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Acedapsone Treatment of Leprosy Patients: Response versus Drug Disposition^*

In 22 lepromatous Filipino patients receiving their first injection of 225 mg acedapsone (DADDS), dapsone (DDS), and monoacetyl DDS (MADDS) were present in plasma in approximately equal quantities. Peak levels of parent drug, DDS, and MADDS occurred between 22 and 35 days. The half-times of disappearance (T) from plasma were 43 days for DDS and MADDS and 46 days for DADDS. Acetylator phenotyping with sulfamethazine (SMZ) and DDS showed that 17 patients were rapid and 5 patients were slow acetylators. Correlations between acetylation of SMZ and DDS after DDS and of acetylation of DDS after DDS and DADDS were highly significant. However, acetylation of DDS after DADDS did not differentiate the patients into acetylator phenotypes. The T of DDS after DDS in the patients was directly related to the minimum levels of DDS at 77 days after DADDS treatment. These minimum levels were 8-fold higher than the minimum inhibitory concentration (MIC) of DDS for Mycobacterium leprae in mice and rats, but not all patients responded satisfactorily. No relationship could be demonstrated between the bacteriologic response and any of the pharmacologic parameters examined in these Filipino patients. In a companion study, minimum levels of DADDS, MADDS, and DDS were determined in 447 leprosy patients of all disease types from the Karimui District of Papua New Guinea who had been receiving 225 mg DADDS every 70 to 80 days for the past 5 years. All patients exhibited DDS levels above the MIC of DDS for M. leprae, no significant differences in plasma sulfone levels were found among disease types, no relationship between rate of healing in paucibacillary patients and sulfone levels were found, and type of response in multibacillary patients and sulfone levels were unrelated. No substantial accumulation of the sulfones in the Karimui patients receiving continuous therapy with DADDS for 5 years was indicated from a comparison with the levels in the Filipino patients following a single injection of DADDS.

Accepted for publication July 24, 1976.

^* Some of these data were presented at the 10th International Leprosy Congress, Bergen, Norway, August 1973, and at the 9th Joint U.S.-Japan Conference on Leprosy, Kyoto, Japan, October 1974. Plasma samples from patients in the Philippines were collected by the staf of the Leonard Wood Memorial—Eversley Childs Sanatarium Leprosy Research Laboratory, Cebu, Philippines, in a collaborative effort of the U.S. Leprosy Panel and the Leonard Wood Memorial to compare the therapeutic efficacy of DADDS (225 mg) intramuscularly every 77 days, with that of DADDS (225 mg) plus oral rifampin (1,500 mg) every 77 days, and with that of oral rifampin (600 mg) daily. Plasma samples from patients in New Guinea were collected by D. A. Russell. This work was supported in part by the United States-Japan Cooperative Medical Science Program administered by the National Institute of Allergy and Infectious Diseases (Grant R22-AI-08214, Contract NIH 70-2283, and Interagency Agreement 2-Y01-AI-10004), National Institutes of Health, Department of Health, Education, and Welfare.