TY - JOUR
T1 - A Combination Regimen Design Program Based on Pharmacodynamic Target Setting for Childhood Tuberculosis
T2 - Design Rules for the Playground
AU - Srivastava, Shashikant
AU - Deshpande, Devyani
AU - Pasipanodya, Jotam G.
AU - Thomas, Tania
AU - Swaminathan, Soumya
AU - Nuermberger, Eric
AU - Gumbo, Tawanda
N1 - Funding Information:
National Institute of Allergy and Infectious Diseases of the National Institutes of Health (grant number R56 AI111985).
Publisher Copyright:
© 2016 The Author. Published by Oxford University Press for the Infectious Diseases Society of America.
PY - 2016/11/1
Y1 - 2016/11/1
N2 - 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.
AB - 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.
KW - disseminated tuberculosis
KW - drug regimen design
KW - pharmacokinetics/pharmacodynamics
KW - target setting
KW - young children
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U2 - 10.1093/cid/ciw472
DO - 10.1093/cid/ciw472
M3 - Article
C2 - 27742637
AN - SCOPUS:84994660122
SN - 1058-4838
VL - 63
SP - S75-S79
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
ER -