Phase 2 trial of WR6026, an orally administered 8-aminoquinoline, in the treatment of visceral leishmaniasis caused by Leishmania chagasi.
There are no recognized orally administered treatments for any of the leishmaniases. The 8-aminoquinoline WR6026 is an orally administered analog of primaquine that cured 50% of patients with kala-azar in Kenya at a dose of 1 mg/kg/day for 28 days. A further phase 2, open-label, dose-escalating safety and efficacy study was performed for kala-azar in Brazil. Cure rates for Brazilian patients treated for 28 days were as follows: 1 mg/kg/day: 0 of 4 (0%); 1.5 mg/kg/day: 1 of 6 (17%); 2.0 mg/kg/day: 4 of 6 (67%); 2.5 mg/kg/day: 1 of 5 (20%); and 3.25 mg/kg/day: 0 of 1 (0%). Nephrotoxicity that was not anticipated from preclinical animal studies or from phase 1 studies was seen at 2.5 mg/kg/day in 2 patients and in the single patient administered 3.25 mg/kg/day. WR6026 demonstrated the unusual clinical features of lack of increased efficacy against Brazilian kala-azar with increased dosing above 2 mg/kg/day and toxicity that was not present in previous investigations.
Dietze
R
R
Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo, Vitoria, Brazil.
Carvalho
S F
SF
Valli
L C
LC
Berman
J
J
Brewer
T
T
Milhous
W
W
Sanchez
J
J
Schuster
B
B
Grogl
M
M
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000634:Aminoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced; D007891:Leishmania / Q000302:isolation & purification; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
D000634:Aminoquinolines; D000981:Antiprotozoal Agents; C080436:8-aminoquinoline