title: Population Pharmacokinetics of Rifampin in Pregnant Women with Tuberculosis and HIV Coinfection in Soweto, South Africa.
abstract: Effective treatment of tuberculosis during pregnancy is essential for preventing maternal and fetal mortality, but little is known about the effects of pregnancy on the disposition of antituberculosis drugs. We explored the effects of pregnancy on the pharmacokinetics of rifampin, the key sterilizing drug in tuberculosis treatment, in Tshepiso, a prospective cohort study involving pregnant HIV-infected women with or without tuberculosis in Soweto, South Africa. Participants receiving standard first-line tuberculosis treatment underwent sparse sampling for rifampin at 37 weeks' gestation or delivery and then postpartum. Cord blood was collected when possible. A population pharmacokinetic model was developed to investigate the effects of pregnancy on rifampin pharmacokinetics. Among the 48 participants, median age and weight were 28 years and 67 kg, respectively. A one-compartment model with first-order elimination, transit compartment absorption, and allometric scaling described the data well. Pregnancy reduced rifampin clearance by 14%. The median (interquartile range) model-estimated rifampin area under the concentration-time curve over 24 h (AUC0-24) during pregnancy or intrapartum was 40.8 h · mg/liter (27.1 to 54.2 h · mg/liter) compared to 37.4 h · mg/liter (26.8 to 50.3 h · mg/liter) postpartum. The maximum concentrations were similar during pregnancy and postpartum. Rifampin was detectable in 36% (8/22) of cord blood samples, and 88% (42/48) of the women had successful treatment outcomes. There was one case of perinatal tuberculosis. In conclusion, rifampin clearance is modestly reduced during the last trimester of pregnancy. Exposures are only slightly increased, so dose adjustment during pregnancy is not needed. Rifampin was detected in cord blood samples when delivery occurred soon after dosing. The consequences of exposure to this potent inducer of metabolizing enzymes among HIV-exposed infants are unclear.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Paolo
authors.initials: P
authors.lastname: Denti
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Perinatal HIV Research Unit, MRC Soweto Matlosana Collaborating Centre for HIV/AIDS and TB, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Neil
authors.initials: N
authors.lastname: Martinson
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Cohn
authors.affiliation: Perinatal HIV Research Unit, MRC Soweto Matlosana Collaborating Centre for HIV/AIDS and TB, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Fildah
authors.initials: F
authors.lastname: Mashabela
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hoffmann
authors.affiliation: Perinatal HIV Research Unit, MRC Soweto Matlosana Collaborating Centre for HIV/AIDS and TB, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Reginah
authors.initials: R
authors.lastname: Msandiwa
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Sandra
authors.initials: S
authors.lastname: Castel
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Chaisson
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA kdooley1@jhmi.edu.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Dooley
mesh_terms: D000328:Adult; D000904:Antibiotics, Antitubercular / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D015331:Cohort Studies; D060085:Coinfection / Q000188:drug therapy; D005260:Female; D005312:Fetal Blood / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007231:Infant, Newborn; D049590:Postpartum Period; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy*; D011446:Prospective Studies; D012293:Rifampin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013019:South Africa; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000904:Antibiotics, Antitubercular; D012293:Rifampin