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Table 3 Plasma PK parameters following SAD of IR and MR PF-06650833 formulations

From: Safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06650833, a selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, in single and multiple ascending dose randomized phase 1 studies in healthy subjects

 IR PF-06650833 dose group
IR 1 mgIR 3 mgIR 10 mgIR 30 mgIR 30 mg (Fed)IR 100 mgIR 300 mgIR 1000 mgIR 2000 mg (fed)IR 6000 mg (fed)MR 30 mgMR 30 mg (fed)MR 100 mgMR 300 mg
N, na8, 88, 88, 715, 148, 78, 58, 68, 68, 08, 68, 78, 88, 78, 4
AUCinf, ng•h/mL5.141 (37)17.33 (49)82.65 (48)206.4 (29)325.7 (29)646.4 (48)1477 (71)2429 (40)NC10,380 (26)262.6 (20)292.7 (19)838.6 (23)2042 (45)
AUClast, ng•h/mL4.920 (38)17.01 (49)81.91 (44)203.7 (29)328.3 (27)549.4 (38)1436 (57)2270 (39)6346 (26)10,200 (25)248.8 (17)291.6 (19)762.2 (20)1968 (39)
Cmax, ng/mL1.747 (22)5.543 (32)22.57 (33)57.96 (34)53.45 (21)108.0 (44)171.7 (46)308.8 (34)650.0 (27)847.2 (21)15.76 (33)41.24 (34)42.81 (36)64.51 (46)
Tmax, hb1 (0.500–1.00)0.525 (0.500–1.00)1 (0.500–4.00)0.517 (0.500–2.00)4.00 (2.00–6.00)1 (0.500–2.03)2 (0.500–2.00)0.75 (0.500–2.00)4 (2.00–6.00)6 (2.00–6.15)6.00 (4.00–12.2)6.00 (4.00–8.02)8.00 (2.00–16.0)4.00 (2.00–12.0)
t½, hc1.86 ± 0.2402.34 ± 0.6703.54 ± 0.13910.2 ± 6.064.43 ± 1.4315.0 ± 5.2219.9 ± 9.5444.9 ± 69.6NC72.1 ± 53.911.7 ± 3.266.33 ± 1.669.35 ± 3.6238.8 ± 21.1
CL/F, L/h194.3 (37)173.1 (49)121.0 (48)145.5 (29)92.08 (29)154.7 (48)203.3 (71)411.4 (40)NC577.8 (26)114.1 (20)102.5 (19)119.0 (23)147.1 (45)
Vz/F, L516.9 (31)567.3 (39)617.5 (50)1829 (80)565.5 (27)3189 (51)5310 (69)14,600 (163)NC49,220 (71)1865 (35)898.6 (33)1476 (31)6817 (46)
Clast, ng/mL0.08150 (25)0.09984 (69)0.1366 (54)0.2196 (84)0.1651 (98)1.218 (147)0.9585 (411)0.07431 (48)0.1599 (348)0.08257 (35)0.2631 (233)0.1490 (91)1.881 (345)0.1478 (435)
Tlast, hb8.04 (8.00–12.0)12 (12.0–24.0)24 (24.0–24.0)48 (24.0–48.1)36.0 (24.0–48.0)48 (48.0–48.0)96 (96.0–96.0)170 (168–363)313 (169–313)480 (192–481)72.0 (48.0–96.0)72.0 (48.0–96.0)48.0 (48.0–48.0)d493 (96.0–528)
MRT, hc3.12 ± 0.5253.40 ± 0.6224.31 ± 0.7876.82 ± 3.385.43 ± 1.1011.2 ± 4.8120.6 ± 12.618.7 ± 4.37NC18.1 ± 6.1117.5 ± 2.359.27 ± 0.6019.3 ± 5.7350.6 ± 15.9
  1. Data presented as geometric mean (% geometric coefficient of variation) unless otherwise noted. AUCinf and t½ were reported for all treatments when the following criteria were met: a well-characterized terminal phase defined as one with at least three data points and a goodness-of-fit statistic for the log-linear regression (r2) ≥ 0.9. In addition, AUCinf was reported since the percentage of AUC extrapolated from AUClast was < 20% for all subjects
  2. All doses were administered orally under fasting conditions (overnight fast of ≥ 10 h) unless otherwise indicated. Fed doses were administered after consumption of a high-fat breakfast meal
  3. AUC area under the concentration-time profile curve, AUCinf AUC from time zero extrapolated to infinity, AUClast AUC from Clast, CL/F apparent oral clearance, Clast last quantifiable concentration, Cmax maximum observed concentration, IR immediate-release, MR modified-release, MRT mean residence time, NC not calculated if fewer than three subjects had reportable parameter values, PK pharmacokinetic, SAD single ascending doses, t½ terminal half-life, Tlast time of Clast, Tmax time of Cmax, Vz/F apparent volume of distribution
  4. aN, number of evaluable subjects; n, number of subjects where t½, AUCinf, CL/F, Vz/F, and MRT were determined
  5. bMedian (range)
  6. cMean (± standard deviation)
  7. dData were only received for MR 100 mg up to 48 h (instead of 96 h); thus, data are not presented for PF-06650833 at 96 h and Tlast was 48.0 h