Study Objective: To define the pharmacokinetics of zidovudine (azidothymidine) in children with human immunodeficiency virus infection.
Design: Plasma, urine, and cerebrospinal fluid were obtained following a single 80 mg/m2 body surface dose infused over 1 hour (n = 9), and during a continuous infusion of 0.5 (n = 3), 0.9 (n = 8), 1.4 (n = 7), or 1.8 (n = 3) mg/kg body weight per hour.
Setting: Outpatient clinic and inpatient ward of the Pediatric Branch of the National Cancer Institute.
Patients: Twenty-one children (seventeen boys) ranging in age from 14 months to 12 years with symptomatic human immunodeficiency virus infection who were being treated on a phase I-II study of continuous intravenous infusion zidovudine.
Measurements and Main Results: Zidovudine disappearance following bolus administration was rapid and biexponential with half-lives of 9.6 and 92 minutes, and a total clearance of 705 ± 330 mL/min · m2. Zidovudine remained above 1 µmol/L, the optimal virostatic concentration in vitro, for only 1.5 hours. In contrast, with continuous infusion steady-state plasma zidovudine concentrations (Css) were maintained above 1 µmol/L continuously, even at the lowest infusion rate. At steady state the ratio of cerebrospinal fluid zidovudine concentration to plasma was 24% ± 9%. Patients who developed severe neutropenia (absolute neutrophil count < 0.5 X 109L) on the continuous, infusion regimen had significantly higher plasma Css. Six of eight had a Css greater than 3.0 µmol/L.
Conclusions: Pharmacokinetic parameters show that continuous infusion is better than an intermittent schedule in maintaining minimal virostatic concentrations of the drug with a lower daily dose.