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Nakamaru Y.,Mitsubishi Group | Hayashi Y.,Mitsubishi Group | Ikegawa R.,Mitsubishi Group | Kinoshita S.,Mitsubishi Group | And 8 more authors.
Xenobiotica | Year: 2014

1. The absorption, metabolism and excretion of teneligliptin were investigated in healthy male subjects after a single oral dose of 20mg [ 14C]teneligliptin. 2. Total plasma radioactivity reached the peak concentration at 1.33h after administration and thereafter disappeared in a biphasic manner. By 216h after administration, 90% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 45.4% and 46.5%, respectively. 3. The most abundant metabolite in plasma was a thiazolidine-1-oxide derivative (designated as M1), which accounted for 14.7% of the plasma AUC (area under the plasma concentration versus time curve) of the total radioactivity. The major components excreted in urine were teneligliptin and M1, accounting for 14.8% and 17.7% of the dose, respectively, by 120h, whereas in faeces, teneligliptin was the major component (26.1% of the dose), followed by M1 (4.0%). 4. CYP3A4 and FMO3 are the major enzymes responsible for the metabolism of teneligliptin in humans. 5. This study indicates the involvement of renal excretion and multiple metabolic pathways in the elimination of teneligliptin from the human body. Teneligliptin is unlikely to cause conspicuous drug interactions or changes in its pharmacokinetics patients with renal or hepatic impairment, due to a balance in the elimination pathways. © 2014 Informa UK Ltd.


Spinelli T.,Helsinn Healthcare SA | Calcagnile S.,Helsinn Healthcare SA | Giuliano C.,Helsinn Healthcare SA | Rossi G.,Helsinn Healthcare SA | And 4 more authors.
Journal of Clinical Pharmacology | Year: 2014

Netupitant is a new, selective NK1 receptor antagonist under development for the prevention of chemotherapy-induced nausea and vomiting. Two studies were conducted to evaluate the brain receptor occupancy (RO) and disposition (ADME) of netupitant in humans. Positron emission tomography (PET) imaging with the NK1 receptor-binding-selective tracer [ 11C]-GR205171 was used to evaluate the brain penetration of different doses of netupitant (100, 300, and 450 mg) and to determine the NK1-RO duration. ANK1-RO of 90% or higher was achieved with all doses in the majority of the tested brain regions at Cmax, with a long duration of RO. The netupitant minimal plasma concentration predicted to achieve a NK1-RO of 90%, C90%, in the striatum was 225 ng/mL; after administration of netupitant 300 mg, concentrations exceeded the C90%. In the ADME study, a single nominal dose of [14C]-netupitant 300 mg was used to assess its disposition. Absorption was rapid and netupitant was extensively metabolized via Phase I and II hepatic metabolism. Elimination of >90% was predicted at day 29 and was principally via hepatic/biliary route (>85%) with a minor contribution of the renal route (<5%). In conclusion, these studies demonstrate that netupitant is a potent agent targeting NK1 receptors with long lasting RO. In addition, netupitant is extensively metabolized and is mainly eliminated through the hepatic/biliary route and to a lesser extent via the kidneys. © 2013 The Authors.


Benito-Gallo P.,University of Nottingham | Franceschetto A.,University of Nottingham | Franceschetto A.,University of Padua | Wong J.C.M.,University of Nottingham | And 4 more authors.
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2015

Triglycerides (TG) are one of the most common excipients used in oral lipid-based formulations. The chain length of the TG plays an important role in the oral bioavailability of the co-administered drug. Fatty acid (FA) chain-length specificity of porcine pancreatic lipase was studied by means of an in vitro lipolysis model under bio-relevant conditions at pH 6.80. In order to determine the total extent of lipolysis, back-titration experiments at pH 11.50 were performed. Results suggest that there is a specific chain length range (C2-C8) for which pancreatic lipase shows higher activity. This specificity could result from a combination of physicochemical properties of TGs, 2-monoglycerides (2-MGs) and FAs, namely the droplet size of the TGs, the solubility of 2-MGs within mixed micelles, and the relative stability of the FAs as leaving groups in the hydrolysis reaction. During experimentation, it was evident that an optimisation of lipolysis conditions was needed for tighter control over pH levels so as to better mimic in vivo conditions. 1 M NaOH, 3.5 mL/min maximum dosing rate, and 3 μL/min minimum dosing rate were the optimised set of conditions that allowed better pH control, as well as the differentiation of the lipolysis of different lipid loads. © 2015 Elsevier B.V. All rights reserved.


