Pharmacokinetics, Safety, and Tolerability of Fevipiprant (QAW039), a Novel CRTh2 Receptor Antagonist: Results From 2 Randomized, Phase 1, Placebo‐Controlled Studies in Healthy Volunteers

Erpenbeck, Veit J.; Vets, Eva; Gheyle, Lien; Osuntokun, Wande; Larbig, Michael; Neelakantham, Srikanth; Sandham, David A.; Dubois, Gerald; Elbast, Walid; Goldsmith, Paul; Weiss, Michel

doi:10.1002/cpdd.244

Cited by 25 publications

(17 citation statements)

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“…Two phase 1 studies investigated the pharmacokinetics (PK), safety, and tolerability of fevipiprant after single and multiple ascending doses in healthy subjects (Erpenbeck et al, 2016). On administration of single and multiple oral doses, fevipiprant peak plasma concentrations were observed 1-3 hours after the dose, and the apparent terminal half-life was approximately 20 hours.…”

Section: Introductionmentioning

confidence: 99%

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Absorption, Distribution, Metabolism, and Excretion of the Oral Prostaglandin D2 Receptor 2 Antagonist Fevipiprant (QAW039) in Healthy Volunteers and In Vitro

et al. 2017

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Fevipiprant is a novel oral prostaglandin D receptor 2 (DP; also known as CRTh2) antagonist, which is currently in development for the treatment of severe asthma and atopic dermatitis. We investigated the absorption, distribution, metabolism, and excretion properties of fevipiprant in healthy subjects after a single 200-mg oral dose of [C]-radiolabeled fevipiprant. Fevipiprant and metabolites were analyzed by liquid chromatography coupled to tandem mass spectrometry and radioactivity measurements, and mechanistic in vitro studies were performed to investigate clearance pathways and covalent plasma protein binding. Biotransformation of fevipiprant involved predominantly an inactive acyl glucuronide (AG) metabolite, which was detected in plasma and excreta, representing 28% of excreted drug-related material. The AG metabolite was found to covalently bind to human plasma proteins, likely albumin; however, in vitro covalent binding to liver protein was negligible. Excretion was predominantly as unchanged fevipiprant in urine and feces, indicating clearance by renal and possibly biliary excretion. Fevipiprant was found to be a substrate of transporters organic anion transporter 3 (OAT3; renal uptake), multidrug resistance gene 1 (MDR1; possible biliary excretion), and organic anion-transporting polypeptide 1B3 (OATP1B3; hepatic uptake). Elimination of fevipiprant occurs via glucuronidation by several uridine 5'-diphospho glucuronosyltransferase (UGT) enzymes as well as direct excretion. These parallel elimination pathways result in a low risk of major drug-drug interactions or pharmacogenetic/ethnic variability for this compound.

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Section: Introductionmentioning

confidence: 99%

“…An acyl-glucuronide (AG) metabolite without DP 2 antagonist activity was detected in plasma. Fevipiprant was well-tolerated at single and multiple oral doses up to 500 mg/day (Erpenbeck et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Absorption, Distribution, Metabolism, and Excretion of the Oral Prostaglandin D2 Receptor 2 Antagonist Fevipiprant (QAW039) in Healthy Volunteers and In Vitro

et al. 2017

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“…Before experimentation, ASM cells from each individual donor were incubated in media in the presence of a selective DP 2 agonist [DK-PGD 2 ; Cayman Chemical Company] (30) or selective DP 2 antagonists [CAY10471, OC000459, and fevipiprant, Cayman Chemical Company and Novartis (31)(32)(33) versus appropriate vehicle controls: dimethyl sulfoxide (DMSO) for DK-PGD 2 , CAY10471, and OC000459 and 10% dH 2 O in DMSO for fevipiprant].…”

Section: Immunohistochemistrymentioning

confidence: 99%

DP ₂ antagonism reduces airway smooth muscle mass in asthma by decreasing eosinophilia and myofibroblast recruitment

