P2026: Pharmacokinetic Properties of Antiretroviral and Anti-Tuberculosis Drugs during Pregnancy and Postpartum

Study Location:

BaltimoreIndia

Topic:

Maternal-Child Health and HIV

Enrollment:

Open

Trial Period:

Ongoing

IMPAACT P1026s, the predecessor of this study, was first approved in 2003. P1026s enrolled over 1000 pregnant/postpartum women, studied the PK of more than 25 HIV and TB drugs in these women and published 27 manuscripts presenting these data. P1026s data was cited in 32% of the 76 perinatal pharmacology studies in the 2017 version of the United States (US) Department of Health and Human Services (DHHS) Perinatal HIV Guidelines and in 63% of the 27 drug sections contained in these guidelines. Data from the P1026s elvitegravir-cobicistat arm was used as the basis for the 2018 revision of the labels for cobicistat and the cobicistat- containing fixed dose products Stribild, Genvoya, Prezcobix, Eyotaz, and Symtuza to say that these products are “not recommended for use during pregnancy because of substantially lower exposures of cobicistat and elvitegravir during pregnancy”

Pregnant women continue to be excluded from prelicensure ARV drug development programs, so antiretroviral drugs are approved for use in the absence of pregnancy specific pharmacokinetic and safety data and the need for a study like IMPAACT P1026s continues. Changes in the HIV and TB treatment landscape, in addition to the need to make updates to the protocol to meet current IMPAACT Network standards for protocol documents, data collection, regulatory compliance, and quality assurance, necessitate a new protocol to replace P1026s to continue this critical research. IMPAACT 2026 is an opportunistic study of ARV and TB drugs which are being used as part of clinical care in pregnant and postpartum women but for which there are insufficient or no pregnancy-specific pharmacokinetic or safety data. 

IMPAACT 2026 will provide the following: 
The first data describing plasma PK during pregnancy of bictegravir and doravirine, the newest ARVs, and the first data describing intracellular TFV-DP with use of TAF during pregnancy 
The first data describing washout PK data during pregnancy and postpartum after long-acting injection of CAB 
Critical pregnancy ARV and TB drug PK data for women receiving treatment with first- and second-line TB treatment drugs during pregnancy 
The first data describing the kinetics of mother to infant breast milk drug transfer for several ARVs and TB treatment drugs 

The IMPAACT Network and its stakeholders encourages the use of IMPAACT 2026 data in support of modifications of FDA drug labels regarding recommendations for use of a drug during pregnancy. While drug labels should include data and recommendations about use and dosing in pregnancy, pregnant women are excluded from the prelicensing drug development programs for ARVs. As a result, no human PK or safety data relevant to pregnancy are included in initial labels for ARVs. IMPAACT 2026 will continue to provide a primary source of PK data for ARVs in pregnancy. 

ARV drug pharmacology in neonates is different from that in older infants and children due to immaturity and the physiologic changes experienced by the neonate during the adaptation to the extrauterine environment in the first weeks of life. ARV drugs may be used in the neonate to prevent or treat HIV infection. Clinical trials studying the neonatal elimination of ARV drugs acquired across the placenta after maternal dosing during pregnancy are critical first steps in understanding the pharmacology of ARV drugs in neonates and establishing safe and effective neonatal dosing regimens. Washout pharmacokinetic data from P1026s infants born to mothers receiving ARVs under study facilitated development of Phase I studies of several ARVs in newborns and infants, including maraviroc and dolutegravir. IMPAACT 2026 will continue to provide initial washout PK data to characterize drug elimination in infants who have received the ARV in utero and to inform the design of further studies including initial dose finding and PK/pharmacodynamic studies in newborns. 

Primary Objectives 
The primary objectives of this study are to: 
2.1.1  Component 1: Describe the PK parameters during pregnancy of selected ARV drugs administered to WLHIV who are not receiving TB drugs, and to compare these parameters to (a) historical PK data from non-pregnant women and (b) each participant’s own postpartum PK data. 
2.1.2  Component 2: Describe the kinetics of (a) placental and breast milk transfer of CAB LA from mother to fetus/infant and (b) infant elimination of CAB LA acquired across the placenta after maternal dosing during pregnancy. 
2.1.3  Component 3: Describe the PK parameters during pregnancy and postpartum of selected ARV drugs and first-line TB treatment drugs co-administered to WLHIV. 
2.1.4  Component 4: Describe the PK parameters during pregnancy and postpartum of second- line TB treatment drugs administered to WLHIV and HIV-uninfected women. 
2.1.5  Component 5: Describe the kinetics of drug transfer of selected ARVs from mother to infant via breast milk. 
Secondary Objectives 
The secondary objectives of this study are to: 
2.2.1  All Components: Describe maternal and infant safety and clinical outcomes. 
2.2.2  Components 1, 3 and 4: Compare drug concentrations in plasma from cord blood with concentrations in maternal plasma at delivery for selected ARV and/or TB treatment drugs. 
2.2.3  Components 1, 3 and 4: Describe the neonatal elimination of selected ARV and/or TB treatment drugs acquired across the placenta after maternal dosing during pregnancy. 
2.2.4  Components 3 and 4: To describe the kinetics of drug transfer of selected ARVs and/or TB treatment drugs from mother to infant via breast milk. 
2.2.5  Component 4: Describe the PK parameters of selected ARVs when co-administered with selected second-line TB treatment drugs to WLHIV during pregnancy and postpartum. 

Preg/postpartum women. Infants

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