Population pharmacokinetics of dapsone administered biweekly to human immunodeficiency virus-infected patients

Abstract

The population pharmacokinetics of dapsone were examined in human immunodeficiency virus-infected patients receiving dapsone at a dosage of 100 mg twice weekly for the prevention of Pneumocystis carinii pneumonia. Nonlinear mixed-effect modeling was used to determine the best pharmacostatistical model for the data. A one-compartment open model with first-order absorption and elimination was used as the structural pharmacokinetic model. Several covariates were tested for their influence on pharmacokinetic parameters. Rifampin was found to increase the values of clearance/bioavailability (CL/F) and volume of distribution/ bioavailability (V/F) by approximately 70%. CL/F and V/F were 1.83 liters/h and 69.6 liters, respectively, for patients not taking rifampin. The effect of rifampin on the pharmacokinetic parameters of dapsone was appreciably less than expected on the basis of studies with healthy volunteers. Increased bilirubin levels were associated with a significant decrease in the absorption rate constant (K a ). However, this finding may be considered clinically irrelevant because the post hoc Bayesian estimates of K a for patients with high bilirubin levels (>1.2 mg/dl) were at the lower bound of the values for patients with normal bilirubin levels. The value of K a was 0.957 h ؊1 for a patient with a bilirubin level of 0.7 mg/dl. After inclusion of covariates in the model, the interpatient variability was 35% for CL/F, not significant for V/F, and 85% for K a . Simulation of plasma concentration-versus-time curves indicated that the administration of 100 mg of dapsone biweekly is associated with sustained dapsone levels in the plasma of the majority of the patients. Dosage adjustments for patients concomitantly treated with rifampin may be necessary.

Dapsone‐induced methemoglobinemia

“…These data raise the question of whether dapsone could be effectively used in PCP prophylaxis in pediatrics at a lower dose, where methemoglobinemia risk was much lower. Pharmacokinetic data from HIV patients suggest that this is indeed possible, with efficacy and adequate lung penetration evident when given once per week17–18. Several subsequent studies in pediatric HIV have suggested that 2–3 times weekly dosing of 2mg/kg results in acceptable drug levels and lung penetration19–21.…”

“…Pharmacokinetic data from HIV patients suggest that this is indeed possible, with efficacy and adequate lung penetration evident when dapsone was given once per week. 17,18 Several subsequent studies in pediatric HIV have suggested that 2 to 3Â times weekly dosing of 2 mg/kg results in acceptable drug levels and lung penetration. [19][20][21] One study comparing dapsone dosing (1 mg/kg/d vs 4 mg/kg/wk vs 2 mg/kg/d) in 94 pediatric HIV-positive children demonstrated no statistically significant difference in PCP breakthrough.…”

Ursodeoxycholic acid — adverse effects and drug interactions

“…Dapsone has been suggested as a CYP3A model drug, [111][112][113][114][115] and dapsone metabolism is affected by CYP3A inducers and inhibitors. 116 Thus, the induction of CYP3A by UDCA might enhance the biotransformation of dapsone, resulting in a reduced efficacy. The tissue distribution of drugs is determined by their transport across membranes.…”

“…Dermatitis herpetiformis improved markedly after discontinuation of UDCA treatment, and exacerbated again following the reintroduction of UDCA. Dapsone has been suggested as a CYP3A model drug, 111–115 and dapsone metabolism is affected by CYP3A inducers and inhibitors 116 . Thus, the induction of CYP3A by UDCA might enhance the biotransformation of dapsone, resulting in a reduced efficacy.…”

HIV–TB Drug Interactions

“…It has been suggested that rifampin decreases the serum concentration of dapsone through the induction of CYP3A4 and, indeed, one study has shown dapsone clearance to be increased by between 69% and 122% [42]. It was not clear whether this reduction in concentration would result in a decreased efficacy in clinical practice [43], though some experts believed this to be the case [44].…”