Emanuel I.A.,San Francisco State University | Blaiss M.S.,Allergy and Asthma Care | Meltzer E.O.,Allergy and Asthma Medical Group and Research Center | Evans P.,Quotient Clinical Ltd. | Connor A.,Quotient Clinical Ltd.
American Journal of Rhinology and Allergy | Year: 2014

Background: Sensory attributes of intranasal corticosteroids, such as rundown to the back of the throat, may influence patient treatment preferences. This study compares the nasal deposition and nasal retention of a radiolabeled solution of ciclesonide nasal aerosol (CIC-hydrofluoroalkane [HFA]) with a radiolabeled suspension of mometasone furoate monohydrate aqueous nasal spray (MFNS) in subjects with either perennial allergic rhinitis (AR) or seasonal AR. Methods: In this open-label, single-dose, randomized, crossover scintigraphy study, 14 subjects with symptomatic AR received a single dose of radiolabeled 74-μg CIC-HFA (37 μg/spray, 1 spray/each nostril) via a nasal metered-dose inhaler or a single dose of radiolabeled 200-μg MFNS (50 μg/spray, 2 sprays/each nostril), with a minimum 5-day washout period between treatments. Initial deposition (2 minutes postdose) of radiolabeled CIC-HFA and MFNS in the nasal cavity, nasopharynx, and on nasal wipes, and retention of radioactivity in the nasal cavity and nasal run-out on nasal wipes at 2, 4, 6, 8, and 10 minutes postdose were quantified with scintigraphy. Results: At 2 and 10 minutes postdose, deposition of radiolabeled CIC-HFA was significantly higher in the nasal cavity versus radiolabeled MFNS (99.42% versus 86.50% at 2 minutes, p = 0.0046; and 81.10% versus 54.31% at 10 minutes, p < 0.0001, respectively; p values unadjusted for multiplicity). Deposition of radioactivity on nasal wipes was significantly higher with MFNS versus CIC-HFA at all five time points, and posterior losses of radiolabeled formulation were significantly higher with MFNS at 6, 8, and 10 minutes postdose. Conclusion: In this scintigraphic study, significantly higher nasal deposition and retention of radiolabeled aerosol CIC-HFA were observed versus radiolabeled aqueous MFNS in subjects with AR. Copyright © 2014, OceanSide Publications, Inc.


PubMed | BioCryst Pharmaceuticals, PharStat Inc. and Quotient Clinical Ltd
Type: Journal Article | Journal: Allergy | Year: 2016

Avoralstat is a potent small-molecule oral plasma kallikrein inhibitor under development for treatment of hereditary angioedema (HAE). This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of avoralstat.This double-blind, placebo-controlled, ascending-dose cohort trial evaluated avoralstat single doses of 50, 125, 250, 500, and 1000 mg and multiple doses up to 2400 mg daily (100, 200, 400, and 800 mg every 8 h [q8 h] up to 7 days).Avoralstat (n = 71) was generally well tolerated with no signals for a safety concern; there were no serious adverse events (AEs) or discontinuations due to AEs, and compared to placebo (n = 18), no notable difference in AEs. Four moderate severity AEs were reported in two subjects; syncope after a single 250 mg dose (one subject) and abdominal pain, back pain, and eczema after multiple doses of 800 mg avoralstat (one subject). For multiple-dose cohorts, the incidence of gastrointestinal AEs was highest at the 2400 mg/day dose. Elimination of avoralstat was bi-exponential with a terminal half-life of 12-31 h. Inhibition of plasma kallikrein was observed at all doses, and the degree of inhibition was highly correlated with avoralstat concentrations (R = 0.93). Mean avoralstat concentrations at doses 400 mg q8 h met or exceeded plasma kallikrein ECAvoralstat was well tolerated, and drug exposure was sufficient to meet target levels for inhibition of plasma kallikrein. Based on these results, the 400 mg q8 h dose was selected for further evaluation in patients with HAE.

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