¹Boston University School of Medicine, Children's Hospital, and Harvard School of Public Health, Boston; University of California San Diego, San Diego; Jacobus Pharmaceutical Company, Inc, Princeton; the National Institute of Child Health and Human Development, Bethesda; Schneider Children's Hospital, North Shore-Long Island Jewish Health System, New Hyde Park; SUNY Stony Brook, Stony Brook; Children's Memorial Hospital, Chicago; and the University of Massachusetts Medical School, Worcester.

Correspondence: Mark Mirochnick, MD, Boston Medical Center, Maternity 6, One Boston Medical Center Place, Boston, MA 02118. E-mail: markm@bu.edu

^*Supported in part by the Pediatric AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases, by the Pediatric/Perinatal HIV Clinical Trials Network of the National Institute of Child Health and Human Development, and by the General Clinical Research Center Units funded by the National Center for Research Resources.

Received 5 December 2000; Accepted 19 March 2001.

Abstract

Background: Previous studies of dapsone pharmacokinetics in children have been too small to allow assessment of the relationships between dapsone pharmacokinetic parameters and patient characteristics or markers of efficacy and toxicity.

Methods: We used population analysis to estimate dapsone pharmacokinetic parameters in children participating in a phase I/II study of daily and weekly dapsone in children with human immunodeficiency virus (HIV) infection. With use of the program NONMEM and a 1-compartment open model, the influence of demographic and clinical characteristics on oral clearance (CL/F) and oral volume of distribution (V/F) were examined. Measures of drug exposure (area under the concentration–time curve [AUC] and predicted concentrations just before and 2 hours after administration) were estimated for each patient and correlated with markers of efficacy and toxicity.

Results: Sixty children (median age, 3 years; age range, 2 months to 12 years) contributed 412 dapsone concentrations collected after 175 study doses. Final parameter estimates were 1.40 L/kg for V/F, 0.0283 L/kg/h for CL/F, and 2.66 for the absorption rate constant. Of the clinical characteristics evaluated, dapsone CL/F was significantly increased by 50% in children taking rifabutin, by 39% in black children, and by 38% in children younger than 2 years old. Although no significant correlations were found between any dapsone exposure parameter and markers of toxicity, increased AUC was associated with a decreased risk of Pneumocystis carinii pneumonia (PCP).

Conclusion: Ethnicity, age, and concomitant rifabutin use were associated with dapsone CL/F, with more rapid clearance observed in black children, children younger than 2 years old, and children receiving rifabutin. Dapsone pharmacokinetic parameters were not associated with toxicity, but higher dapsone AUC was associated with decreased risk of PCP. Monitoring of serum dapsone levels may be needed for optimal management of dapsone for PCP prophylaxis in children.