et al. 2019

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Increased airway smooth muscle mass, a feature of airway remodeling in asthma, is the strongest predictor of airflow limitation and contributes to asthma-associated morbidity and mortality. No current drug therapy for asthma is known to affect airway smooth muscle mass. Although there is increasing evidence that prostaglandin D2 type 2 receptor (DP2) is expressed in airway structural and inflammatory cells, few studies have addressed the expression and function of DP2 in airway smooth muscle cells. We report that the DP2 antagonist fevipiprant reduced airway smooth muscle mass in bronchial biopsies from patients with asthma who had participated in a previous randomized placebo-controlled trial. We developed a computational model to capture airway remodeling. Our model predicted that a reduction in airway eosinophilia alone was insufficient to explain the clinically observed decrease in airway smooth muscle mass without a concomitant reduction in the recruitment of airway smooth muscle cells or their precursors to airway smooth muscle bundles that comprise the airway smooth muscle layer. We experimentally confirmed that airway smooth muscle migration could be inhibited in vitro using DP2-specific antagonists in an airway smooth muscle cell culture model. Our analyses suggest that fevipiprant, through antagonism of DP2, reduced airway smooth muscle mass in patients with asthma by decreasing airway eosinophilia in concert with reduced recruitment of myofibroblasts and fibrocytes to the airway smooth muscle bundle. Fevipiprant may thus represent a potential therapy to ameliorate airway remodeling in asthma.

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“…Preliminary data confirm a good safety profile and improvement of FEV1, especially in patients with more severe obstruction. 68 Another Phase II study in patients with uncontrolled allergic asthma showed no improvement in pulmonary function. However, a subgroup analysis revealed that patients with impaired respiratory function (FEV1 <70%) had improved pulmonary function and asthma control when treated with QAW039.…”

Section: Antagonist Of the Prostaglandin D2 Receptormentioning

confidence: 99%

Innovative treatments for severe refractory asthma: how to choose the right option for the right patient?

Menzella

Galeone

Bertolini

et al. 2017

JAA

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The increasing understanding of the molecular biology and the etiopathogenetic mechanisms of asthma helps in identification of numerous phenotypes and endotypes, particularly for severe refractory asthma. For a decade, the only available biologic therapy that met the unmet needs of a specific group of patients with severe uncontrolled allergic asthma has been omalizumab. Recently, new biologic therapies with different mechanisms of action and targets have been approved for marketing, such as mepolizumab. Other promising drugs will be available in the coming years, such as reslizumab, benralizumab, dupilumab and lebrikizumab. Moreover, since 2010, bronchial thermoplasty has been successfully introduced for a limited number of patients. This is a nonpharmacologic endoscopic procedure which is considered a promising therapy, even though several aspects still need to be clarified. Despite the increasing availability of new therapies, one of the major problems of each treatment is still the identification of the most suitable patients. This sudden abundance of therapeutic options, sometimes partially overlapping with each other, increases the importance to identify new biomarkers useful to guide the clinician in selecting the most appropriate patients and treatments, without forgetting the drug-economic aspects seen in elevated direct cost of new therapies. The aim of this review is, therefore, to update the clinician on the state of the art of therapies available for refractory asthma and, above all, to give useful directions that will help understand the different choices that sometimes partially overlap and to dispel the possible doubts that still exist.

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Pharmacokinetics, Safety, and Tolerability of Fevipiprant (QAW039), a Novel CRTh2 Receptor Antagonist: Results From 2 Randomized, Phase 1, Placebo‐Controlled Studies in Healthy Volunteers

Cited by 25 publications

References 20 publications

Absorption, Distribution, Metabolism, and Excretion of the Oral Prostaglandin D2 Receptor 2 Antagonist Fevipiprant (QAW039) in Healthy Volunteers and In Vitro

Absorption, Distribution, Metabolism, and Excretion of the Oral Prostaglandin D2 Receptor 2 Antagonist Fevipiprant (QAW039) in Healthy Volunteers and In Vitro

DP ₂ antagonism reduces airway smooth muscle mass in asthma by decreasing eosinophilia and myofibroblast recruitment

Innovative treatments for severe refractory asthma: how to choose the right option for the right patient?

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Pharmacokinetics, Safety, and Tolerability of Fevipiprant (QAW039), a Novel CRTh2 Receptor Antagonist: Results From 2 Randomized, Phase 1, Placebo‐Controlled Studies in Healthy Volunteers

Cited by 25 publications

References 20 publications

Absorption, Distribution, Metabolism, and Excretion of the Oral Prostaglandin D2 Receptor 2 Antagonist Fevipiprant (QAW039) in Healthy Volunteers and In Vitro

Absorption, Distribution, Metabolism, and Excretion of the Oral Prostaglandin D2 Receptor 2 Antagonist Fevipiprant (QAW039) in Healthy Volunteers and In Vitro

DP 2 antagonism reduces airway smooth muscle mass in asthma by decreasing eosinophilia and myofibroblast recruitment

Innovative treatments for severe refractory asthma: how to choose the right option for the right patient?

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DP ₂ antagonism reduces airway smooth muscle mass in asthma by decreasing eosinophilia and myofibroblast recruitment