Pharmacokinetics of tenofovir during pregnancy and postpartum

B M Best, S Burchett, H Li, A Stek, C Hu, J Wang, E Hawkins, M Byroads, D H Watts, E Smith, C V Fletcher, E V Capparelli, M Mirochnick, International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) P1026s Team, Francesca Aweeka, Emily Barr, Nantasak Chotivanich, Tim Roy Cressey, Lisa M Frenkel, Amita Gupta, Amy Jennings, Gonzague Jourdain, Regis Kreitchmann, Rita Patel, Kittipong Rungruengthanakit, David Shapiro, Pra-ornsuda Sukrakanchana, Andrea Kovacs, James Homans, LaShonda Spencer, Francoise Kramer, Shelley Buschur, Hunter Hammill 2nd, Mary E Paul, Chivon McMullen-Jackson, Ann Melvin, Corry Venema-Weiss, Jenna Lane, Jane Hitti, Katherine Knapp, Edwin Thorpe Jr, L Jill Utech, Nina Sublette, Diane Wara, Deborah Cohan, Nicole Tilton, Mary Elizabeth Vachon, Mirza Mahboobullah Baig, Murli Udharam Purswani, Jenny Gutierrez, Katherine Luzuriaga, Sharon Cormier, Margaret McManus, Andrew Hull, Mary Caffery, Kimberly Norris, Stephen A Spector, Margaret A Keller, Susan Ballagh, Judy Hayes, Yolanda Gonzalez, Emily Barr, Tara Kennedy, Alisa Katai, Jenna Wallace, James B McAuley, Helen Cejtin, Maureen McNichols, Julie Schmidt, Douglas Watson, Judy Ference, Corinda Hilyard, Marilyn Crain, Tina Y Simpson, Alan T N Tita, Irma L Febo, Carmen D Zorrilla, Vivian Tamayo-Agrait, Ruth Santos, B M Best, S Burchett, H Li, A Stek, C Hu, J Wang, E Hawkins, M Byroads, D H Watts, E Smith, C V Fletcher, E V Capparelli, M Mirochnick, International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) P1026s Team, Francesca Aweeka, Emily Barr, Nantasak Chotivanich, Tim Roy Cressey, Lisa M Frenkel, Amita Gupta, Amy Jennings, Gonzague Jourdain, Regis Kreitchmann, Rita Patel, Kittipong Rungruengthanakit, David Shapiro, Pra-ornsuda Sukrakanchana, Andrea Kovacs, James Homans, LaShonda Spencer, Francoise Kramer, Shelley Buschur, Hunter Hammill 2nd, Mary E Paul, Chivon McMullen-Jackson, Ann Melvin, Corry Venema-Weiss, Jenna Lane, Jane Hitti, Katherine Knapp, Edwin Thorpe Jr, L Jill Utech, Nina Sublette, Diane Wara, Deborah Cohan, Nicole Tilton, Mary Elizabeth Vachon, Mirza Mahboobullah Baig, Murli Udharam Purswani, Jenny Gutierrez, Katherine Luzuriaga, Sharon Cormier, Margaret McManus, Andrew Hull, Mary Caffery, Kimberly Norris, Stephen A Spector, Margaret A Keller, Susan Ballagh, Judy Hayes, Yolanda Gonzalez, Emily Barr, Tara Kennedy, Alisa Katai, Jenna Wallace, James B McAuley, Helen Cejtin, Maureen McNichols, Julie Schmidt, Douglas Watson, Judy Ference, Corinda Hilyard, Marilyn Crain, Tina Y Simpson, Alan T N Tita, Irma L Febo, Carmen D Zorrilla, Vivian Tamayo-Agrait, Ruth Santos

Abstract

Objectives: Tenofovir disoproxil fumarate (TDF) is increasingly used in the highly active antiretroviral therapy (HAART) regimens of pregnant women, but limited data exist on the pregnancy pharmacokinetics of chronically dosed TDF. This study described tenofovir pharmacokinetics during pregnancy and postpartum.

Methods: International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) P1026s is a prospective, nonblinded pharmacokinetic study of HIV-infected pregnant women that included a cohort receiving 300 mg TDF once daily. Steady-state 24-hour pharmacokinetic profiles were measured at the second and third trimesters, postpartum, and in maternal and umbilical cord samples collected at delivery. Tenofovir was measured by liquid chromatography-mass spectrometry (LC-MS). The target area under the concentration versus time curve from time 0 to 24 h post dose (AUC) was ≥ 1.99 μg h/mL (nonpregnant historical control 10th percentile).

Results: The median tenofovir AUC was decreased during the second (1.9 μg h/mL) and third (2.4 μg h/mL; P = 0.005) trimesters versus postpartum (3.0 μg h/mL). Tenofovir AUC exceeded the target for two of four women (50%) in the second trimester, 27 of 37 women [73%; 95% confidence interval (CI) 56%, 86%] in the third trimester, and 27 of 32 women (84%; 95% CI 67%, 95%) postpartum (P > 0.05). Median second/third-trimester troughs were lower (39/54 ng/mL) than postpartum (61 ng/mL). Median third-trimester weight was greater for subjects below the target AUC versus those above the target (97.9 versus 74.2 kg, respectively; P = 0.006). The median ratio of cord blood to maternal concentrations was 0.88. No infants were HIV infected.

Conclusions: This study found lower tenofovir AUC and troughs during pregnancy. Transplacental passage with chronic TDF use during pregnancy was high. Standard TDF doses appear to be appropriate for most HIV-infected pregnant women but therapeutic drug monitoring with dose adjustment should be considered in pregnant women with high weight (> 90 kg) or inadequate HIV RNA response.

Keywords: HIV; antiretrovirals; pregnancy; prevention of perinatal transmission; tenofovir.