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Relationship between Dideoxyinosine Exposure, CD4 Counts, and p24 Antigen Levels in Human Immunodeficiency Virus Infection
A Phase I Trial
- George L. Drusano, MD;
- Geoffrey J. Yuen, PharmD;
- John S. Lambert, MD;
- Mindell Seidlin, MD;
- Raphael Dolin, MD; and
- Fred T. Valentine, MD
Abstract
▪ Objective: To determine the relation between exposure to dideoxyinosine (ddl) and increased CD4 cell counts and suppression of serum p24 antigen in patients infected with the human immunodeficiency virus (HIV).
▪ Design: Open-label, phase I study.
▪ Setting: Two university hospitals. Patients were studied in both inpatient and outpatient settings.
▪ Patients: Of 36 HIV-infected patients enrolled, 18 had adequate pharmacokinetic information for analysis.
▪ Intervention: Dideoxyinosine was administered intravenously every 12 hours for 2 weeks. Patients were switched to oral administration at twice the intravenous dose. Pharmacokinetic profiles were obtained twice during each period. A 40-fold range of dose was examined.
▪ Measurements: CD4-positive T-lymphocyte counts and serum p24 antigen levels were determined. Plasma area under the ddl concentration-time curve was determined for a single dose and at steady state.
▪ Results: Increases in CD4-positive T-lymphocyte counts were independent of ddl exposure and were proportional to the starting CD4 count. Suppression of circulating p24 antigen was influenced by cumulative exposure to ddl and was statistically significant.
▪ Conclusions: The CD4-positive T-lymphocyte count increased at low ddl concentrations or exposures; the extent of this increase was directly proportional to the patient's CD4 count at the start of therapy. Suppression of p24 antigen was related to cumulative exposure to ddl. Therapeutic responses can probably be obtained with ddl, while minimizing long-term toxicity, using daily doses of 10 mg/kg body weight, or less.
Article and Author Information
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From the University of Maryland School of Medicine, the University of Maryland School of Pharmacy, Baltimore, Maryland; the University of Rochester School of Medicine and Dentistry, Rochester, New York; and New York University School of Medicine, New York, New York. For current author addresses, see end of text.
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Grant Support: In part by a grant from the Bristol-Myers-Squibb Company.
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Requests for Reprints: George L. Drusano, MD, Program of Clinical Pharmacology, Division of Infectious Diseases, University of Maryland, 10 South Pine Street, Baltimore, MD 21201.
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Current Author Addresses: Dr. Drusano: Program of Clinical Pharmacology, Division of Infectious Diseases, University of Maryland, 10 South Pine Street, Baltimore, MD 21201.
Dr. Yuen: The University of Maryland School of Pharmacy, 20 North Pine Street, Baltimore, MD 21201.
Drs. Lambert and Dolin: University of Rochester Medical Center, Box 689, 601 Elmwood Avenue, Rochester, NY 14642.
Dr. Seidlin: Bellevue Hospital Center, AIDS Unit, 27th Street and First Avenue, Room 12-E-12, New York, NY 10016.
Dr. Valentine: Department of Medicine, NYU Medical Center, 550 First Avenue, New York, NY 10016.
- © 1992 American College of Physicians
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