708 
Pharmacokinetics and Safety of Tenofovir Disoproxil Fumarate in HIV-1-infected Pregnant Women and their Infants
John Rodman*1, P Flynn1, D Shapiro2, A Bardeguez3, S Huang4, S Fiscus5, V Koen6, J Rooney7, L Mofenson8, J P Patrick9, and PACTG 394 Study Team
1St Jude Children's Res Hosp, Memphis, TN, US; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3Univ of Med and Dentistry of New Jersey, Newark, US; 4Statistical and Data Analysis Ctr, Boston, MA, US; 5Univ of North Carolina at Chapel Hill, US; 6Univ of California, Davis, US; 7Gilead Sci, Foster City, CA, US; 8Natl Inst Child Hlth and Devt, NIH, DHHS, Bethesda, MD, US; and 9Div of AIDS, NIAID, NIH, DHHS, Bethesda, MD, US
Background: Tenofovir (TFV) is effective for prevention of
simian immunodeficiency virus (SIV) transmission in a macaque model, is
available as an oral agent (tenofovir disoproxil fumarate, TDF) for treatment
of HIV infection, and offers potential advantages over current short-course regimens
for reducing mother-to-child HIV transmission (MTCT) in terms of development of
drug resistance. The initial pharmacokinetics and safety of oral TDF
administered at the onset of labor was determined in a dose escalation trial to
provide a regimen for future phase 3 trials for prevention of MTCT.
Methods: TDF 600 mg was given at onset of labor for
vaginal delivery or 4 hours prior to caesarian section with standard intravenous
zidovudine (ZDV) prophylaxis. Maternal blood samples at 7 intervals over 24 hours,
a cord blood sample, and infant samples at 3 intervals over 36 hours
post-delivery were obtained and assayed for TFV by LC/MS-MS.
Results: TDF was safe and well tolerated in 14 mother/infant
pairs. Complete pharmacokinetic data from 9 mother/infant pairs were available
and met evaluation criteria for the study. Among the 9 mothers, median (range)
age and HIV RNA viral load at entry were 24 years (21 to 44) and 1.86 log10
copies/mL (1.08 to 2.64). Maternal ART
regimens at entry included a minimum of 2 nucleoside reverse transcriptase
inhibitors (NRTI) plus either a protease inhibitor (PI) (n = 4), nevirapine (NVP) (n
= 2), or a third NRTI (n = 3). Median
(range) time from TDF dose to delivery was 5.7 hours (2 to 19.5). Medians
(range) for maternal TFV AUC, Cmax, Tmax, and C24 hour
were 2377 ng/mL*h (1344 to 4480), 264 ng/mL (83 to 595), 1 hour (1 to 12), and
49 ng/mL (34 to 94). Median (range) cord blood TFV was 64 ng/mL (<25 to 223)
with cord blood/maternal ratio of 0.66 (0.35 to 1.0) for 8 of 9 mother/infant
pairs with measurable maternal TFV. TFV concentrations in infants were all
<25 ng/mL after 12 hours of age and detectable in only 5 infants. No infants
show evidence of HIV infection.
Conclusions:
TDF demonstrated an acceptable absorption
profile, with no clinically significant adverse events in mothers or infants.
However maternal TFV concentrations are substantially lower than previously
reported in adults receiving the same single dose and HIV-infected patients at
steady state receiving TDF 300 mg once daily. TFV placental transfer is
sufficient to achieve cord blood concentrations with ART activity, but maternal
inter-subject pharmacokinetics and cord blood TFV variability is substantial. Low-TFV
infant post-delivery concentrations allows immediate postpartum TDF
administration. A higher maternal TDF dose with infant dosing will be evaluated
in a second cohort to more consistently achieve TFV concentrations likely to be
effective in preventing MTCT.
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