Mg (n 2) Cohort B, 200 mg (n two) Cohort C, 400 mg (n 2) Cohort D, 800 mg (n six) Cohort E, 1,500 mg (n six) Cohort G,b 800 mg (n 6) Cohort F1, two,000 mg (n 3) Cohort F2, three,000 mg (n 3) Cohort F3, four,000 mg (n three)Element A Portion BValue1 -4 0 four 8 12 16 20 24 28 32 36 40 44 48Time (h)FIG 1 Imply concentration-time profile of GSK1322322.the dose proportionality assessment indicated that right after a single oral dose of GSK1322322, Cmax and AUC of GSK1322322 had been greater than dose proportional amongst 100 and 1,500 mg and less than dose proportional amongst 1,500 and four,000 mg (Table two). Even so, because of the tiny number of volunteers, specially for doses from 100 to 400 mg (n 2 per cohort) and from two,000 to four,000 mg (n 3 per cohort), these data will need to become interpreted with caution. In the projected clinically relevant dose variety (800 to 1,500 mg, exactly where n 6 per cohort), when the dose approximately doubled from 800 to 1,500 mg, Cmax and AUC approximately doubled. The predicted bioavailabilities from the oral 100-, 400-, 800-, and 1,500-mg doses of GSK1322322 determined by the ACAT model were 64 , 77 , 80 , and 82 , respectively, suggesting an increase in oral bioavailability with rising dose. When GSK1322322 was administered with a high-fat meal at a dose of 800 mg, Cmax was lowered by 65 (four.1 versus 11.6 g/ml), and Tmax was delayed by two.5 h (three.0 versus 0.5 h); nonetheless, AUC was unchanged (i.e., AUC0 of 22.8 versus 22.5 g h/ml) compared with the fasted state. When comparing AUC values (i.e., AUC0 4, AUC0 , and AUC0 ) of GSK1322322 at 800 mg within the fed versus fasted state, the point estimates had been close to 1, and the 90 CI included 1, indicating that a high-fat meal had no effect around the systemic exposure of GSK1322322 (Table 3). A related t1/2 was observed involving the fasted state and also the fed state. Low and moderate within-volunteer variabilities were connected with these PK parameters.Lysophosphatidylcholines p38 MAPK TABLE 2 Dose proportionality assessment of GSK1322322 pharmacokinetic parametersAdjusted imply slope worth (90 CI) for GSK1322322 dose Parameter AUC04 ( g h/ml) AUC0( g h/ml) AUC0 ( g h/ml) Cmax ( g/ml) one hundred,500 mg 1.BPC 157 Autophagy 31 (1.PMID:23460641 23, 1.40) 1.31 (1.23, 1.39) 1.32 (1.24, 1.40) 1.23 (1.09, 1.37) 1,500,000 mg 0.64 (0.27, 1.01) 0.66 (0.30, 1.02) 0.66 (0.30, 1.02) 0.16 ( 1.29, 1.62) All doses 1.22 (1.09, 1.35) 1.22 (1.10, 1.35) 1.23 (1.ten, 1.36) 1.04 (0.87, 1.22)aac.asm.orgNaderer et al.TABLE three Meals effect assessed by comparing GSK1322322 pharmacokinetic parameters for cohort Ga versus cohort DbValue Parameter AUC04 ( g h/ml) AUC0( g h/ml) AUC0 ( g h/ml) Cmax ( g/ml) Tmax (h) t1/2 (h)a bTABLE four GSK1322322 urine pharmacokinetic parametersMean value ( CVb)a for GSK1322322 dose CVw ( )c 13.23 13.25 13.23 18.73 26.19 Parameter Ae02 ( g) Ae124 ( g) Ae04 ( g) CLR (liters/h)aPoint estimate 1.01 1.01 1.01 0.35 two.5d 0.90 CI 0.88, 1.17 0.87, 1.17 0.88, 1.17 0.29, 0.43 1.0, 3.5 0.55, 0.100 mg (n two) 17,191 (10) 692 (22) 17,900 (9) 11.five (16)400 mg (n two) 66,241 (13) 3,128 (18) 69,371 (13) 7.9 (20)1,500 mg (n 6) 242,639 (68) 12,750 (46) 257,779 (63) 5.four (68)4,000 mg (n three) 506,163 (32) 40,528 (21) 549,774 (28) 6.2 (eight)CVb, between-volunteer coefficient of variation.An 800-mg dose under the fed situation. An 800-mg dose below the fasted situation. c CVw, within-volunteer coefficient of variation. d Estimated median distinction for Tmax only.Urine PK was assessed at 100-, 400-, 1,500-, and 4,000-mg dose levels only. The amount of GSK1322322 excreted inside the urine within 24 h postdose (Ae0 four) enhanced as th.