Acoziborole (SCYX-7158) is an effective, safe and orally active antiprotozoal agent for the research of human african trypanosomiasis (HAT). In the T. b. brucei S427 strain, the MIC value for SCYX-7158 is 0.6 µg/mL.

Acoziborole is active in vitro against relevant strains of Trypanosoma brucei, including T. b. rhodesiense and T. b. gambiense.In whole cell assays, Acoziborole exhibits potent activity against representative T. b. brucei, T. b. rhodesiense and T. b. gambiense strains. IC₅₀ values for Acoziborole are approximately 0.07 µg/mL to 0.37 µg/mL following incubation of the parasite strains with Acoziborole for 72 h. In the T. b. brucei S427 strain, the MIC value for Acoziborole is 0.6 µg/mL, approximately two times the IC₅₀ measured for this strain. In contrast to the potent activity of Acoziborole against trypanosomes, no significant inhibition of cell proliferation is observed in an in vitro mammalian cell (L929 mouse cell line) assay at drug concentrations up to 50 µg/mL. The potential for Acoziborole to inhibit cytochrome P450 (CYP) enzymes is evaluated using P450-Glo assays for the human isoforms CYP3A4, CYP1A2, CYP2C19, CYP2C9 and CYP2D6. The IC₅₀ values for Acoziborole in these assays are all above 10 µM.

西域 has not independently confirmed the accuracy of these methods. They are for reference only.

In uninfected mice, 4.3 mg/kg intravenous dose of Acoziborole show an apparent elimination half-life (t_1/2) of 26.6 h; systemic clearance (CL) of 0.089 L/h/kg; a volume of distribution (Vd_ss) of 1.69 L/kg and area under the concentration-time curve (AUC_{0-24 h}) of 48 h•μg/mL. Following an oral dose of 13.4 mg/kg, which corresponds to the lowest efficacious dose in the murine stage 2 HAT model, Acoziborole is rapidly absorbed, as a C_max of 6.96 µg/mL is achieved in plasma at 6 h after dose, with an oral clearance (Cl/F) value of 0.163 L/h/kg, an AUC_{0-24 h} of 82 h•μg/mL and absolute oral bioavailability of 55%. After a 26 mg/kg oral dose, which corresponds to the dose giving a 100% cure rate in the murine stage 2 HAT model, C_max increases to 9.8 µg/mL and the AUC_{0-24 h} is 113 h•μg/mL. In uninfected rats, following oral administration of Acoziborole at a nominal dose of 25 mg/kg (dose affording a 100% cure rate in mice), C_max increases approximately 2 fold more than that in mice (C_max=18.2 µg/mL) and AUC_{0-24 h}, and hence oral clearance, improves approximately 4 fold (AUC_{0-24 h} 291 h•μg/mL and CL/F=0.092 L/kg/h). The time to maximum concentration is similar to that in mice (t_max=8 h). Uninfected male and female cynomolgus monkeys are treated with Acoziborole at 2 mg/kg (IV) on study day 1 and 10 mg/kg (NG) on study day 8. Acoziborole exhibits excellent plasma pharmacokinetics, with CL of 0.022 L/h/kg; Vd_ss of 0.656 L/kg and area under the concentration-time curve 78.8 h•μg/mL, and 94.4 for AUC_{0-24 h} and AUC_0-inf, respectively, following intravenous administration.

西域 has not independently confirmed the accuracy of these methods. They are for reference only.

In uninfected mice, 4.3 mg/kg intravenous dose of Acoziborole show an apparent elimination half-life (t_1/2) of 26.6 h; systemic clearance (CL) of 0.089 L/h/kg; a volume of distribution (Vd_ss) of 1.69 L/kg and area under the concentration-time curve (AUC_{0-24 h}) of 48 h•μg/mL. Following an oral dose of 13.4 mg/kg, which corresponds to the lowest efficacious dose in the murine stage 2 HAT model, Acoziborole is rapidly absorbed, as a C_max of 6.96 µg/mL is achieved in plasma at 6 h after dose, with an oral clearance (Cl/F) value of 0.163 L/h/kg, an AUC_{0-24 h} of 82 h•μg/mL and absolute oral bioavailability of 55%. After a 26 mg/kg oral dose, which corresponds to the dose giving a 100% cure rate in the murine stage 2 HAT model, C_max increases to 9.8 µg/mL and the AUC_{0-24 h} is 113 h•μg/mL. In uninfected rats, following oral administration of Acoziborole at a nominal dose of 25 mg/kg (dose affording a 100% cure rate in mice), C_max increases approximately 2 fold more than that in mice (C_max=18.2 µg/mL) and AUC_{0-24 h}, and hence oral clearance, improves approximately 4 fold (AUC_{0-24 h} 291 h•μg/mL and CL/F=0.092 L/kg/h). The time to maximum concentration is similar to that in mice (t_max=8 h). Uninfected male and female cynomolgus monkeys are treated with Acoziborole at 2 mg/kg (IV) on study day 1 and 10 mg/kg (NG) on study day 8. Acoziborole exhibits excellent plasma pharmacokinetics, with CL of 0.022 L/h/kg; Vd_ss of 0.656 L/kg and area under the concentration-time curve 78.8 h•μg/mL, and 94.4 for AUC_{0-24 h} and AUC_0-inf, respectively, following intravenous administration.

西域 has not independently confirmed the accuracy of these methods. They are for reference only.

• . Jacobs RT, et al. SCYX-7158, an orally-active benzoxaborole for the treatment of stage 2 human African trypanosomiasis. PLoS Negl Trop Dis. 2011 Jun;5(6):e1151.  [Content Brief]