Escalating Multiple-Dose Safety and Tolerance Study of Oral WR 6026 in HIV-Infected Subjects: AIDS Clinical Trials Group 173

Abstract

WR 6026 is an 8-aminoquinoline with activity against Pneumocystis carinii in vitro and in an animal model of P. carinii pneumonia that has predicted the clinical utility of related compounds. This study was conducted to assess the safety and tolerance of WR 6026 given once daily for 21 days to HIV-infected subjects with CD4 counts <500 cells/microl. This double-blind, placebo-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/microl and 12 subjects with CD4 counts <100 cells/microl, entered the study. The 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 > or =19 days. Methemoglobin level was correlated with peak plasma WR 6026 concentrations. Three other study subjects developed skin rashes that may have been drug-related, and two developed asymptomatic serum triglyceride levels >1000 mg/dl. We conclude that WR 6026 is well tolerated at doses up to 120 mg/day for 21 days in HIV-infected volunteers including those with CD4 counts <200 cells/microl. Methemoglobinemia appears to be the primary dose-limiting toxicity.

Phase 2 trial of WR6026, an orally administered 8-aminoquinoline, in the treatment of visceral leishmaniasis caused by Leishmania chagasi.

“…8 Three of 6 patients with HIV who were administered ϳ 2 mg/kg/day for 3 weeks had methemoglobinemia values in excess of 20%. 9 In the current clinical study, despite a slightly higher peak dose (3 mg/kg/day) and longer duration of treatment (4 weeks) than that used in the HIV study, maximal mean methemoglobin blood levels remained Ͻ 6%. The same lot of drug was used for the present study, the HIV study, and the dog study.…”

In-vitro and in-vivo studies on a topical formulation of sitamaquine dihydrochloride for cutaneous leishmaniasis

“…Sitamaquine dihydrochloride metabolism and/or elimination in the mouse model might also explain its lack of efficacy. Although extensive metabolism of sitamaquine dihydrochloride is known to occur following oral administration (Theoharides et al 1985;Sherwood et al 1994;Petty et al 1999;Dietze et al 2001), it is unlikely to occur in this case. The skin does contain many of the enzymes present in the liver; however, the metabolic capability is much lower (Hotchkiss 1998).…”

“…Accumulation, which may occur in melanin-rich tissues (e.g. eyes, hair, skin), could account for the associated sideeffects such as visual disturbances, hair depigmentation/loss and skin reactions (Petty et al 1999). As such, knowledge of melanin binding may therefore indicate whether a drug is likely to accumulate in tissues.…”

Clinical status of agents being developed for leishmaniasis

“…In the dog model, dosing had to stop at 3 mg/kg/day because of methaemoglobin formation, but there was no evidence of nephrotoxicity in dogs. In a toxicity study in HIV patients without leishmaniasis, methemoglobinaemia (> 20%) was seen in three of the six subjects who received 150 mg/day (∼ 2.5 mg/kg/day) but nephrotoxicity was not observed [14]. Thus, methaemoglobinaemia, expected for a primaquine analogue and seen in dog studies and a non-Leishmania clinical study, was not seen in the visceral leishmaniasis patients but nephrotoxicity, not expected from any previous work, was seen in visceral leishmaniasis patients receiving ≥ 2.5 mg/kg/day.…”