Clofazimine, a lipophilic riminophenazine antibiotic, possesses both antimycobacterial and anti-inflammatory activities. However, its efficacy has been demonstrated only in the treatment of leprosy, not in human tuberculosis, despite the fact that this agent is impressively active in vitro against multidrug-resistant strains of Mycobacterium tuberculosis. Recent insights into novel targets and mechanisms of antimicrobial and anti-inflammatory activity coupled with the acquisition of innovative drug delivery technologies have, however, rekindled interest in clofazimine as a potential therapy for multidrug- and extensively multidrug-resistant tuberculosis in particular, as well as several autoimmune diseases. The primary objective of this review is to critically evaluate these recent developments and to assess their potential impact on improving the therapeutic efficacy and versatility of clofazimine.
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From Médecins Sans Frontières (L.G., F.V.), Sorbonne Université, INSERM Unité 1135, Centre d'Immunologie et des Maladies Infectieuses (L.G.), Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Universitaire Sorbonne Université, Hôpital Pitié-Salpêtrière, Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux (L.G.), and Epicentre (M.G., E. Baudin), Paris, and Translational Research on HIV and Endemic and Emerging Infectious Diseases, Montpellier Université de Montpellier, Montpellier, Institut de Recherche pour le Développement, Montpellier, INSERM, Montpellier (M.B.) - all in France; Interactive Development and Research, Singapore (U.K.); McGill University, Epidemiology, Biostatistics, and Occupational Health, Montreal (U.K.); UCSF Center for Tuberculosis (G.E.V., P.N., P.P.J.P.) and the Division of HIV, Infectious Diseases, and Global Medicine (G.E.V.), University of California at San Francisco, San Francisco; the National Scientific Center of Phthisiopulmonology (A.A., E. Berikova) and the Center of Phthisiopulmonology of Almaty Health Department (A.K.), Almaty, and the City Center of Phthisiopulmonology, Astana (Z.D.) - all in Kazakhstan; Médecins Sans Frontières (C.B., I.M.), the Medical Research Council Clinical Trials Unit at University College London (I.M.), and St. George's University of London Institute for Infection and Immunity (S.W.) - all in London; MedStar Health Research Institute, Washington, DC (M.C.); Médecins Sans Frontières, Mumbai (V. Chavan), the Indian Council of Medical Research Headquarters-New Delhi, New Delhi (S. Panda), and the Indian Council of Medical Research-National AIDS Research Institute, Pune (S. Patil) - all in India; the Centre for Infectious Disease Epidemiology and Research (V. Cox) and the Department of Medicine (H. McIlleron), University of Cape Town, and the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (S.W.) - both in Cape Town, South Africa; the Institute of Tropical Medicine, Antwerp, Belgium (B. C. J.); Médecins Sans Frontières, Geneva (G.F., N.L.); Médecins Sans Frontières, Yerevan, Armenia (O.K.); the National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia (N.K.); Partners In Health (M.K.) and Jhpiego Lesotho (L.O.) - both in Maseru; Socios En Salud Sucursal Peru (L.L., S.M.-T., J.R., E.S.-G., D.E.V.-V.), Hospital Nacional Sergio E. Bernales, Centro de Investigacion en Enfermedades Neumologicas (E.S.-G.), Hospital Nacional Dos de Mayo (E.T.), Universidad Nacional Mayor de San Marcos (E.T.), and Hospital Nacional Hipólito Unanue (D.E.V.-V.) - all in Lima; Global Health and Social Medicine, Harvard Medical School (L.L., K.J.S., M.L.R., C.D.M.), Partners In Health (L.L., K.J.S., M.L.R., C.D.M.), the Division of Global Health Equity, Brigham and Women's Hospital (K.J.S., M.L.R., C.D.M.), the Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, (L.T.), and Harvard T.H. Chan School of Public Health (L.T.) - all in Boston; and the Indus Hospital and Health Network, Karachi, Pakistan (H. Mushtaque, N.S.).
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Methods: We conducted a phase 3, multinational, open-label, randomized, controlled noninferiority trial to compare standard therapy for treatment of fluoroquinolone-susceptible, rifampin-resistant tuberculosis with five 9-month oral regimens that included various combinations of bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C), and pyrazinamide (Z).
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Adult Cystic Fibrosis Centre, The Prince Charles Hospital, Brisbane, Queensland, Australia.
Therapeutic drug monitoring (TDM) of elexacaftor/tezacaftor/ivacaftor (ETI) remains challenging due to a lack of clarity around the parameters that govern ETI plasma concentrations, whilst the use of concomitant CYP3A inducers rifabutin and rifampicin is not recommended. We present the complexities of TDM for ETI performed in a person with cystic fibrosis and refractory pulmonary disease. Utilising National Association of Testing Authorities (NATA) accredited assays and target considerations published by the Therapeutic Goods Administration (TGA), Australia, ETI plasma concentration variability was monitored over the course of an acute admission with added complexity from an antibiotic regimen including rifabutin, a moderate cytochrome P450 3A (CYP3A) inducer, and clofazimine, a mild CYP3A inhibitor.
View Article and Find Full Text PDFCharacteristics of children and adolescents with multidrug-resistant and rifampicin-resistant tuberculosis and their association with treatment outcomes: a systematic review and individual participant data meta-analysis.
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Stellenbosch University, Faculty of Medicine and Health Sciences, Department of Paediatrics and Child Health, Desmond Tutu TB Centre, Tygerberg, South Africa.
Background: There are few data on the treatment of children and adolescents with multidrug-resistant (MDR) or rifampicin-resistant (RR) tuberculosis, especially with more recently available drugs and regimens. We aimed to describe the clinical and treatment characteristics and their associations with treatment outcomes in this susceptible population.
Methods: We conducted a systematic review and individual participant data meta-analysis.
Development and validation of an LC-MS/MS multiplex assay for the quantification of bedaquiline, n-desmethyl bedaquiline, linezolid, levofloxacin, and clofazimine in dried blood spots.
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Dried blood spot (DBS) assays to quantify novel and repurposed drugs for the treatment of rifampicin-resistant tuberculosis (RR-TB) would facilitate pharmacokinetic studies and therapeutic drug monitoring in low-middle income settings, considering their ease of application and simple sample storage requirements. We describe a DBS method for the simultaneous quantification of bedaquiline and metabolite N-desmethyl bedaquiline, linezolid, levofloxacin, and clofazimine. The analytes were extracted from the matrix and isolated by solid-phase extraction.
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Pharmaceutics
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University of Belgrade-Faculty of Chemistry, Studentski trg 12-16, 11000 Belgrade, Serbia.
Background/objectives: Clofazimine (CFZ) is a Biopharmaceutics Classification System (BCS) II drug introduced in the US market in 1986 for the treatment of leprosy. However, CFZ was later withdrawn from the market due to its extremely low aqueous solubility and low absorption. In the literature, the intrinsic solubility of CFZ has been estimated to be <0.
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