title: A Combination Regimen Design Program Based on Pharmacodynamic Target Setting for Childhood Tuberculosis: Design Rules for the Playground.
abstract: Children with tuberculosis are treated with drug regimens copied from adults despite significant differences in antibiotic pharmacokinetics, pathology, and the microbial burden between childhood and adult tuberculosis. We sought to develop a new and effective oral treatment regimen specific to children of different ages. We investigated and validated the concept that target drug concentrations associated with therapy failure and death in children are different from those of adults. On that basis, we proposed a 4-step program to rapidly develop treatment regimens for children. First, target drug concentrations for optimal efficacy are derived from preclinical models of disseminated tuberculosis that recapitulate pediatric pharmacokinetics, starting with monotherapy. Second, 2-drug combinations were examined for zones of synergy, antagonism, and additivity based on a whole exposure-response surface. Exposures associated with additivity or synergy were then combined and the regimen was compared to standard therapy. Third, several exposures of the third drug were added, and a 3-drug regimen was identified based on kill slopes in comparison to standard therapy. Fourth, computer-aided clinical trial simulations are used to identify clinical doses that achieve these kill rates in children in different age groups. The proposed program led to the development of a 3-drug combination regimen for children from scratch, independent of adult regimens, in <2 years. The regimens and doses can be tested in animal models and in clinical trials.
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
authors.forename: Shashikant
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
authors.forename: Devyani
authors.initials: D
authors.lastname: Deshpande
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
authors.forename: Jotam G
authors.initials: JG
authors.lastname: Pasipanodya
authors.affiliation: Division of Infectious Diseases and International Health, University of Virginia, Charlottesville.
authors.forename: Tania
authors.initials: T
authors.lastname: Thomas
authors.affiliation: Tuberculosis Research Center, Chennai, India.
authors.forename: Soumya
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Department of International Health, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Eric
authors.initials: E
authors.lastname: Nuermberger
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
mesh_terms: D000367:Age Factors; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002675:Child, Preschool; D003198:Computer Simulation; D016903:Drug Monitoring; D004359:Drug Therapy, Combination / Q000379:methods / Q000592:standards; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents
keywords: disseminated tuberculosis; drug regimen design; pharmacokinetics/pharmacodynamics; target setting; young children