being cytotoxic to fibroblasts and no mutagenic liabilities were observed. In conclusion, the PPADT polymer demonstrated to be a promising material for stimuli-responsive delivery of hydrophobic small molecules in the treatment of inflammatory skin diseases.

Fragment-Based Discovery of 6-Arylindazole JAK Inhibitors.

Janus kinase (JAK) inhibitors are emerging as novel and efficacious drugs for treating psoriasis and other inflammatory skin disorders, but their full potential is hampered by systemic side effects. To overcome this limitation, we set out to discover soft drug JAK inhibitors for topical use. A fragment screen yielded an indazole hit that was elaborated into a potent JAK inhibitor using structure-based design. Growing the fragment by installing a phenol moiety in the 6-position afforded a greatly improved potency. Fine-tuning the substituents on the phenol and sulfonamide moieties afforded a set of compounds with lead-like properties, but they were found to be phototoxic and unstable in the presence of light.

PKPD model of interleukin-21 effects on thermoregulation in monkeys--application and evaluation of stochastic differential equations.

PURPOSE: To describe the pharmacodynamic effects of recombinant human interleukin-21 (IL-21) on core body temperature in cynomolgus monkeys using basic mechanisms of heat regulation. A major effort was devoted to compare the use of ordinary differential equations (ODEs) with stochastic differential equations (SDEs) in pharmacokinetic pharmacodynamic (PKPD) modelling. METHODS: A temperature model was formulated including circadian rhythm, metabolism, heat loss, and a thermoregulatory set-point. This model was formulated as a mixed-effects model based on SDEs using NONMEM. RESULTS: The effects of IL-21 were on the set-point and the circadian rhythm of metabolism. The model was able to describe a complex set of IL-21 induced phenomena, including 1) disappearance of the circadian rhythm, 2) no effect after first dose, and 3) high variability after second dose. SDEs provided a more realistic description with improved simulation properties, and further changed the model into one that could not be falsified by the autocorrelation function. CONCLUSIONS: The IL-21 induced effects on thermoregulation in cynomolgus monkeys are explained by a biologically plausible model. The quality of the model was improved by the use of SDEs.

Non-linear mixed effects modeling of sparse concentration data from rats: application to a glycogen phosphorylase inhibitor.

We investigated the use of non-linear mixed effects modeling in two preclinical studies of the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB). In a 28-day repeated-dose toxicity study rats were dosed once daily p.o. with 0, 20, 45, 100, or 470 mg/kg of DAB in aqueous solutions by oral gavage. Three blood samples were obtained from each animal using a staggered sampling scheme. During the cause of model development, data were included from a safety pharmacological cardiovascular study, in which rats were dosed once orally with 0, 4, 40, or 400 mg/kg of DAB thereby enabling an extension of the dose range of the model. DAB was assayed in plasma using a validated LC/MS/MS method. Non-linear mixed effects modeling was performed using the software NONMEM. The covariate analysis comprised dose, sex and time. Exposure results (Cmax, AUC) obtained by mixed effects modeling were compared to results from noncompartmental analysis using naïve pooling of data. The final model was a one-compartment model with first order absorption and a saturation-like dose dependent increase of the (oral) clearance (CL/f) and volume of distribution (V/f). Furthermore, V/f increased (by 55%) from Day 1 to Day 28. The dose dependencies of CL/f and V/f were most likely due to dose dependent decreases of the fraction systemically absorbed (f). The mechanism behind the dose dependencies may be saturation of a (putative) carrier mediated transport or modulation of tight junctions causing a reduced paracellular transport across the intestinal epithelium. Exposure results obtained from the model compared well with results obtained using noncompartmental analysis. An analysis of the data requirements for non-linear mixed effects modeling showed that at least three concentration values per animal were required for model development. We conclude that non-linear mixed effects modeling is feasible even with dose dependent pharmacokinetics in preclinical studies, such as 28-day toxicity studies in rodents. Supplementing data from additional preclinical studies may be required in order to extend the dose range. Non-linear mixed effects models may prove to be valuable tools in early PK and PK-PD modeling during drug development.