title: Partnerships to Design Novel Regimens to Treat Childhood Tuberculosis, Sui Generis: The Road Ahead.
abstract: There has been a recent expansion of preclinical models to predict the efficacy of regimens to treat adults with tuberculosis. Despite increasing global interest in childhood tuberculosis, these same tools have not been employed to develop pediatric regimens. Children differ from adults in bacillary burden, spectrum of disease, the metabolism and distribution of antituberculosis drugs, and the toxicity experienced. The studies documented in this series describe a proof-of-concept approach to pediatric regimen development. We propose a program of investigation that would take this forward into a systematic and comprehensive method to find optimal drug combinations to use in children, ideal exposures, and required dosing. Although the number of possible drug combinations is extensive, a series of principles could be employed to select likely effective regimens. Regimens should avoid drugs with overlapping toxicity or linked mechanisms of resistance and should aim to include drugs with different mechanisms of action and ones that are able to target different subpopulations of mycobacteria. Finally drugs should penetrate into body sites necessary for treating pediatric disease. At an early stage, this body of work would need to engage with regulatory agencies and bodies that formulate guidelines, so that once regimens and dosages are identified, translation into clinical studies and clinical practice can be rapid. The development of child-friendly drug formulations would need to be carried out in parallel so that pharmacokinetic studies can be undertaken as formulations are created. Significant research and development would be required and a wide range of stakeholders would need to be engaged. The time is right to consider a more thoughtful and systematic approach toward identifying, testing, and comparing combinations of drugs for children with tuberculosis.
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas Department of Medicine, University of Cape Town, Observatory, South Africa.
authors.forename: Tawanda
authors.initials: T
authors.lastname: Gumbo
authors.affiliation: Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Mamodikoe K
authors.initials: MK
authors.lastname: Makhene
authors.affiliation: Centre for International Child Health, Department of Paediatrics, Imperial College London, United Kingdom.
authors.forename: James A
authors.initials: JA
authors.lastname: Seddon
mesh_terms: D000367:Age Factors; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002648:Child; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D006801:Humans; D008962:Models, Theoretical; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D012107:Research Design; D014376:Tuberculosis / Q000188:drug therapy*; D014944:World Health Organization
chemical_list: D000995:Antitubercular Agents
keywords: PK/PD; children; future; hollow fiber; investment; tuberculosis