Emerging Treatments for COPD: Evidence to Date on Revefenacin

Jučaitė²,

Ewing³

et al. 2023

Front. Nucl. Med.

IntroductionMolecular imaging has not been used to support the development of drugs for the treatment of pulmonary disorders. The aim of the present translational study was to advance quantitative pulmonary PET imaging by demonstrating occupancy of the reference asthma drug tiotropium at muscarinic acetylcholine receptors (mAChR).MethodsPET imaging was performed using the muscarinic radioligand [11C]VC-002. The key methodological step involved estimating muscarinic receptor binding while disentangling it from the background of non-specific binding. The relationship between tiotropium exposure and receptor occupancy (RO) was assessed in non-human primates (NHPs) after intravenous injection of tiotropium doses at a broad dose interval (0.03–1 µg/kg). The feasibility of measuring RO in the human lung was then confirmed in seven healthy human subjects after inhalation of a single therapeutic dose of tiotropium (18 µg).ResultsThere was an evident effect of tiotropium on [11C]VC-002 binding to mAChRs in lungs in both NHPs and humans. In NHPs, RO was 11 to 78% and increased in a dose dependent manner. Non-displaceable binding in NHPs was about 10% of total binding. In humans, RO was 6%–65%, and non-displaceable binding was about 20% of total binding at baseline.DiscussionThe results demonstrate that [11C]VC-002 binds specifically to mAChRs in the lungs enabling the assessment of RO following administration of muscarinic antagonist drugs. Furthermore, the methodology has potential not only for dose finding and comparison of drug formulations in future applied studies, but also for evaluating changes in lung receptor distribution during disease or in response to therapy.Clinical Trial RegistrationClinicalTrials.gov, identifier: NCT03097380.

Section: Introductionmentioning

confidence: 99%

Proof of lung muscarinic receptor occupancy by tiotropium: Translational Positron Emission Tomography studies in non-human primates and humans

Jučaitė²,

Ewing³

et al. 2023

Front. Nucl. Med.

“…Muscarinic receptor (mAChR) antagonists together with other bronchodilators are the current mainstay for relieving dyspnoea in patients with chronic lung disorders (Matera et al 2020; Maia et al 2017, Melani 2015). The clinical e cacy of the rst long-acting mAChR antagonist (LAMA) tiotropium has over the years spurred development of new LAMAs (Lal et al 2020). However, despite their widespread use, the extent and duration of LAMA binding to receptors in human lung tissue in vivo is still poorly understood (Backman et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Lung muscarinic receptor occupancy by tiotropium: translational PET studies in non-human primates and humans

Jučaitė

Ewing

et al. 2022

Preprint

BackgroundThe aim of the present translational PET study was to estimate occupancy of tiotropium at muscarinic acetylcholine receptors (mAChR) in the lungs in vivo. The relationship between the tiotropium exposure and receptor occupancy (RO) in the lung was assessed in non-human primates (NHPs) after intravenous injection of tiotropium doses at a broad dose interval (0.1-1mg/kg). The feasibility of measuring mAChR occupancy in the human lung was then confirmed in seven healthy human subjects after inhalation of a single therapeutic dose of tiotropium (18mg). PET examinations were performed using radioligand [11C]VC-002. Occupancy in lungs was estimated using Lassen plot analysis of parametric images showing total radioligand binding (total distribution volume, VT).ResultsThere was an evident effect of tiotropium on [11C]VC-002 binding to mAChRs in lungs in both NHPs and humans. In NHPs, the occupancy was 11 to 78%, increasing in a dose dependent manner. The Lassen-plot based estimate of non-displaceable binding in NHPs was about 10% of the VT. In humans, occupancy was 6-65%, and non-displaceable binding (VND) was about 20% of total binding, VT at baseline. ConclusionsThe results demonstrated that [11C]VC-002 binds specifically to mAChRs in the lungs such that it allows for the detection and quantification of lung muscarinic receptor occupancy following administration of an intravenously administered or inhaled muscarinic antagonist drugs. The methodology has potential for dose finding and comparison of drug formulations in future applied studies. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT03097380, registered: 31 March 2017, url: https://clinicaltrials.gov/ct2/show/NCT03097380

“…Muscarinic receptor (mAChR) antagonists together with other bronchodilators are the current mainstay for relieving dyspnoea in patients with chronic lung disorders [1][2][3] . The clinical e cacy of the rst longacting mAChR antagonist (LAMA) tiotropium has over the years spurred development of new LAMAs 4 . However, despite their widespread use, the extent and duration of LAMA binding to receptors in human lung tissue in vivo is still poorly understood 5 .…”

Section: Introductionmentioning

confidence: 99%

Lung muscarinic receptor occupancy by tiotropium: translational Positron Emission Tomography studies in non-human primates and humans

Jučaitė

Ewing

et al. 2022

Preprint

Purpose Molecular imaging has not been used to support the development of drugs for the treatment of pulmonary disorders. The aim of the present translational study was to advance quantitative pulmonary PET imaging by demonstrating occupancy of the reference asthma drug tiotropium at muscarinic acetylcholine receptors (mAChR). Materials and methods PET imaging was performed using the muscarinic radioligand [11C]VC-002. The key methodological step involved estimating muscarinic receptor binding while disentangling it from the background of non-specific binding. The relationship between tiotropium exposure and receptor occupancy (RO) was assessed in non-human primates (NHPs) after intravenous injection of tiotropium doses at a broad dose interval (0.1-1mg/kg). The feasibility of measuring RO in the human lung was then confirmed in seven healthy human subjects after inhalation of a single therapeutic dose of tiotropium (18mg). Results There was an evident effect of tiotropium on [11C]VC-002 binding to mAChRs in lungs in both NHPs and humans. In NHPs, RO was 11 to 78% and increased in a dose dependent manner. Non-displaceable binding in NHPs was about 10% of total binding. In humans, RO was 6-65%, and non-displaceable binding was about 20% of total binding at baseline. Conclusions The results demonstrate that [11C]VC-002 binds specifically to mAChRs in the lungs enabling the assessment of RO following administration of muscarinic antagonist drugs. Furthermore, the methodology has potential not only to support early drug development, but also for evaluating changes in lung receptor distribution in a diagnostic setting, during disease or in response to therapy.