title: Genital tract, cord blood, and amniotic fluid exposures of seven antiretroviral drugs during and after pregnancy in human immunodeficiency virus type 1-infected women.
abstract: The objective of the study was to measure antiretroviral exposures in four physiological compartments during pregnancy, delivery, and postpartum. This prospective, open-label, longitudinal study collected paired blood plasma (BP) and genital tract (GT) aspirates antepartum, at delivery, and up to 12 weeks postpartum. Antiretroviral cord BP and amniotic fluid concentrations were also measured. Drug concentrations were analyzed by validated high-performance liquid chromatography/UV and liquid chromatography/tandem mass spectrometry methods, with secondary compartment concentrations presented as the percentage of BP. Fourteen women taking lamivudine plus zidovudine and either lopinavir-ritonavir (n = 7), nelfinavir (n = 6), or nevirapine (n = 1) were enrolled; four also received tenofovir. GT penetration relative to BP was highest for the nucleoside reverse transcriptase inhibitors compared to the protease inhibitors and nevirapine. Only antepartum nelfinavir GT penetration was significantly higher than in the second trimester (geometric mean ratio [GMR], 179.3) or third trimester (GMR, 41.9). Compared to nonpregnant historical controls, antepartum GT penetration was significantly lower (P < 0.05) for zidovudine (GMR, 0.25) and lopinavir (GMR, 0.03); postpartum lopinavir GT penetration continued to be significantly lower (GMR, 0.27). Cord BP exposures were highest for lamivudine and tenofovir (> or = 100%), with cord BP levels of the remaining drugs ranging from 49 to 86% of that of the respective BP level. Amniotic exposures for lamivudine, zidovudine, tenofovir, and nelfinavir were > or = 100%, nevirapine exposure was 53%, and lopinavir and ritonavir exposures were < or = 6% that of BP. We conclude that GT, cord BP, and amniotic fluid exposures vary within and between antiretroviral drug classes and biologic sites. Measurement of antiretroviral exposure in maternal genital secretions, cord BP, and amniotic fluid may be needed to identify signals of subtherapeutic or supratherapeutic drug exposure.
authors.affiliation: School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Rosa F
authors.initials: RF
authors.lastname: Yeh
authors.forename: Naser L
authors.initials: NL
authors.lastname: Rezk
authors.forename: Angela D M
authors.initials: AD
authors.lastname: Kashuba
authors.forename: Julie B
authors.initials: JB
authors.lastname: Dumond
authors.forename: Hiba L
authors.initials: HL
authors.lastname: Tappouni
authors.forename: Hsiao-Chuan
authors.initials: HC
authors.lastname: Tien
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Chen
authors.forename: Manoli
authors.initials: M
authors.lastname: Vourvahis
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Horton
authors.forename: Susan A
authors.initials: SA
authors.lastname: Fiscus
authors.forename: Kristine B
authors.initials: KB
authors.lastname: Patterson
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000328:Adult; D000653:Amniotic Fluid / Q000378:metabolism*; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D005260:Female; D005312:Fetal Blood / Q000378:metabolism*; D005836:Genitalia, Female / Q000378:metabolism* / Q000821:virology; D015497:HIV-1; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000652:urine; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy*; D012367:RNA, Viral / Q000097:blood
chemical_list: D019380:Anti-HIV Agents; D012367:RNA, Viral; C001380:6 beta-hydroxycortisol; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D006854:Hydrocortisone