Background: Data describing the pharmacokinetics and safety of tenofovir in neonates are lacking.
Methods: The HIV Prevention Trials Network 057 protocol was a phase 1, open-label study of the pharmacokinetics and safety of tenofovir disoproxil fumarate (TDF) in HIV-infected women during labor and their infants during the first week of life with 4 dosing cohorts: maternal 600 mg doses/no infant dosing; no maternal dosing/infant 4 mg/kg doses on days 0, 3, and 5; maternal 900 mg doses/infant 6 mg/kg doses on days 0, 3, and 5; maternal 600 mg doses/infant 6 mg/kg daily for 7 doses. Pharmacokinetic sampling was performed on cohort 1 and 3 mothers and all infants. Plasma, amniotic fluid, and breast milk tenofovir concentrations were determined by liquid chromatographic–tandem mass spectrometric assay. The pharmacokinetic target was for infant tenofovir concentration throughout the first week of life to exceed 50 ng/mL, the median trough tenofovir concentration in adults receiving standard chronic TDF dosing.
Results: One hundred twenty-two mother–infant pairs from Malawi and Brazil were studied. Tenofovir exposure in mothers receiving 600 and 900 mg exceeded that in nonpregnant adults receiving standard 300 mg doses. Tenofovir elimination in the infants was equivalent to that in older children and adults, and trough tenofovir plasma concentrations exceeded 50 ng/mL in 74%–97% of infants receiving daily dosing.
Conclusions: A TDF dosing regimen of 600 mg during labor and daily infant doses of 6 mg/kg maintains infant tenofovir plasma concentration above 50 ng/mL throughout the first week of life and should be used in the studies of TDF efficacy for HIV prevention of mother-to-child transmission and early infant treatment.
*Department of Pediatrics, Boston University School of Medicine, Boston, MA;
†Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD;
‡HIV/AIDS Research Department, Irmandade da Santa Casa de Misericordia de Porto Alegre, Rio Grande do Sul, Brazil;
§Department of Pediatrics, David Geffen UCLA School of Medicine, Los Angeles, CA;
‖Malawi College of Medicine, Blantyre, Malawi;
¶Infectious Diseases Department, Hospital Federal dos Servidores do Estado, Rio de Janiero, Brazil;
#Department of Pediatrics, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil;
**Serviço de Infectologia, Hospital Nossa Senhora da Conceicao, Porto Alegre, Rio Grande do Sul, Brazil;
††Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD;
‡‡Gilead Sciences, Foster City, CA;
§§Statistical Center for HIV/AIDS Research and Prevention, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
‖‖Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD;
¶¶Family Health International, Durham, NC;
##Makerere University—Johns Hopkins University Research Collaboration, Kampala, Uganda;
***National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; and
†††Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD.
Correspondence to: Mark Mirochnick, MD, Boston Medical Center, 771 Albany Street, Dowling 4N—Room 4111, Boston, MA 02043 (e-mail: email@example.com).
Supported by the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) and HIV Prevention Trials Network (HPTN). Overall support for IMPAACT was provided by the National Institute of Allergy and Infectious Diseases (NIAID) (U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) (AI068632). Study was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the NIAID cooperative agreement 5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group and 1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the NIAID and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C). The HPTN is sponsored by the NIAID, NICHD, National Institute on Drug Abuse, NIMH, and Office of AIDS Research of the National Institutes of Health, US Department of Health and Human Services under award U01 AI046749.
M.M. has served as a consultant for Abbott Laboratories and has received support for travel from Farmanguinhos/FIOCRUZ, Rio de Janeiro, Brazil. B.K. is an employee of Gilead Sciences. The remaining authors have no conflicts of interest to disclose. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Dedicated in memory of our colleague and friend George Kafulafula, MBBS, MMED, FCOG (Protocol Co-Chair).
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Received May 20, 2013
Accepted August 12, 2013