939 
Single-dose Tenofovir Disoproxil Fumarate with and without Emtricitabine in HIV-1-infected Pregnant Women and Their Infants: Pharmacokinetics and Safety
Patricia Flynn*1, M Mirochnick2, D Shapiro3, A Bardeguez4, S Huang3, S Fiscus5, J Rooney6, H Watts7, L Mofenson7, P Jean-Philippe8, and PACTG/IMPAACT 394 Study Team
1St Jude Children`s Res Hosp, Memphis, TN, US; 2Boston Med Ctr, Boston Children`s Hosp, MA, US; 3Statistical and Data Analysis Ctr, Harvard Sch of Publ Hlth, Boston, MA, US; 4Univ of Med and Dentistry of New Jersey, Newark, US; 5Univ of North Carolina at Chapel Hill, US; 6Gilead Sci, Foster City, CA, US; 7Natl Inst of Child Hlth and Human Devt, NIH, Rockville, MD, US; and 8Henry M Jackson Fndn, Div of AIDS, NIAID, NIH, Bethesda, MD, US
Background: Tenofovir (TDF) is effective for
prevention of simian immunodeficiency virus (SIV) transmission in a macaque
model and is available as an oral agent (TDF). We conducted a phase I trial of
TDF and TDF + emtricitabine (FTC) in HIV-infected pregnant women and their
infants. Pharmacokinetics and safety of 600-mg oral TDF has been reported by
this group. We now report the pharmacokinetics and safety of 900 mg TDF alone
and with 600 mg FTC (given as TruvadaŽ) in mothers and 4 mg/kg TDF and 3 mg/kg
FTC administered to their newborns.
Methods: TDF (n = 7) or TDF/FTC (n = 8) was given
during active labor for patients with vaginal delivery (VD) or 4 hours prior to
scheduled caesarian section. Infants received the same regimen as their mothers
and were dosed as soon as possible after birth. All women received HAART during
pregnancy and women and infants received the ACTG 076 zidovudine regimen
peripartum. Maternal (M) blood samples at 7 intervals over 24 hours
post-dosing, a cord blood sample, and infant (IN) samples at 5 intervals over
36 hours post-dosing were obtained and assayed for TDF by liquid
chromatography/mass spectrometry/mass spectrometry. FTC pharmacokinetics is
pending.
Results: TDF and TDF/FTC were safe and well
tolerated in 15 mothers and 16 infants. Among the mothers, median (range) age
and HIV RNA viral load at entry were 28 years (19 to 37) and 1.53 log10
copies/mL (0.95 to 3.17). Median (range) time from TDF dose to delivery was 7 hours
(1.5 to 21) and from birth to TDF dose in infants was 5.5 hours (1.8 to 11). Pharmacokinetic
findings from the TDF and TDF/FTC groups were similar and combined; median and
ranges are presented in the table. Maternal TFV at delivery was 108.5 ng/mL (n =
15, 0 to 381) and cord blood TDF was 68.3 ng/mL (n = 15, 0 to 224.2). Cord
blood TDF exceeded the target of 50 ng/mL in 10 of 15. Cord blood/maternal was
66.5% (n = 14). Women delivering by vaginal delivery (n = 9) had lower AUC (↓38%)
and Cmax (↓62%) compared to caesarian section (n = 6) but
these differences were not statistically significant. TDF Cmax
increased by 83% compared to 600-mg dosing but AUC was similar. No infant was
HIV infected and no mother demonstrated a new K65R resistance mutation by week
12.
Conclusions: TDF is safe and demonstrated an
acceptable absorption profile. Maternal TDF AUC and TDF placental transfer is
sufficient to achieve cord blood concentrations with antiretroviral activity. TDF
exposures were lower in infants, suggesting either altered absorption or more
rapid clearance. The appropriate dosing schedule in infants to maintain
effective concentrations over the first days of life remains to be determined.
|
