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Table 4 Plasma and urine PK parameters following MAD of IR and MR PF-06650833

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

 PF-06650833 dose group
IR 25 mg BIDIR 100 mg BIDIR 250 mg BIDIR 750 mg BIDIR 1000 mg QIDaIR 330 mg TIDMR 300 mg QD
Day 1
N8888888
 AUCtau, ng•h/mL163.7 (26)566.3 (32)1348 (40)2581 (28)2008 (25)1500 (38)1150 (62)
Cmax, ng/mL29.96 (34)101.8 (38)226.4 (35)470.3 (24)517.3 (30)309.0 (37)149.3 (51)
Tmax, hb2.03 (1.00–4.00)2.03 (1.00–4.00)4.00 (2.00–4.00)3.12 (2.03–4.07)4.00 (2.00–4.02)2.03 (2.00–4.00)4.00 (2.00–10.0)
Day 14
N888787
 AUCtau, ng•h/mL204.2 (26)776.5 (16)1360 (39)2475 (24)1599 (28)975.4 (65)
Cmax, ng/mL36.19 (31)127.6 (16)238.5 (33)420.7 (25)317.9 (27)146.8 (49)
Tmax, hb2.00 (0.500–4.00)2.02 (1.00–4.00)2.02 (2.00–4.03)2.00 (2.00–4.00)2.00 (1.00–4.00)4.00 (2.00–7.50)
 CL/F, L/h122.4 (26)128.9 (16)183.7 (39)302.9 (24)206.1 (28)308.0 (65)
Vz/F, L9650 (37)8064 (27)10,170 (44)13,160 (29)10,070 (24)11,600 (46)
Cmin, ng/mL4.064 (46)14.13 (40)20.07 (76)33.07 (50)51.48 (68)6.471 (55)
Cav, ng/mL17.03 (26)64.72 (16)113.3 (39)206.3 (24)200.1 (28)40.62 (65)
 PTF1.868 (21)1.740 (16)1.911 (14)1.868 (12)1.307 (18)3.383 (37)
Rac1.250 (19)1.373 (23)1.009 (13)0.9377 (32)1.068 (26)0.8985 (24)
Rac, Cmax1.209 (22)1.253 (28)1.052 (22)0.8689 (38)1.029 (28)1.078 (29)
t½, hcNRNRNR29.4d ± 1.7831.4e ± 5.6025.4f ± 6.41
 MRT, hNRNRNR6.15d ± 0.3665.29e ± 1.1820.3f ± 9.46
 Ae24%0.7288 (27)0.9414 (29)0.4822 (53)0.4885 (24)0.6372 (34)0.300 (70)
 CLr, mL/min13.62 (19)18.54 (19)13.92 (18)23.14 (19)18.83 (21)15.39 (30)
  1. Data presented as geometric mean (% geometric coefficient of variation) unless otherwise noted
  2. All doses were administered orally under fed conditions (standard meal)
  3. Ae24 cumulative amount of drug recovered unchanged in urine up to 24 h; AUC area under the concentration-time profile curve; AUCtau AUC from time 0 to time tau, the dosing interval, where tau = 6, 8, 12, and 24 h for QID, TID, BID, and QD dosing, respectively; BID twice daily; Cav average concentration for the dosing interval; CL/F apparent oral clearance; CLr renal clearance; Cmax maximum observed concentration; Cmin lowest concentration observed during the dosing interval; IR immediate-release; MAD multiple ascending doses; MR modified-release; MRT mean residence time; NR not recorded; PK pharmacokinetic; PTF peak-trough fluctuation; QD once daily; QID four times per day; Rac observed accumulation ratio; t½ terminal half-life; TID three times per day; Tmax time of Cmax; Vz/F apparent volume of distribution
  4. aDay 14 data for cohort 5 (PF-06650833 IR 1000 mg QID) were not available due to discontinuation of this cohort on day 9
  5. bMedian (range)
  6. cMean (± standard deviation)
  7. dN = 4
  8. eN = 3
  9. fN = 6