Table 2. In Vivo Efficacy and Terminal Plasma Concentrations of 8a and Flubendazolea.
drug
concentration (μM) |
|||||||
---|---|---|---|---|---|---|---|
in vivo model | drug treatment | worm count median ± SEM (range) | adult worm reduction/animals with no worms | P ≤ | 24 h after last dose | interim | necropsy |
B. malayi; necropsy on day 42 | vehicle (SC study), n = 5 | 12 ± 0.73 (11–15) | N/A | N/A | N/A | ||
flubendazole, 10 mg/kg × 5 days, QD, SC, n = 10 | 0 ± 0 (0–0) | 100%/100% | 0.0001 | 0.173 | NM | 0.043 | |
8a, 150 mg/kg × 14 days, QD, SC (solution), n = 6 | 2 ± 2.14 (0–12) | 83.3%/50% | 0.0622 | 2.47 | 0.07 (day 28) | 0.01 | |
8a, 100 mg/kg × 14 days, QD, SC (suspension), n = 16 | 0 ± 0.19 (0–3) | 100%/87.5% | 0.0001 | 4.10 | 5.36 (day 28) | 3.38 | |
vehicle (PO study), n = 5 | 8 ± 0.81 (5–10) | N/A | N/A | N/A | |||
8a, 100 mg/kg × 28 days, QD, PO (suspension), n = 10 | 7 ± 1.38 (4–16) | 12.5%/0% | 0.9999 | 0.128 | NM | <LOQ | |
B. pahangi; necropsy on day 63; n = 5 per group | vehicle | 89 ± 12.79 (64–146) | N/A | N/A | N/A | ||
flubendazole, 10 mg/kg × 5 days, QD, SC | 0 ± 0 (0–0) | 100%/100% | 0.0009 | 0.178 | NM | 0.018 | |
8a, 100 mg/kg × 14 days, QD, SC (suspension) | 0 ± 0.333 (0–2) | 100%/83% | 0.0024 | 5.87 | NM | 1.15 | |
8a, 100 mg/kg × 28 days, QD, PO (suspension) | 67.5 ± 14.86 (2–114) | 24%/0% | 0.9999 | 0.13 | NM | <LOQ | |
L. sigmodontis; necropsy on day 63; n = 4 vehicle; n = 6 other groups | vehicle | 8.5 ± 3.28 (5–20) | N/A | N/A | |||
flubendazole, 10 mg/kg × 5 days, QD, SC | 0 ± 0 (0–0) | 100%/100% | 0.0208 | 0.283 | NM | 0.040 | |
8a, 100 mg/kg × 14 days, QD, SC (suspension) | 0 ± 0.34 (0–2) | 100%/33.3% | 0.1207 | 9.30 | NM | 0.069 | |
8a, 300 mg/kg × 7 days, QD, SC (suspension) | 0 ± 0 (0–0) | 100%/100% | 0.0208 | 7.85 | 10.6 (day 21) | 0.48 | |
4.64 (day 42) | |||||||
8a, 100 mg/kg × 28 days, QD, PO (suspension) | 20 ± 6.92 (5–50) | –135.3%/0% | 0.999 | 0.210 | 0.006 (day 42) | 0.003 |
NM = not measured. N/A = not applicable. Statistical significance was tested by Kruskal–Wallis followed by Dunn’s multiple comparisons test.