title: Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus.
abstract: This study evaluated the safety, tolerability, and pharmacokinetics of zidovudine administered intravenously and orally to infants born to women infected with the human immunodeficiency virus. Thirty-two symptom-free infants were enrolled before 3 months of age. The pharmacokinetics of zidovudine were evaluated in each infant after single intravenously and orally administered doses of zidovudine on consecutive days, and during long-term oral administration of the drug for 4 to 6 weeks. As new patients were enrolled, doses of zidovudine were progressively increased from 2 to 4 mg/kg. Therapy was continued for up to 12 months in 7 of the infants proved to be infected with human immunodeficiency virus. Zidovudine was generally well tolerated; 20 children (62.5%) had anemia (hemoglobin level < 10.0 gm/dl) during therapy and 9 (28.1%) had neutropenia (neutrophil count < or = 750 cells/mm3); these hematologic abnormalities usually resolved spontaneously. The total body clearance of zidovudine increased significantly with age, from an average of 10.9 ml/min per kilogram in infants < or = 14 days of age to 19.0 ml/min per kilogram in older infants (p < 0.0001). Concurrently, there was a significant decrease in serum half-life from 3.12 hours in infants < or = 14 days to 1.87 hours in older infants (p = 0.0002). Oral absorption was satisfactory and bioavailability decreased significantly with age, from 89% in infants < or = 14 days to 61% in those > 14 days of age (p = 0.0002). Plasma concentrations of zidovudine were calculated to be in excess of 1 mumol/L (0.267 micrograms/ml) for 4.12 +/- 1.86 hours and 2.25 +/- 0.78 hours after oral doses of 2 mg/kg in infants younger than 2 weeks and 3 mg/kg in older infants, respectively. We conclude that zidovudine administered at oral doses of 2 mg/kg every 6 hours to infants aged less than 2 weeks and 3 mg/kg every 6 hours to infants older than 2 weeks resulted in plasma concentrations that are considered virustatic against human immunodeficiency virus. Zidovudine was well tolerated by infants at these doses.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, California.
authors.forename: F D
authors.initials: FD
authors.lastname: Boucher
authors.forename: J F
authors.initials: JF
authors.lastname: Modlin
authors.forename: S
authors.initials: S
authors.lastname: Weller
authors.forename: A
authors.initials: A
authors.lastname: Ruff
authors.forename: M
authors.initials: M
authors.lastname: Mirochnick
authors.forename: S
authors.initials: S
authors.lastname: Pelton
authors.forename: C
authors.initials: C
authors.lastname: Wilfert
authors.forename: R
authors.initials: R
authors.lastname: McKinney
authors.forename: M J
authors.initials: MJ
authors.lastname: Crain
authors.forename: M M
authors.initials: MM
authors.lastname: Elkins
mesh_terms: D000284:Administration, Oral; D000740:Anemia / Q000139:chemically induced; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D005260:Female; D015658:HIV Infections / Q000151:congenital* / Q000188:drug therapy* / Q000635:transmission; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D008297:Male; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D015215:Zidovudine; C055886:3'-azido-3'-deoxy-5'-O-beta-glucopyranuronosylthymidine