https://doi.org/10.55788/c5d67cf6
Bosutinib is a dual Abl/Src tyrosine kinase inhibitor which is already approved at a daily oral dose of 400ā600 mg for the treatment of chronic myeloid leukaemia (CML), with manageable side effects [1,2]. In preclinical studies, bosutinib (1ā10 mg/kg) reduced neuropathological processes, including accumulation of neurotoxic proteins [3]. Bosutinib also increased brain dopamine levels (by >60%) in models of alpha-synucleinopathies [4]. Bosutinib has been shown to penetrate the brain, promote autophagic degradation of neurotoxic proteins, and improve motor and cognitive behaviour in Alzheimerās disease (AD) and Parkinsonās disease (PD) models [5].
Dr Fernando PagƔn (Georgetown University Hospital, DC, USA) and colleagues evaluated the safety and pharmacokinetics of 12-week oral treatment of bosutinib 100 mg [6]. Their single-centre, double-blind, placebo-controlled, phase 2 study enrolled 26 patients (25 male) with mild-to-moderate DLB. Average age of participants was 73 years. Randomisation was preceded by an open-label pharmacokinetics study, in which the 26 participants were randomised to a single dose of bosutinib 100 mg, 200 mg, or placebo. Both single doses of bosutinib resulted in a dose-dependent increase in plasma and CSF bosutinib levels.
The most important observation in the main study was that multiple dosing (during 12 weeks) of 100 mg bosutinib resulted in a dose-dependent effect: a more than 2-fold elevation in plasma and 9-fold elevation in CSF. The volume of distribution was large, suggesting that bosutinib was distributed extensively into tissues with low bioavailability. Bosutinib also exhibited high protein binding of 94%.
Bosutinib achieved a sufficiently high level to directly inhibit both Abl and Src in plasma, indicating dual target engagement. Bosutinib inhibited Abl/Src at IC50=1.2 nM. Bosutinib significantly reduced CSF alpha-synuclein (P=0.023) and the ratio of oligomeric/total alpha-synuclein (P=0.045) compared with placebo. Plasma oligomeric alpha-synuclein (P=0.04) and ptau181/AĪ²42 (P=0.03) also significantly decreased. Finally, bosutinib significantly (P=0.034) improved activities of daily living (ADCS-ADL-MCI). There were no serious adverse events.
These results suggest that bosutinib 100 mg may be (or nearly be) the lowest effective dose to inhibit CSF Abl in DLB. More adequately powered studies are needed to further explore the effects of bosutinib.
- Cortes JE, et al. Blood. 2011;118(17):4567ā76.
- Khoury HJ, et al. Blood. 2012;119(15):3403ā12.
- Boschelli F, et al. Eur J Cancer. 2010;46(10):1781ā9.
- Lonskaya I, et al. EMBO Mol Med. 2013;5(8):1247ā62.
- Hebron ML, et al. Autophagy. 2013;9(8):1249ā50.
- Pagan F, et al. Safety, Target Engagement and Effects of Bosutinib in Dementia with Lewy Bodies. S20.010, AAN 2022, 02ā07 April, Seattle, USA.
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Table of Contents: AAN 2022
Featured articles
Letter from the Editor
Interview with Prof. Natalia Rost
Alzheimerās Disease and Other Dementias
Targeting senescent cells to treat age-related diseases
Cardiorespiratory fitness protects against dementia
Safety and effects of bosutinib in Lewy body dementia
Epilepsy
āWomen with epilepsy should be encouraged to breastfeedā
Fenfluramine: possible new treatment for Lennox-Gastaut syndrome
Laser interstitial thermal therapy for refractory epilepsy
Migraine
Migraine may be an important obstetric risk factor
Intranasal zavegepant safe and well tolerated in healthy adults
Telemedicine during COVID-19 pandemic highly appreciated
Multiple Sclerosis
Ublituximab versus teriflunomide in relapsing MS patients
Ketogenic diet may improve disability and quality of life
Favourable additional safety data for ofatumumab
Predicting new T2 lesions using a machine learning algorithm
Evobrutinib reduces volume of slowly expanding lesions
Sustained long-term efficacy and safety of satralizumab in NMOSD
Muscle and Neuro-Muscular Disorders
Ravulizumab in patients with generalised myasthenia gravis
Gene therapy effective in older patients with spinal muscular atrophy
Losmapimod for facioscapulohumeral muscular dystrophy
SRP-9001 for treating patients with Duchenne muscular dystrophy
Cerebrovascular Disease and Stroke
Intravenous thrombolysis after ischaemic stroke: When in doubt, leave it out?
Better outcomes with mechanical thrombectomy in elderly stroke patients
Plasma NfL levels associated with cardiovascular risk
Non-invasive vagus nerve stimulation for acute stroke
Parkinsonās Disease
Prasinezumab in Parkinsonās disease: delayed-start analysis of PASADENA trial
IPX203 versus immediate release carbidopa-levodopa
Impact of COVID-19 public health interventions
COVID-19
Cognitive, EEG, and MRI features in COVID-19 survivors
Neurological manifestations of COVID-19 worsen prognosis
New evidence for biological basis of āCOVID-19 brain fogā
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