TABLE 2.
Plasma pharmacokinetic parameters in NHPs after oral administration of AT-527a
Compound | Cmaxb (μM) | C12c (μM) | Tmaxd (h) | t1/2 (h) | AUC0–12e (μM·h) |
---|---|---|---|---|---|
AT-511 (parent prodrug) | 0.64 ± 0.08 | ND | 0.5–1 | 0.7 | 0.44 ± 0.09 |
AT-551 (intermediate prodrug) | 0.68 ± 0.25 | 0.20 ± 0.07 | 1–4 | 8.8 | 4.35 ± 1.77 |
AT-273 (plasma surrogate for intracellular TP) | 0.16 ± 0.02 | 0.10 ± 0.01 | 2 | 16 | 1.56 ± 0.18 |
Nonhuman primates (NHPs) were given a loading dose of 60 mg/kg AT-527, followed by five doses of 30 mg/kg every 12 h. Plasma samples were collected prior to the 5th dose and then 0.5, 1, 2, 4, 6, 8, 12 (preceding the 6th dose), and 14 h thereafter and analyzed for AT-511 and its metabolites by LC-MS/MS. Data are expressed as means ± SEs (n = 3). ND, not detected. The analytes in the putative metabolic pathway for AT-527 are shown in Fig. 1.
Cmax, maximum concentration across the time points measured.
C12, concentration at 12 h.
Tmax, time at which Cmax was observed.
AUC0–12, area under the plasma concentration versus time curve, from 0 to 12 h.