Escalating multiple-dose safety and tolerance study of oral WR 6026 in HIV-infected subjects: AIDS clinical trials group 173

WR 6026 is an 8-aminoquinoline with activity against Pneumocystis carinii i n vitro and in an animal model of P. carinii pneumonia that has predicted t he clinical utility of related compounds. This study was conducted to asses s the safety and tolerance of WR 6026 given once daily for 21 days to HIV-i nfected subjects with CD4 counts <500 cells/mu l. This double-blind, placeb o-controlled study employed WR 6026 doses starting at 30 mg once daily and increasing to 60, 90, 120, or 150 mg once daily. Weekly visits for clinical and laboratory monitoring were conducted. Forty-nine study subjects, including 25 subjects with CD4 counts <200 cells /mu l and 12 subjects with CD4 counts <100 cells/mu l, entered the study. T he maximum tolerated dose was 120 mg/day. Dose-limiting methemoglobinemia > 20%) was seen in 3 of 6 study subjects who received 150 mg/day for greater than or equal to 19 days. Methemoglobin level was correlated with peak plas ma WR 6026 concentrations. Three other study subjects developed skin rashes that may have been drug-related, and two developed asymptomatic serum trig lyceride levels >1000 mg/dl. We conclude that WR 6026 is well tolerated at doses up to 120 mg/day for 21 days in HN-infected volunteers including thos e with CD4 counts <200 cells/mu l. Methemoglobinemia appears to be the prim ary dose-limiting toxicity.