Absorption, Metabolism, and Excretion of [C]-Tolebrutinib After Oral Administration in Humans, Contribution of the Metabolites to Pharmacological Activity.

Background And Objective: Tolebrutinib is a covalent inhibitor of Bruton's tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are thought to be major drivers of inflammation in multiple sclerosis. This excretion balance and metabolism study evaluated the metabolite profile of tolebrutinib in healthy male volunteers.

Methods: Six healthy volunteers received a 60-mg oral dose of [C]-tolebrutinib, and metabolite profiling of C-labeled metabolites was performed using a combination of liquid chromatography, mass spectrometry, and radioactivity assay methods.

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to parasite resistance.

The emergence and spread of resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials.

Clinical assessment of drug-induced QT prolongation in association with heart rate changes.

Background: The formulas for heart rate (HR) correction of QT interval have been shown to overcorrect or undercorrect this interval with changes in HR. A Holter-monitoring method avoiding the need for any correction formulas is proposed as a means to assess drug-induced QT interval changes.

Methods: A thorough QT study included 2 single doses of the alpha1-adrenergic receptor blocker alfuzosin, placebo, and a QT-positive control arm (moxifloxacin) in 48 healthy subjects.