Pharmacokinetics and Safety of Single-Dose Tenofovir Disoproxil Fumarate and Emtricitabine in HIV-1-Infected Pregnant Women and Their Infants

St Jude Children’s Research Hospital, Memphis, Tennessee 138105-2794, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 09/2011; 55(12):5914-22. DOI: 10.1128/AAC.00544-11
Source: PubMed


Tenofovir (TFV) is effective in preventing simian immunodeficiency virus (SIV) transmission in a macaque model, is available as the oral agent tenofovir disoproxil fumarate (TDF), and may be useful in the prevention of mother-to-child transmission of human immunodeficiency virus (HIV). We conducted a trial of TDF and TDF-emtricitabine (FTC) in HIV-infected pregnant women and their infants. Women received a single dose of either 600 mg TDF, 900 mg TDF, or 900 mg TDF-600 mg FTC at labor onset or prior to a cesarean section. Infants received no drug or a single dose of TDF at 4 mg/kg of body weight or of TDF at 4 mg/kg plus FTC at 3 mg/kg as soon as possible after birth. All regimens were safe and well tolerated. Maternal areas under the serum concentration-time curve (AUC) and concentrations at the end of sampling after 24 h (C(24)) were similar between the two doses of TDF; the maximum concentrations of the drugs in serum (C(max)) and cord blood concentrations were higher in women delivering via cesarean section than in those who delivered vaginally (P = 0.04 and 0.046, respectively). The median ratio of the TFV concentration in cord blood to that in the maternal plasma at delivery was 0.73 (range, 0.26 to 1.95). Without TDF administration, infants had a median TFV concentration of 12 ng/ml 12 h after birth. Following administration of a single dose of TDF at 4 mg/kg, infant TFV concentrations fell below the targeted level, 50 ng/ml, by 24 h postdose. In HIV-infected pregnant women and their infants, 600 mg of TDF is acceptable as a single dose during labor. Low concentrations at birth support infant dosing as soon after birth as possible. Rapidly decreasing TFV levels in infants suggest that multiple or higher doses of TDF will be necessary to maintain concentrations that are effective for viral suppression.

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    ABSTRACT: According to the European AIDS Clinical Society, tenofovir disoproxil fumarate can be used in HIV-infected pregnant women if started prior to pregnancy, although no data are available on the pharmacokinetics of tenofovir (TFV) during pregnancy. The aim of this study was to describe TFV pharmacokinetics in HIV-infected women and to evaluate the effect of pregnancy on TFV disposition. Samples were collected according to a therapeutic drug monitoring in 186 women, including 46 pregnant women treated with TFV and retrospectively analyzed by a population approach. TFV pharmacokinetics were ascribed to an open two-compartment model with linear absorption and elimination. The mean population parameter estimates (between-subject variability) were as follows: absorption rate constant, 0.56 h−1; elimination clearance, 59.9 liters h−1 (0.436); central volume of distribution, 552 liters (1.96); intercompartmental clearance, 172 liters/h; and peripheral volume of distribution, 1,390 liters. Pregnant women had a 39% higher apparent clearance compared to nonpregnant women. Apparent clearance significantly decreased with age. In order to obtain an exposure similar to the known exposure in adults and guarantee similar trough concentrations (Cmin) as observed in adults, an increase in the TFV dose should be considered for women from the second trimester to delivery.
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