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The Pharmacokinetics of Zidovudine Administered by Continuous Infusion in Children

Frank M. Balis, MD; Philip A. Pizzo, MD; Robert F. Murphy, BS; Janie Eddy, RN, MSN, PNP; Paul F. Jarosinski, BS; Judith Falloon, MD; Samuel Broder, MD; and David G. Poplack, MD
[+] Article, Author, and Disclosure Information

Requests for Reprints: Frank M. Balis, MD, Pediatric Branch, National Cancer Institute, Bldg. 10, Rm. 13N240, National Institutes of Health, Bethesda, MD 20892.

Current Author Addresses: Drs. Balis, Pizzo, Falloon, and Poplack, and Mr. Murphy and Ms. Eddy: Pediatric Branch, National Cancer Institute, Bldg. 10, Rm. 13N240, National Institutes of Health, Bethesda, MD 20892.

Mr. Jarosinski: Pharmacy Department, CC, Bldg. 10, Rm. 13N240, National Institutes of Health, Bethesda, MD 20892.

Dr. Broder: Clinical Oncology Program, Bldg. 10, Rm. 12N214, National Cancer Institute, Bethesda, MD 20892.

Ann Intern Med. 1989;110(4):279-285. doi:10.7326/0003-4819-110-4-279
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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.





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