Search

Abstract Most bacteria in nature exist in aggregated communities known as biofilms, and cells within a biofilm demonstrate major physiological changes compared to their planktonic counterparts. Biofilms are associated with many different types of infections which can have severe impacts on patients. Infections involving a biofilm component are often chronic and highly recalcitrant to antibiotic therapy as a result of intrinsic physical factors including extracellular matrix production, low growth rates, altered antibiotic target production and efficient exchange of resistance genes. This review describes the biofilm lifecycle, phenotypic characteristics of a biofilm, and contribution of matrix and persister cells to biofilms intrinsic tolerance to antimicrobials. We also describe how biofilms can evolve antibiotic resistance and transfer resistance genes within biofilms. Multispecies biofilms and the impacts of various interactions, including cooperation and competition, between species on tolerance to antimicrobials in polymicrobial biofilm communities are also discussed.

Myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, splenomegaly, anemia, and constitutional symptoms, with a median survival of ≈6 years from diagnosis. While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis‐related anemia, a negative prognostic factor for survival. Momelotinib is a novel JAK1/JAK2/activin A receptor type 1 (ACVR1) inhibitor approved in the US, European Union, and the UK and is the first JAK inhibitor indicated specifically for patients with myelofibrosis with anemia. Momelotinib not only addresses the splenomegaly and symptoms associated with myelofibrosis by suppressing the hyperactive JAK–STAT (signal transducer and activator of transcription) pathway but also improves anemia and reduces transfusion dependency through ACVR1 inhibition. The recommended dose of momelotinib is 200 mg orally once daily, which was established after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Momelotinib is metabolized primarily by CYP3A4 and excreted as metabolites in feces and urine. Steady‐state maximum concentration is 479 ng/mL (CV%, 61%), with a mean AUCtau of 3288 ng.h/mL (CV%, 60%); its major metabolite, M21, is active (≈40% of pharmacological activity of parent), with a metabolite‐to‐parent AUC ratio of 1.4–2.1. This review describes momelotinib's mechanism of action, detailing how the JAK–STAT pathway is involved in myelofibrosis pathogenesis and ACVR1 inhibition decreases hepcidin, leading to improved erythropoiesis. Additionally, it summarizes the pivotal studies and data that informed the recommended dosage and risk/benefit assessment. [ABSTRACT FROM AUTHOR]

Momelotinib—approved for treatment of myelofibrosis in adults with anemia—and its major active metabolite, M21, were assessed as drug–drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple‐dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single‐dose rifampin), and a strong CYP3A4 inducer (multiple‐dose rifampin). Momelotinib DDI perpetrator potential (multiple‐dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively). DDI was assessed from changes in maximum plasma concentration (Cmax), area under the concentration–time curve (AUC), time to reach Cmax, and half‐life. The increase in momelotinib (23% Cmax, 14% AUC) or M21 (30% Cmax, 24% AUC) exposure with ritonavir coadministration was not clinically relevant. A moderate increase in momelotinib (40% Cmax, 57% AUC) and minimal change in M21 was observed with single‐dose rifampin. A moderate decrease in momelotinib (29% Cmax, 46% AUC) and increase in M21 (31% Cmax, 15% AUC) were observed with multiple‐dose rifampin compared with single‐dose rifampin. Due to potentially counteracting effects of OATP1B1/1B3 inhibition and CYP3A4 induction, multiple‐dose rifampin did not significantly change momelotinib pharmacokinetics compared with momelotinib alone (Cmax no change, 15% AUC decrease). Momelotinib did not alter the pharmacokinetics of midazolam (8% Cmax, 16% AUC decreases) or 1′‐hydroxymidazolam (14% Cmax, 16% AUC decreases) but increased rosuvastatin Cmax by 220% and AUC by 170%. Safety findings were mild in this short‐term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments. [ABSTRACT FROM AUTHOR]

Myelofibrosis is a chronic myeloproliferative disorder characterized by bone marrow fibrosis, splenomegaly, anemia, and constitutional symptoms, with a median survival of ≈6 years from diagnosis. While currently approved Janus kinase (JAK) inhibitors (ruxolitinib, fedratinib) improve splenomegaly and symptoms, most can exacerbate myelofibrosis-related anemia, a negative prognostic factor for survival. Momelotinib is a novel JAK1/JAK2/activin A receptor type 1 (ACVR1) inhibitor approved in the US, European Union, and the UK and is the first JAK inhibitor indicated specifically for patients with myelofibrosis with anemia. Momelotinib not only addresses the splenomegaly and symptoms associated with myelofibrosis by suppressing the hyperactive JAK-STAT (signal transducer and activator of transcription) pathway but also improves anemia and reduces transfusion dependency through ACVR1 inhibition. The recommended dose of momelotinib is 200 mg orally once daily, which was established after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Momelotinib is metabolized primarily by CYP3A4 and excreted as metabolites in feces and urine. Steady-state maximum concentration is 479 ng/mL (CV%, 61%), with a mean AUC tau of 3288 ng.h/mL (CV%, 60%); its major metabolite, M21, is active (≈40% of pharmacological activity of parent), with a metabolite-to-parent AUC ratio of 1.4-2.1. This review describes momelotinib's mechanism of action, detailing how the JAK-STAT pathway is involved in myelofibrosis pathogenesis and ACVR1 inhibition decreases hepcidin, leading to improved erythropoiesis. Additionally, it summarizes the pivotal studies and data that informed the recommended dosage and risk/benefit assessment., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)