Evaluation of the Pharmacokinetics and Safety of a Single Dose of Acalabrutinib in Subjects With Hepatic Impairment.

Acalabrutinib received approval for the treatment of adult patients with mantle cell lymphoma who received at least 1 prior therapy and adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. This study investigated the impact of hepatic impairment (HI) on acalabrutinib pharmacokinetics (PK) and safety at a single 50-mg dose in fasted subjects. This study was divided into 2 parts: study 1, an open-label, parallel-group study in Child-Pugh class A or B subjects and healthy subjects; and study 2, an open-label, parallel-group study in Child-Pugh class C subjects and healthy subjects. Baseline characteristics and safety profiles were similar across groups. Acalabrutinib exposure (area under the plasma concentration-time curve) increased slightly (1.90- and 1.48-fold) in subjects with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment compared with healthy subjects. In severe hepatic impairment (Child-Pugh class C), acalabrutinib exposure (area under the plasma concentration-time curve and maximum plasma concentration) increased ≈5.0- and 3.6-fold, respectively. Results were consistent across total and unbound exposures. Severe hepatic impairment did not impact total/unbound metabolite (ACP-5862) exposures; the metabolite-to-parent ratio decreased to 0.6 to 0.8 (vs 3.1-3.6 in healthy subjects). In summary, single oral dose of 50-mg acalabrutinib was safe and well tolerated in subjects with mild, moderate, and severe hepatic impairment and in healthy control subjects. In subjects with severe hepatic impairment, mean acalabrutinib exposure increased by up to 5-fold and should be avoided. Acalabrutinib does not require dose adjustment in patients with mild or moderate hepatic impairment.

A Synthetic Quorum Sensing System Reveals a Potential Private Benefit for Public Good Production in a Biofilm.

Bacteria predominantly reside in microbial communities known as biofilms, where cells are encapsulated and protected by the extracellular matrix (ECM). While all biofilm cells benefit from the ECM, only a subgroup of cells carries the burden of producing this public good. This dilemma provokes the question of how these cells balance the cost of ECM production. Here we show that ECM producing cells have a higher gene expression response to quorum sensing (QS) signals, which can lead to a private benefit. Specifically, we constructed a synthetic quorum-sensing system with designated "Sender" and "Receiver" cells in Bacillus subtilis. This synthetic QS system allowed us to uncouple and independently investigate ECM production and QS in both biofilms and single cells. Results revealed that ECM production directly enhances the response to QS signals, which may offset the cost of ECM production.