Single-dose pharmacokinetics and safety of the oral antiviral compound adefovir dipivoxil in children infected with human immunodeficiency virus type 1. The Pediatrics AIDS Clinical Trials Group

Abstract

The acyclic phosphonate analog adefovir is a potent inhibitor of retroviruses, including human immunodeficiency virus (HIV) type 1, and, unlike some antiviral nucleosides, does not require the initial phosphorylation step for its activity. Two oral dosages of the adefovir prodrug adefovir dipivoxil were evaluated in a phase I study with children with HIV infection. A total of 14 patients were stratified into age groups ranging from 6 months to 18 years of age. Eight patients received 1.5 mg of adefovir dipivoxil per kg of body weight, and six patients received 3.0 mg of adefovir dipivoxil per kg. Serum samples were obtained at intervals during the 8 h postdosing and were analyzed for adefovir concentrations. Patients were monitored for adverse effects. All samples collected resulted in quantifiable levels of adefovir (lower limit of quantitation, 25 ng/ml) from each patient. The areas under the concentration-versus-time curves (AUCs) were similar (P = 0.85) for the 1.5- and 3.0-mg/kg doses, while the apparent oral clearance (CL/F) was significantly higher (P = 0.05) for the 3-mg/kg dose. Pharmacokinetic parameters differed by patient age. In comparing those children older and younger than the median age of 5.1 years, AUC (P = 0.03), maximum concentration of drug in serum (P = 0.004), and the concentration at 8 h postdosing (P = 0.02) were significantly lower for the younger children. There were no significant differences for apparent volume of distribution and CL/F normalized to body surface area, but there was a suggestive difference in half-life (P = 0.07) among the subjects in the older and younger age groups. No significant adverse events were encountered. These data provide the basis for a multidose phase II study of adefovir dipivoxil in HIV-infected infants and children.

FIG. 1

Comparison of the dose of adefovir dipivoxil (bis-POM PMEA) and the AUC for adefovir (PMEA). (A) Dose based on body weight. (B) Dose based on body surface area (r² = 0.81).

FIG. 2

Comparison of age and AUC for PMEA or concentration in serum. (A) AUC compared with age (r² = 0.71). (B) C_max compared with age (r² = 0.71). (C) C₈ compared with age (r² = 0.75).

FIG. 3

Comparison of C_max and C₈ with dose (A) and age (B) and comparison of AUC with age (C). (A) Box plots showing the influence of adefovir dipivoxil dose on the C_max and C₈ of PMEA in serum. (B) Box plots showing the influence of patient age on the C_max and C₈ of PMEA in serum. (C) Box plots showing the influence of patient age on the AUC for PMEA in serum. D, range of AUC.

FIG. 4

Measured concentrations of adefovir dipivoxil at nominal times after the administration of 1.5- and 3.0-mg/kg doses.