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The pharmacokinetics of zidovudine administered by continuous infusion in children
F M Balis1, P A Pizzo, R F Murphy
1National Institutes of Health, Bethesda, Maryland.
Insights
Continuous infusion of zidovudine (azidothymidine) maintains optimal virostatic concentrations in HIV-infected children. This method is superior to intermittent dosing, achieving therapeutic drug levels with reduced daily doses.
Area of Science:
- Pediatric pharmacology
- Antiviral pharmacokinetics
Background:
- Zidovudine (azidothymidine) is a key antiretroviral medication.
- Understanding its pharmacokinetics in pediatric HIV is crucial for effective treatment.
Purpose of the Study:
- To define the pharmacokinetics of zidovudine in children with human immunodeficiency virus infection.
- To compare the efficacy of continuous infusion versus intermittent dosing for maintaining therapeutic drug concentrations.
Main Methods:
- Pharmacokinetic analysis of zidovudine in plasma, urine, and cerebrospinal fluid.
- Dosing regimens included a single bolus infusion and continuous infusions at varying rates.
- Study involved 21 pediatric patients with symptomatic HIV infection.
Main Results:
- Rapid zidovudine elimination after bolus dosing, with levels only above 1 mumol/L for 1.5 hours.
- Continuous infusion maintained steady-state plasma concentrations above 1 mumol/L throughout treatment.
- Cerebrospinal fluid to plasma ratio was 24% +/- 9%; higher concentrations correlated with neutropenia.
Conclusions:
- Continuous infusion of zidovudine is more effective than intermittent dosing for maintaining therapeutic concentrations in pediatric HIV patients.
- Lower daily doses can be used with continuous infusion to achieve sustained virostatic activity.
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 mumol/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 mumol/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 less than 0.5 X 10(9)/L) on the continuous infusion regimen had significantly higher plasma Css. Six of eight had a Css greater than 3.0 mumol/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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