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PK/PD Optimized Cephalosporins Based Treatment Regimens for Children With MDR-TB

Award Number: R01HD099756
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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PK/PD Optimized Cephalosporins Based Treatment Regimens for Children With MDR-TB - Project summary/Abstract Children exposed to tuberculosis (TB) bacterium have a greater risk of progressing to active TB disease. Younger children (<2 years) are especially susceptible to developing disseminated disease due to ineffective immunologic containment. As per World Health Organization 2017 report, ~1 million children become ill with TB each year representing nearly 10% of the total TB cases. In 2016, ~3% of the reported cases in children diagnosed to have multi-drug resistant (MDR) TB (defined as being resistant to the two most potent first-line anti-TB drugs, isoniazid and rifampin). One of the hurdles in pediatric TB management is the availability of a safe and effective treatment regimen for MDR-TB designed specifically for children considering the age specific pharmacokinetic variability. Our broad objective is to use our hollow fiber system model for TB to streamline TB drug development. Given that the pipeline for novel TB drugs is still slim, there is renewed interest in repurposing old drugs for new use. β-lactam antibiotics are the backbone of many antibacterial treatment regimens; however, their efficacy against Mycobacterium tuberculosis (Mtb) have not been fully explored. We screened 13 drugs from the β-lactams class of the antibiotics including the cephalosporins sub-class, against drug resistant clinical strains of Mtb. In this grant application we will advance 6 cephalosporins to the next phase of investigations. Cephalosporins have an advantage because the pharmacokinetic and safety profile in children is well defined. We will combine the leading cephalosporins with two other oral drugs—moxifloxacin, an integral backbone of MDR-TB treatment regimens in people of all ages, and tedizolid, a new oxazolidinone effective against gram-positive pathogens as well as Mtb to create a potent regimen effective against MDR-TB in children. Our drug and combination regimen development approach apply pharmacokinetic/pharmacodynamic science using our validated hollow fiber system model for intracellular Mtb (HFS-TB). We have information on each drug’s optimal exposure target for maximal Mtb kill as monotherapy from the HFS-TB studies performed to collect preliminary data. The workflow of the current application will be - (1) use of checkerboard studies to evaluate additivity, synergy or antagonism of each cephalosporin with moxifloxacin, (2) add tedizolid at concentration to achieve optimal exposure target to the cephalosporins-moxifloxacin drug pair(s) to test in the HFS-TB comparing Mtb kill rates with a second-line MDR-TB regimen of five drugs (amikacin-levofloxacin-ethionamide-cycloserine-pyrazinamide) using MDR-TB clinical strains, (3) mathematical modeling of the HFS-TB results to predict Mtb time-to-extinction that will inform optimal duration of therapy with the proposed novel drug combination regimens, (4) in silico clinical trial simulations incorporating pediatric-specific pharmacokinetic variability as well as Mtb-strain minimum inhibitory concentration variability to establish optimal dose of each drug to achieve exposure targets among pediatric populations. The outcome will be novel treatment regimen(s) specially designed for MDR-TB in children in relatively short time span, addressing a major unmet clinical need in the global era of TB elimination.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $306,226 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER, THE	11937 US HWY 271	TYLER	TX	75708	SMITH	USA	Child Health and Human Development Extramural Research	000	5	7/13/2023	NON-COMPETING CONTINUATION	$306,226
														Subtotal = $306,226

Issue Date FY: 2022 ( Subtotal = $306,226 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER, THE	11937 US HWY 271	TYLER	TX	75708	SMITH	USA	Child Health and Human Development Extramural Research	000	4	7/18/2022	NON-COMPETING CONTINUATION	$306,226
														Subtotal = $306,226

Issue Date FY: 2021 ( Subtotal = $306,226 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER, THE	11937 US HWY 271	TYLER	TX	75708	SMITH	USA	Child Health and Human Development Extramural Research	000	3	7/12/2021	NON-COMPETING CONTINUATION	$306,226
														Subtotal = $306,226

Issue Date FY: 2020 ( Subtotal = $320,679 )
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER, THE	11937 US HWY 271	TYLER	TX	75708	SMITH	USA	Child Health and Human Development Extramural Research	001	2	7/24/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$320,679
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER, THE	11937 US HWY 271	TYLER	TX	75708	SMITH	USA	Child Health and Human Development Extramural Research	003	2	8/13/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$295,083
2020	2019	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Child Health and Human Development Extramural Research	002	1	8/13/2020	NEW	-$295,083
2020	2019	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Child Health and Human Development Extramural Research	000	1	7/24/2020	NEW	$0
														Subtotal = $320,679

Issue Date FY: 2019 ( Subtotal = $333,852 )
2019	2019	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Child Health and Human Development Extramural Research	000	1	8/29/2019	NEW	$333,852
														Subtotal = $333,852

Grand Total All Awards = $1,573,209

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PK/PD Optimized Cephalosporins Based Treatment Regimens for Children With MDR-TB

Award Number: R01HD099756

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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