Distinguishing the Concentration- vs. Bioaccumulation-Dependent Immunological and Metabolic Effects of Clofazimine.

The antimycobacterial drug clofazimine (CFZ) is used as a single agent at high doses, to suppress the exaggerated inflammation associated with leprosy. Paradoxically, increasing doses of CFZ leads to bioaccumulation of CFZ in the spleen and other organs under physiologically relevant dosing regimens, without accompanying dose-dependent elevation in the concentrations of the circulating drug in the blood. In long-term oral dosing regimens, CFZ induces immunological and metabolic changes resulting in splenomegaly, while the mass of other organs decreases or remains unchanged.

Molecular design of a pathogen activated, self-assembling mechanopharmaceutical device.

Weakly basic small molecule drugs like clofazimine can be used as building blocks for endowing cells with unnatural structural and functional elements. Here, we describe how clofazimine represents a first-in-class mechanopharmaceutical device, serving to construct inert, inactive and stimulus responsive drug depots within the endophagolysosomal compartment of cells of living organisms. Upon oral administration, clofazimine molecules self-assemble into stable, membrane-bound, crystal-like drug inclusions (CLDI) that accumulate within macrophages to form a "smart" biocompatible, pathogen activatable mechanopharmaceutical device.

An Adaptive Biosystems Engineering Approach towards Modeling the Soluble-to-Insoluble Phase Transition of Clofazimine.

Clofazimine (CFZ) is a weakly basic, small-molecule antibiotic used for the treatment of mycobacterial infections including leprosy and multidrug-resistant tuberculosis. Upon prolonged oral administration, CFZ precipitates and accumulates within macrophages throughout the host. To model the pharmacokinetics of CFZ, the volume of distribution (Vd) was considered as a varying parameter that increases with continuous drug loading.

Quantitative Analysis of the Phase Transition Mechanism Underpinning the Systemic Self-Assembly of a Mechanopharmaceutical Device.

Clofazimine (CFZ) is a poorly soluble, weakly basic, small molecule antibiotic clinically used to treat leprosy and is now in clinical trials as a treatment for multidrug resistant tuberculosis and COVID-19. CFZ exhibits complex, context-dependent pharmacokinetics that are characterized by an increasing half-life in long term treatment regimens. The systemic pharmacokinetics of CFZ have been previously represented by a nonlinear, 2-compartment model incorporating an expanding volume of distribution.

Food effects on the formulation, dosing, and administration of cannabidiol (CBD) in humans: A systematic review of clinical studies.

Cannabidiol (CBD), a non-psychotropic phytocannabinoid from the Cannabis plant, is increasingly being pursued as a treatment for differing ailments. The bioavailability and pharmacokinetics of CBD are not well understood, and proper dosing schemes have not been adequately developed for its clinical use. CBD is a lipophilic molecule and exhibits low water solubility, so its formulation expectedly impacts its gastrointestinal absorption and subsequent blood plasma concentrations.

An Expandable Mechanopharmaceutical Device (1): Measuring the Cargo Capacity of Macrophages in a Living Organism.

Purpose: Clofazimine (CFZ) is an FDA-approved, poorly soluble small molecule drug that precipitates as crystal-like drug inclusions (CLDIs) which accumulate in acidic cytoplasmic organelles of macrophages. In this study, we considered CLDIs as an expandable mechanopharmaceutical device, to study how macrophages respond to an increasingly massive load of endophagolysosomal cargo.

Methods: First, we experimentally tested how the accumulation of CFZ in CLDIs impacted different immune cell subpopulations of different organs.