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SummaryBackground ASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T helper (Th)1, Th2 and Th17/Th22 pathways.ObjectivesThe objectives of this study were to evaluate the efficacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate‐to‐severe AD. Methods A total of 36 patients with moderate‐to‐severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28‑day period (20 mg, 40 mg and 80 mg once daily).Results ASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50 (20 mg 20%, P = 0·93; 40 mg 100%, P = 0·003; 80 mg 83%, P = 0·03; placebo 22%), EASI 75 (20 mg 0%, P = 0·27; 40 mg 71%, P = 0·06; 80 mg 33%, P = 0·65; placebo 22%) and in change from baseline in pruritus (20 mg −1·3 ± 2·1, P = 0·81; 40 mg −3·1 ± 2·7, P = 0·27; 80 mg −4·7 ± 2·1, P = 0·01; placebo −1·6 ± 1·8). Adverse events were generally mild and similar across all groups. ASN002 showed dose‐dependent plasma exposure with low interpatient variability, significantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis‐associated biomarker E selectin/SELE.ConclusionsIn patients with moderate‐to‐severe AD, ASN002 showed strong efficacy with rapid onset of action and associated improvements in systemic inflammation.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Hydrogen sulphide (H2S) is a biological mediator and a potential therapeutic agent. In animal studies, the metabolism and pharmacokinetics of H2S have been characterized. WHAT THIS STUDY ADDS• This study is first to demonstrate the pharmacokinetics of an intravenously administered H2S formulation in humans, and to characterize the exhaled H2S response in humans. INTRODUCTIONHydrogen sulphide (H2S) is an endogenous gaseous signaling molecule and potential therapeutic agent. Emerging studies indicate its therapeutic potential in a variety of cardiovascular diseases and in critical illness. Augmentation of endogenous sulphide concentrations by intravenous administration of sodium sulphide can be used for the delivery of H2S to the tissues. In the current study, we have measured H2S concentrations in the exhaled breath of healthy human volunteers subjected to increasing doses sodium sulphide in a human phase I safety and tolerability study. METHODSWe have measured reactive sulphide in the blood via ex vivo derivatization of sulphide with monobromobimane to form sulphide-dibimane and blood concentrations of thiosulfate (major oxidative metabolite of sulphide) via ion chromatography. We have measured exhaled H2S concentrations using a custom-made device based on a sulphide gas detector (Interscan). RESULTSAdministration of IK-1001, a parenteral formulation of Na2S (0.005-0.20 mg kg -1 , i.v., infused over 1 min) induced an elevation of blood sulphide and thiosulfate concentrations over baseline, which was observed within the first 1-5 min following administration of IK-1001 at 0.10 mg kg -1 dose and higher. In all subjects, basal exhaled H2S was observed to be higher than the ambient concentration of H2S gas in room air, indicative of on-going endogenous H2S production in human subjects. Upon intravenous administration of Na2S, a rapid elevation of exhaled H2S concentrations was observed. The amount of exhaled H2S rapidly decreased after discontinuation of the infusion of Na2S. CONCLUSIONExhaled H2S represents a detectable route of elimination after parenteral administration of Na2S.

Intestinal transcellular permeability (P m ), measured across cell lines such as Caco-2 cells in vitro, is often used for assessing oral drug absorption potential in humans. However, the quantitative link between in vitro permeability and apparent in vivo absorption kinetics, based on drug appearance in plasma, is poorly understood. In the current study, a novel absorptiondisposition kinetic model that links traditional pharmacokinetic and mass transfer models was developed. Analytical solutions of k a and F a were deduced, and using Caco-2 permeability, F a in humans was predicted for 51 structurally diverse compounds. Predicted F a values were similar to and correlated highly with their corresponding experimental values with an average error of 1.88 Ϯ 1.06% (Ϫ17 to 22%) and r 2 ϭ 0.934. Simulated concentration profiles for 17 of 18 drugs corresponded to observed plasma concentration profiles in healthy volunteers. The equilibrium solution for k a (k a,eq ) was found to be a key determinant of F a , whereas under sink conditions, k a is likely to be a determinant of plasma concentration kinetics. The current version of the model offers a quantitative approach for predicting human oral absorption kinetics from in vitro permeability. It also establishes, for the first time, a quantitative link between P m and k a and between k a,eq and F a . This will facilitate better in vitro or in situ-in vivo correlations since it establishes a basis for incorporating permeability coefficients from the various experimental formats based on drug loss or appearance that are commonly used in the laboratory for permeability determination.Oral administration is the most commonly used drug-dosing route. Therefore, the ability to predict the rate and extent of absorption of drug candidates after oral administration is crucial during the preclinical phase of development. Such knowledge complements high throughput drug screening and allows scientists to select the best drug candidates early in the drug development cycle. Drug absorption from the gastrointestinal (GI) tract is affected by many factors. Besides the physiological conditions of the GI tract (e.g., absorptive surface area, local pH, food effects, intestinal transit time, and passive intestinal permeability) and chemical properties of the drug (e.g., solubility, molecular size, and stability), intestinal transporters and enzymes are being increasingly implicated in controlling oral drug absorption (Martinez and Amidon, 2002). Because of this, the challenging task of quantitatively predicting oral drug absorption properties has attracted the attention of many scientists. So far, most predictive models have been developed based on intestinal transport mechanisms and physiological parameters or statistical/probabilistic analysis. Typically, the statistical models have been built using regression results from a training set (e.g., Zhao et al., 2001), and correlation results are then used to predict F a for compounds outside of this training set. These models rely heavil...

ABSTRACT:The objective of this investigation was to differentiate the roles of P-glycoprotein (Pgp), multidrug resistance-associated protein 2 (Mrp2), and CYP3A on saquinavir ( -(((3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl) ((3-(dimethylamino-3-oxopropyl)thio)methyl)-thio) propanoic acid (MK571)], and/or CYP3A (midazolam). Plasma concentrations of SQV and related metabolites were analyzed by liquid chromatography-tandem mass spectrometry. When given alone, SQV absorption was extremely low both in situ (F a ‫؍‬ 0.07%) and in vivo [C max ‫؍‬ 0.068 g/ml; area under the curve (AUC) ‫؍‬ 6.8 g ⅐ min/ml]. Coadministration of GF120918 boosted SQV absorption by more than 20-fold with decreased variation in AUCs (percent coefficient of variation ‫؍‬ 30% versus 100%). In contrast, coadministration of MK571 or midazolam increased SQV absorption only 2-to 3-fold without improving the variation in AUCs. SQV oral absorption was not further improved when it was given with GF120918 and midazolam or with GF120918 and MK571. The current results provide, for the first time, direct and explicit evidence that the low oral absorption of SQV is controlled by a secretory transporter, Pgp, and not by limited passive diffusion owing to its poor physicochemical properties. Pgp-mediated transport is also responsible for the highly variable oral bioavailability of SQV. In contrast, intestinal Mrp2 and intestinal CYP3A appear to play minor roles in SQV oral bioavailability. Given the differential and complex roles of Pgp and CYP3A in SQV oral absorption, the optimization of AIDS boosting regimens requires careful consideration to avoid therapylimiting drug-drug transporter and enzyme interactions.