Pharmacokinetics of dapsone in human immunodeficiency virus-infected children

Abstract

Dapsone, administered at various doses and schedules, has been proven to be a safe and effective alternative to trimethoprim-sulfamethoxazole for prevention of Pneumocystis carinii pneumonia (PCP) in adults with human immunodeficiency virus (HIV) infection. Dapsone is also recommended by the Centers for Disease Control for PCP prophylaxis in HIV-infected children. However, the suggested dosage regimen is based upon clinical experience with children with leprosy and dermatitis herpetiformis rather than pharmacokinetic and pharmacodynamic data obtained from the target patient population. In order to determine a rational dosage regimen that could be tested in clinical studies aimed at the evaluation of dapsone for the prevention of PCP in HIV-infected children, we studied the pharmacokinetics of dapsone following a 2-mg/kg of body weight oral dose in twelve HIV-positive children aged 9 months to 9 years. Plasma was collected at the following times after dapsone administration: 0, 2, 4, 6, 12, 24, 48, 72, and 96 h. The levels of dapsone in plasma were determined by high-performance liquid chromatography. Data were analyzed by noncompartmental methods. Expressed as means ؎ standard deviations (ranges), the pharmacokinetic parameters were as follows: peak concentration in plasma, 1.12 ؎ 0.48 (0.44 to 1.81) mg/liter; time to peak concentration in plasma, 3.8 ؎ 1.3 (2 to 6) h; half-life at elimination phase, 24.2 ؎ 7.1 (14.4 to 35.0) h; clearance from plasma divided by bioavailability (CL/F), 1.15 ؎ 0.67 (0.37 to 2.63) ml/min/kg; and volume of distribution divided by bioavailability (V/F), 2.25 ؎ 1.20 (1.00 to 4.57) liters/kg. Oral CL correlated negatively with age (r ‫؍‬ 0.614 and P ‫؍‬ 0.034), as did V (r ‫؍‬ 0.631 and P ‫؍‬ 0.028). As a consequence of the high interindividual variability in growth retardation, pharmacokinetic parameters correlated with measures of body development better than they did with age (e.g., for CL/F to height, r ‫؍‬ 0.765 and P ‫؍‬ 0.004, and for V/F to height, r ‫؍‬ 0.748 and P ‫؍‬ 0.005). Since oral CL from plasma and V were positively and highly correlated (r ‫؍‬ 0.898 and P ‫؍‬ 0.0001), a lower absolute F may be the cause, in part, of higher values for CL/F and V/F in smaller children. The results of this study warrant the testing of a 2-mg/kg dose of dapsone administered twice or thrice weekly to HIV-infected children. The monitoring of drug levels in plasma and dosage adjustment may be necessary for smaller children.

Twice-weekly dapsone for primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1 infection: efficacy, safety and pharmacokinetic data

“…In this study we determined dapsone pharmacokinetics at steady state in three patients and plasma concentrations of the drug in 42 patients treated with 100 mg of dapsone twice weekly. Serum drug concentrations and pharmacokinetic parameters were consistent with reported values for healthy volunteers and HIV‐infected children [30–32]. The plasma concentration‐time data are indicative of a high interpatient variability of dapsone pharmacokinetics in the population that we examined.…”

Effect of SLCO1B1 Polymorphisms on Rifabutin Pharmacokinetics in African HIV-Infected Patients with Tuberculosis

“…Unlike rifampin, rifabutin does not reduce concentrations of concomitantly administered protease inhibitors (PIs) significantly (1). The pharmacokinetics of rifabutin are highly varied (2)(3)(4). As a CYP3A4 substrate, rifabutin is subject to drug interaction with CYP3A4 inhibitors, such as PIs, and increases in exposure can result in an increased risk for adverse effects, particularly uveitis.…”

“…Forty-four patients (61% males) with a mean (standard deviation [SD]) weight, height, body mass index, age, and CD4 lymphocyte count of 60.7 (8.7) kg, 159.6 (7.7) cm, 22.8 (3.3) kg/m 2 , 32.7 (5.9) years, and 126.1 (44.0) cells/mm 3 , respectively, contributed 780 pharmacokinetic observations. The Karnofsky score was 100 for all patients.…”

“…After 6 weeks on standard antituberculosis treatment, patients were switched from rifampin to rifabutin (300 mg daily) for the last 2 weeks of the intensive phase (with standard isoniazid, pyrazinamide, and ethambutol doses) and for the first 2 weeks of the continuation phase (with standard isoniazid doses). All study participants had microbiologically confirmed pulmonary tuberculosis, HIV infection (CD4 lymphocyte count, 50 to 200 cells/mm 3 ), a weight of Ն50 kg or a body mass index of Ͼ18, a Karnofsky score of Ն80%, and no grade 3 or 4 clinical or laboratory findings according to DMID tables (17).…”

“…Following an overnight fast, blood samples were drawn immediately before dosing and at 2, 3,4,5,6,8,12, and 24 h after dosing. A standard hospital breakfast (oats with 2 slices of toast and tea) was served Ͼ2 h after dosing.…”