Intrapulmonary and Systemic Pharmacokinetics of Aerosolized Pentamidine Used for Prophylaxis of Pneumocystis carinii Pneumonia in Patients Infected with the Human Immunodeficiency Virus

Abstract

A study was conducted to determine the intrapulmonary and systemic pharmacokinetics of aerosolized pentamidine prophylaxis (APP) in patients infected with human immunodeficiency virus (HIV). 151 patients received high-dose (300 mg twice a month or 600 mg once a month) APP as part of a previously published clinical trial, and 29 additional patients received standard-dose (300 mg once a month) APP. Serial blood samples were obtained from the first cohort: 577 samples were obtained from 76 patients in the group given 600 mg once a month, and 554 blood samples were obtained from 75 patients in the group given 300 mg twice a month. In 9 of the 151 patients, bronchoscopy and tri-lobar (right upper, middle, and lower lobe) bronchoalveolar lavage (BAL) were performed 6 and 12 months after initiation of APP. Unilobar (right middle lobe) BAL was performed in the 29 patients infected with HIV who underwent bronchoscopy for diagnostic purposes. Pentamidine was measured using a chromatographic (HPLC) assay. The concentrations (mean +/- SD) of pentamidine in plasma in the groups given 300 mg twice a month and 600 mg once a month were 5.3 +/- 6.1 ng/mL and 8.8 +/- 9.6 ng/mL, respectively, and accumulation did not occur. The BAL supernatant and alveolar cell pentamidine concentrations were not significantly different in the 3 lobes and ranged from 16.5 +/- 7.7 ng/mL to 29.2 +/- 19.5 ng/mL and 1255 +/- 1142 ng/mg protein to 1572 +/- 1161 ng/mg protein in the group given 300 mg twice a month; and from 5.5 +/- 2.9 ng/mL to 9.4 +/- 7.7 ng/mL and 339 +/- 201 ng/mg protein to 571+/- 681 ng/mg protein in the group given 600 mg once a month. The intropulmonary concentrations of pentamidine at 6 and 12 months were not significantly different. In 18 of the 29 patients who received 1 to 7 prior monthly doses of standard APP, drug concentrations in BAL increased linearly (y = 2.05x) with the number of doses administered before bronchoscopy. These data indicate that intrapulmonary drug concentrations continue to increase for approximately 6 months after the initiation of APP, at which time steady state is achieved, and that administration of high dose APP is probably safe.

Single-Dose Intrapulmonary Pharmacokinetics of Rifapentine in Normal Subjects

“…The observations presented here confirm our previous experiences (6,7,9,10) and those of others (13,14,25,26) that bronchoscopy and BAL for research purposes can safely be carried out with healthy volunteers.…”

Prevention of Infection Due toPneumocystis carinii

“…Pentamidine aerosol prophylaxis is most effective when it is administered by experienced personnel with a nebulizer (e.g., Fisons or Respirgard II) which produces droplets in the 1-to 3-m range. Dosing at 300 mg twice monthly for secondary prophylaxis may be more effective than monthly administration (21,62,108). At 600 mg per month, accumulation of pentamidine in plasma does not occur (21).…”

“…Dosing at 300 mg twice monthly for secondary prophylaxis may be more effective than monthly administration (21,62,108). At 600 mg per month, accumulation of pentamidine in plasma does not occur (21). However, the pentamidine concentration in the lungs continues to rise for the first 6 months of therapy with aerosolized pentamidine.…”

“…In AIDS patients and in transplant recipients, dapsone (diaminodiphenylsulfone), with or without TMP or pyrimethamine, is widely used for prophylaxis in a variety of combinations (12,41,62,95,104). While low levels of sulfone in serum are attained in vivo, therapeutic levels are maintained in alveolar fluids (21,22). Dapsone has been shown to have activity equivalent to those of SMX and sulfadiazine in in vitro assays of activity against the enzyme dihydropteroate synthase when the drugs are used at equivalent concentrations (22,134).…”

Treatment of Infection Due to Pneumocystis carinii

“…Intravenous pentamidine isethionate is given by slow (1-to 2-h) infusion in 5% glucose solution as a single dosage of 4 mg/kg/day. Evidence exists that lower dosages (3 mg/kg/day) are equally effective (14,15). Pentamidine achieves therapeutic levels in the lungs slowly (5 to 7 days) due to high levels of extrapulmonary tissue binding.…”