RESUMEN
Whereas treatment of allergic diseases such as asthma relies largely on the targeting of dysregulated effector pathways, the conceptually attractive alternative of preventing them by a pharmaceutical, at-source intervention has been stymied until now by uncertainties about suitable targets and the challenges facing drug design. House dust mites (HDMs) are globally significant triggers of allergy. Group 1 HDM allergens, exemplified by Der p 1, are cysteine proteases. Their degradome has a strong disease linkage that underlies their status as risk and initiator allergens acting directly and through bystander effects on other allergens. Our objective was to test whether target-selective inhibitors of group 1 HDM allergens might provide a viable route to novel therapies. Using structure-directed design to optimize a series of pyruvamides, we undertook the first examination of whether pharmaceutically developable inhibitors of group 1 allergens might offer protection against HDM exposure. Developability criteria included durable inhibition of clinically relevant signals after a single aerosolized dose of the drug. The compounds suppressed acute airway responses of rats and mice when challenged with an HDM extract representing the HDM allergome. Inhibitory effects operated through a miscellany of downstream pathways involving, among others, IL-33, thymic stromal lymphopoietin, chemokines, and dendritic cells. IL-13 and eosinophil recruitment, indices of Th2 pathway activation, were strongly attenuated. The surprisingly expansive benefits arising from a unique at-source intervention suggest a novel approach to multiple allergic diseases in which HDMs play prominent roles and encourage exploration of these pharmaceutically developable molecules in a clinical setting.
RESUMEN
Determining a drug dosing regimen that produces consistent bioavailability and patient effects is one of the goals of the drug development process. Food consumption is one factor that can significantly alter the bioavailability of some drugs. This manuscript describes a research approach to determine what recommendations to give patients regarding taking oral ziprasidone in relation to food consumption. Four pharmacokinetic studies, the first three in volunteers and the fourth in patients at steady-state on the maximum recommended daily dose of ziprasidone, investigated the relationship between food intake and ziprasidone absorption. These studies illustrate how sequential studies are used in drug development to investigate increasingly precise questions using data from one study to refine the question being addressed by the next. In the first study, the absorption of ziprasidone was shown to double when taken following a high-calorie, high-fat meal versus the fasting state. The second study showed that the difference in absorption between the fasting and fed states increased with dose. The third study suggested that calorie rather than fat content was the critical variable. This finding was confirmed in the fourth study over a wider variety of meals and under clinically relevant dosing conditions. That study also found reduced pharmacokinetic variability (i.e., more consistent absorption) when ziprasidone was administered with 500-1000 kcal meals without regard to fat content rather than under fasting or low-calorie meal conditions. These results have several clinically important implications. First, the effect of taking ziprasidone in a fasting state cannot be overcome simply by increasing the dose. Second, significant swings in ziprasidone concentration and hence efficacy and tolerability may occur on a day-to-day basis if diet is not controlled. Third, patients should be advised to take ziprasidone with a meal containing at least 500 calories (without regard to fat content) to ensure adequate ziprasidone bioavailability and thus achieve optimal efficacy. These four studies illustrate the sequential and incremental nature of drug development research and what is meant by the concept of bioequivalence.