PHARMACOKINETICS AND SAFETY OF WEEKLY DAPSONE AND DAPSONE PLUS PYRIMETHAMINE FOR PREVENTION OF PNEUMOCYSTIS PNEUMONIA

The safety and pharmacokinetics of weekly dapsone and weekly dapsone p lus pyrimethamine were examined in adult patients with human immunodef iciency virus infection who were at risk for pneumocystis pneumonia be cause of a prior episode or a CD4(+) T-cell count less than 250 cells per mm(3). Groups of patients received 100, 200, and 300 mg of dapsone as a single weekly dose. The maximum tolerated dose of weekly dapsone was established as 200 mg per week in patients receiving at least 500 mg of zidovudine concomitantly. This dose of dapsone was then found t o be well tolerated when combined with pyrimethamine at 25 mg. Further patients were randomized to dapsone at 200 mg or dapsone at 200 mg pl us pyrimethamine at 25 mg once weekly. Twenty-six patients each were f ollowed for a median of 33 weeks on dapsone alone and 45 weeks on the combination. Seven patients in each group withdrew because of toxicity . Five patients receiving dapsone developed documented pneumocystis pn eumonia, while four and two patients receiving dapsone plus pyrimetham ine developed documented and presumptive pneumocystis pneumonia, respe ctively. To evaluate the tolerability of a higher dose of pyrimethamin e, 11 patients had their regimen changed to dapsone at 200 mg plus pyr imethamine at 75 mg, which was well tolerated by 10 of the patients fo r a median period of 11 weeks. The pharmacokinetics of dapsone and pyr imethamine were examined by using a population pharmacokinetic model. Decreases in the apparent volume of the peripheral compartment were ob served when multiple-dose regimens of dapsone were compared with singl e-dose dapsone and when multiple-dose regimens of dapsone with pyrimet hamine were compared with multiple-dose dapsone alone. When administer ed weekly, dapsone at 200 mg and dapsone at 200 mg with pyrimethamine at 25 mg are both well-tolerated regimens. This preliminary study sugg ests that the efficacy of these regimens in preventing pneumocystis pn eumonia, however, may be less than that of trimethoprim-sulfamethoxazo le.