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Population Pharmacokinetic Modeling and Clinical Trial Simulation to optimize HIV Prevention in Pregnancy and Postpartum

Award Number: R21HD106582
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Pre-exposure prophylaxis (PrEP) with oral tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (F or FTC) (F/TDF) is recommended during pregnancy for women at risk for HIV acquisition. F/tenofovir alafenamide fumarate (F/TAF) is not yet approved for PrEP in cisgender women due to lack of efficacy data. Despite the importance of HIV prevention in pregnancy, pregnant women have been excluded from PrEP efficacy studies. PrEP efficacy in pregnancy cannot be extrapolated from non-pregnant populations, as multiple studies indicate that TFV concentrations fall substantially in the 2nd and 3rd trimesters due to increased renal clearance and volume of distribution. Significant declines in FTC concentration are also reported largely due to increased renal excretion. Unlike TDF, TAF has minimal renal clearance, though other changes associated with pregnancy may also reduce its concentration. Given the high TFV blood concentrations required in non-pregnant women to achieve protective concentrations in cervicovaginal tissue, near perfect adherence to F/TDF is required to achieve HIV protection. The decreased TFV and FTC concentrations observed during pregnancy raise concern that a significant proportion of pregnant women on F/TDF for PrEP would not achieve protective concentrations without upward dose adjustment. In anticipation of the eventual approval of F/TAF for HIV prevention in cisgender women, evaluation of pharmacokinetic (PK) parameters and appropriate dosing of both F/TDF and F/TAF for PrEP in pregnancy is critically important to the prevention of both maternal and perinatal transmission. To assist with the future design of clinical trials to correct for this probable underdosing of F/TDF and, possibly, F/TAF, we propose an exploration of F/TAF and F/TDF PK parameters in pregnancy and postpartum. We plan to use F/TDF and F/TAF PK data from completed clinical studies enrolling non-pregnant and pregnant cisgender women in both the treatment and prevention settings, including IMPAACT 1026s, CONRAD 137 and 140, MTN 001, HPTN 066, Partners PrEP, Partners Demonstration Project, and several Gilead PK trials. Our specific aims are to: 1. Build a population PK model of F/TDF and F/TAF related drug analytes with special focus on timing relative to pregnancy in addition to variation in demographic and physiologic variables and building on existing PK models and 2. Simulate two clinical trials, one of F/TAF and one of F/TDF PrEP dosing in pregnancy and postpartum to assist with the future design of clinical trials to validate pregnancy- adjusted doses to maintain non-pregnant levels of HIV protection throughout pregnancy. This population PK research is the critical next step toward a prospective randomized clinical trial to better protect pregnant women and their fetuses against HIV acquisition and is in line with the NICHD Maternal and Pediatric Infectious Disease Branch and Office of AIDS research's stated high priority of “reducing the incidence of HIV” and “adverse pregnancy and infant outcomes related to prevention”.


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: 2025 ( Subtotal = -$140,399 )
2025	2022	MEDSTAR HEALTH RESEARCH INSTITUTE INC	6525 BELCREST RD STE 700	HYATTSVILLE	MD	20782	PRINCE GEORGES	USA	Child Health and Human Development Extramural Research	000	3	11/27/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$140,399
														Subtotal = -$140,399

Issue Date FY: 2023 ( Subtotal = $39,063 )
2023	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	002	2	4/3/2023	NON-COMPETING CONTINUATION	-$184,956
2023	2022	MEDSTAR HEALTH RESEARCH INSTITUTE INC	6525 BELCREST RD	HYATTSVILLE	MD	20782	PRINCE GEORGES	USA	Child Health and Human Development Extramural Research	004	3	5/12/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$105,975
2023	2022	MEDSTAR HEALTH RESEARCH INSTITUTE INC	6525 BELCREST RD	HYATTSVILLE	MD	20782	PRINCE GEORGES	USA	Child Health and Human Development Extramural Research	001	3	3/28/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$224,019
2023	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	1	3/20/2023	NEW	$0
2023	2021	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	003	1	5/12/2023	NEW	-$105,975
														Subtotal = $39,063

Issue Date FY: 2022 ( Subtotal = $184,956 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	2	7/12/2022	NON-COMPETING CONTINUATION	$184,956
														Subtotal = $184,956

Issue Date FY: 2021 ( Subtotal = $235,276 )
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	1	7/16/2021	NEW	$235,276
														Subtotal = $235,276

Grand Total All Awards = $318,896

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Population Pharmacokinetic Modeling and Clinical Trial Simulation to optimize HIV Prevention in Pregnancy and Postpartum

Award Number: R21HD106582

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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