Table 3.

Summary of pharmacokinetic parameters after single and multiple dosing of OSI-906 (S1)

OSI-906 pharmacokinetic parameters following single oral administration (S1, day 1)
Dose, mg10204080150300a450600750
Evaluable, n3333464136
tmax, h2.1 (2.0–3.0)4.0 (1.1–6.0)3.0 (2.0–6.0)2.0 (1.0–3.0)3.1 (2.1–3.2)3.0 (1.0–25.7)7.5 (2.0–8.0)3.9 (2.0–5.9)4.1 (3.0–6.1)
Cmax, μg/mL0.106 (0.0700–0.128)0.176 (0.140–0.178)0.460 (0.220–0.577)0.531 (0.416–1.76)1.08 (0.800–2.70)2.68 (0.638–6.76)3.20 (1.19–4.86)5.39 (3.40–9.01)8.02 (5.81–17.3)
AUCtau, μg × h/mL0.408 (0.173–0.671)0.724 (0.621–0.984)2.19 (1.28–3.96)2.68 (2.19–7.75)8.92 (4.63–16.7)19.8 (3.61–51.1)25.2 (10.6–70.3)56.3 (22.2–98.5)84.1 (47.7–235)
AUCinf, μg × h/mL0.408 (0.173–0.672)0.725 (0.621–0.990)2.21 (1.31–3.97)2.69 (2.20–7.79)9.10 (4.64–16.8)17.1 (3.77–54.2)19.1 (10.6–32.2)56.4 (22.4–106)76.2 (52.6–117)
CL/F, L/h24.5 (14.9–57.8)27.6 (20.2–32.2)18.1 (10.1–30.6)29.7 (10.3–36.4)16.6 (8.91–32.3)17.5 (5.54–79.6)23.5d (14.0–42.3)10.6 (5.64–26.8)10.8 (6.41–14.3)
t1/2λz, h2.10 (1.94–2.23)2.20 (2.01–2.75)3.24 (2.15–4.67)3.14 (2.72–4.31)3.07 (2.72–4.31)2.81 (1.99–5.32)3.62 (2.24–8.75)3.59 (2.35–25.6)6.08 (1.94–10.1)
Vz/F, L68.6 (45.1–186)87.7 (80.2–93.5)84.7 (31.3–206)136 (46.6–142)91.9 (36.7–127)65.5 (29.2–418)135 (66.0–136)67.1 (32.4–122)47.6 (39.4–129)
OSI-906 pharmacokinetic parameters following multiple oral administrations (S1, day 3)
Evaluable, n3333464124
tmax, h4.0 (2.0–6.0)2.0 (2.0–3.0)2.0 (2.0–2.1)2.0 (2.0–2.0)2.0 (2.0–3.0)2.5 (2.0–3.9)6.0 (2.0–8.0)3.0 (1.1–12.0)2.0 (1.2–4.2)
Cmax, μg/mL0.0950 (0.177–0.174)0.203 (0.0938–0.262)0.413 (0.156–0.473)0.472 (0.444–1.51)1.77 (1.09–6.67)3.37 (0.985–8.05)4.03 (1.94–6.67)5.71 (4.03–9.51)6.55 (3.87–8.68)
AUCtau, μg × h/mL0.413 (0.147–0.796)0.958 (0.401–1.21)2.16 (0.820–2.42)2.09 (1.99–8.22)13.0 (6.57–16.5)24.7 (7.53–99.2)33.7 (15.4–112)53.4c (30.7–104)55.3 (33.1–80.8)
AUCinf, μg × h/mL0.413 (0.148–0.802)0.958 (0.402–1.22)2.16 (0.837–2.45)2.10 (2.01–8.36)13.5 (6.61–16.6)24.8b (7.84–124)16.0 (15.5–16.4)53.7d (30.9–110)59.1 (33.1–82.2)
CL/F, L/h24.2 (12.5–66.7)20.9 (16.3–49.8)18.6 (16.3–47.8)38.0 (9.57–39.8)11.2 (9.04–22.7)12.6b (2.42–38.3)28.3 (27.5–29.1)11.2d (5.46–19.4)10.7 (9.12–22.7)
t1/2λz, h2.80 (2.20–3.73)2.17 (2.06–3.45)2.83 (1.43–3.83)3.85 (2.82–3.97)3.75 (2.85–5.36)3.45 (2.99–9.77)4.15 (2.63–11.3)4.64c (2.56–13.5)3.86 (2.22–6.54)
Vz/F, L76.8 (67.0–274)81.3 (62.2–156)90.2 (38.2–195)155 (54.8–221)78.7 (37.2–99.6)57.0b (23.6–264)120 (110–130)66.0d (39.2–133)79.4 (32.9–92.1)

NOTE: Day 1 AUCinf, CL/F, Vz/F: number of patients at 300 (5), 450 (3), 600 (11), and 750 (14).

Abbreviations: AUCinf, area under the concentration–time curve from the time of dosing up to infinity with extrapolation of terminal phase; AUCtau, area under the concentration time curve during dosing interval; CL/F, apparent body clearance after extravascular dosing; Cmax, maximum plasma concentration; s, schedule; t1/2λz, terminal elimination half-life; tmax, median time to reach observed concentration; Vz/F, volume of distribution.

  • aExcluded patients in the fast-fed cohort; bn = 2; cn = 11; dn = 10.