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Determining the pharmacokinetics (PKs) of drug candidates is essential for understanding their biological fate. The ability to obtain human PK information early in the drug development process can help determine if future development is warranted. Microdosing was developed to assess human PKs, at ultra-low doses, early in the drug development process. Microdosing has also been used in animals to confirm PK linearity across subpharmacological and pharmacological dose ranges. The current study assessed the PKs of a novel antimicrobial preclinical drug candidate (GP-4) in rats as a step toward human microdosing studies. Dose proportionality was determined at 3 proposed therapeutic doses (3, 10, and 30 mg/kg of body weight), and PK linearity between a microdose and a pharmacological dose was assessed in Sprague-Dawley rats. Plasma PKs over the 3 pharmacological doses were proportional. Over the 10-fold dose range, the maximum concentration in plasma and area under the curve (AUC) increased 9.5-and 15.8-fold, respectively. PKs from rats dosed with a 14 C-labeled microdose versus a 14 C-labeled pharmacological dose displayed dose linearity. In the animals receiving a microdose and the therapeutically dosed animals, the AUCs from time zero to infinity were 2.6 ng · h/ml and 1,336 ng · h/ml, respectively, and the terminal half-lives were 5.6 h and 1.4 h, respectively. When the AUC values were normalized to a dose of 1.0 mg/kg, the AUC values were 277.5 ng · h/ml for the microdose and 418.2 ng · h/ml for the pharmacological dose. This 1.5-fold difference in AUC following a 300-fold difference in dose is considered linear across the dose range. On the basis of the results, the PKs from the microdosed animals were considered to be predictive of the PKs from the therapeutically dosed animals.T he development of new drugs is a long and costly process, often taking more than 10 years and over $1 billion to get one drug to market (1). The huge cost of new drugs is a consequence of the high failure rate of potential candidates prior to approval. One of the factors contributing to the high attrition rate during development is poor pharmacokinetics (PKs). Poor PK parameters are responsible for up to 40% of drug candidates failing to make it past the first studies in humans (2, 3). The ability to predict complete biodistribution profiles, which include PKs, tissue distribution, and route of elimination, early in the drug development process would provide critical data for decisions about the continued development of a drug lead. These data are also useful for the optimization of dosage regimes, potentiation of therapeutic efficacy, tailoring of drug delivery systems, and evaluation of safety. Early evaluation of these factors in humans would determine if further development is warranted before the initiation of costlier clinical trials.Microdosing is a technique used to assess a compound's in vivo biological fate through the administration of subpharmacological doses of a 14 C-labeled drug candidate that produce virtually no adver...

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Purpose of reviewThe aim is to describe why this review is timely and relevant. Acetylsalicylic acid exacerbated respiratory disease (AERD) is a clinically significant disease affecting approximately 7% of all asthmatics or around 1,400,000 persons in the United States alone. A large portion of these patients remain undiagnosed. This review summarizes up to date knowledge on the pathophysiology, treatment opinions and provides an expert opinion on how to approach the AERD patient. Recent findingsFindings describe the main themes in the literature covered by the article. Review of the current knowledge in terms of the key cells, cytokines/chemokines contributing to the acquired disease state of AERD. It also provides clinical approach toward the AERD patient with regards to current treatment options.