Incorporation of the time-varying postprandial increase in splanchnic blood flow into a PBPK model to predict the effect of food on the pharmacokinetics of orally administered high extraction drugs.
Rachel H. Rose1, David B. Turner1, Sibylle Neuhoff1, Masoud Jamei1
1 Simcyp Ltd (a Certara Company), Blades Enterprise Centre, Sheffield, UK
Supplementary Tables
Table S1. Summary of the study design for simulated studies. All doses were given as a single oral dose.
PK Study / Dose (mg) / Age range (years) / n / % female / ReferencePropranolol / 80 / 24-29 / 6 / 0 / (1)
Propranolol / 80 / 26-43 / 13 / 15 / (2)
Propranolol / 80 / 22-32 / 6 / 0 / (3)
Propranolol / 80 / 19-53 / 11 / 100 / (4)
Propranolol / 80 / 19-39 / 7 / 14 / (5)
Propranolol / 40 / 18-39 / 10 / 50 / (6)
Propranolol/quinidine / 80/50 / 20-37 / 6 / 0 / (7)
Ibrutinib* / 420 / 24-55 / 44 / 14 / (8) - Study 1
Ibrutinib / 560 / 34-55 / 8 / 62.5 / (8) - Study 3
* The clinical study included individuals from multiple races (27.3% white, 2.3% Asian, 65.9% black, 4.5% mixed), but this wasn’t accounted for in the simulations and all individuals were simulated using the built-in Simcyp North European Caucasian population.
Table S2. Geometric mean and range of the fed/fasted AUC ratio and Cmax ratios of propranolol for 20 simulated trials and clinical studies. The number of simulated/ reported individuals are shown in brackets. Trial group number corresponds to Figure 6.
Study / Trial group (n=10) / Fed/fasted AUC ratio / Fed/fasted Cmax ratioGeomean / Min / Max / Geomean / Min / Max
Simulation / 1 / 1.21 / 1.11 / 1.27 / 1.25 / 1.16 / 1.32
2 / 1.22 / 1.04 / 1.41 / 1.29 / 1.21 / 1.46
3 / 1.22 / 1.12 / 1.34 / 1.25 / 1.21 / 1.42
4 / 1.28 / 1.17 / 1.52 / 1.33 / 1.20 / 1.57
5 / 1.25 / 1.15 / 1.36 / 1.31 / 1.19 / 1.49
6 / 1.21 / 0.95 / 1.37 / 1.29 / 1.16 / 1.44
7 / 1.22 / 1.13 / 1.37 / 1.26 / 1.17 / 1.40
8 / 1.26 / 1.13 / 1.48 / 1.33 / 1.25 / 1.52
9 / 1.26 / 1.14 / 1.39 / 1.29 / 1.15 / 1.43
10 / 1.24 / 1.13 / 1.34 / 1.29 / 1.13 / 1.46
11 / 1.26 / 1.14 / 1.34 / 1.31 / 1.19 / 1.41
12 / 1.24 / 1.09 / 1.42 / 1.33 / 1.22 / 1.50
13 / 1.22 / 0.99 / 1.38 / 1.30 / 1.22 / 1.42
14 / 1.26 / 1.16 / 1.38 / 1.31 / 1.22 / 1.43
15 / 1.25 / 1.18 / 1.34 / 1.30 / 1.20 / 1.42
16 / 1.22 / 1.00 / 1.37 / 1.29 / 1.21 / 1.41
17 / 1.25 / 1.14 / 1.37 / 1.31 / 1.20 / 1.48
18 / 1.24 / 1.12 / 1.36 / 1.28 / 1.17 / 1.43
19 / 1.25 / 1.14 / 1.35 / 1.30 / 1.17 / 1.39
20 / 1.21 / 1.09 / 1.32 / 1.24 / 1.12 / 1.35
Total population (n=200) / 1.24 / 0.95 / 1.52 / 1.29 / 1.12 / 1.57
Liedholm 1986 (9) / 21 (n=11) / 1.69 / 0.89 / 3.02 / 1.82 / 0.76 / 2.98
Liedholm 1990 (4)a / 22 (n=11) / 1.24 / 0.29 / 3.54 / 1.40 / 0.38 / 4.62
Liedholm 1990 (4)b / 23 (n=10) / 0.92 / 0.49 / 1.72 / 0.98 / 0.59 / 2.00
McLean 1981 (10)a / 24 (n=8) / 1.97 / 1.30 / 3.90 / 2.29 / 1.06 / 6.54
McLean 1981 (10)b / 25 (n=8) / 1.68 / 0.70 / 4.59 / 1.48 / 0.69 / 6.28
Meleander 1977 (2) / 26 (n=7) / 1.47 / 0.89 / 2.25 / 1.55 / 0.97 / 2.00
Olanoff 1986 (1) / 27 (n=6) / 1.21 / 0.73 / 1.85 / 1.42 / 0.48 / 3.09
Walle 1981 (3) / 28 (n=6) / 1.50 / 1.02 / 1.92 / 1.70 / NA / NA
a High protein meal; b High carbohydrate meal, as defined in publication. Measurements for the different meal types were taken in the same subjects for each meal type.
Table S3. Fed/fasted AUC and Cmax ratios (geometric mean and 90% confidence interval) of ibrutinib for 20 simulated trials and reported by de Jong et al., 2015 (study 1). The number of simulated/reported individuals is shown in brackets.
Trial group (n=44) / Fed/fasted AUC ratio / Fed/fasted Cmax ratioGeomean (90% CI) / Geomean (90% CI)
1 / 1.96 / (1.89, 2.04) / 1.81 / (1.73, 1.89)
2 / 1.92 / (1.86, 1.98) / 1.77 / (1.71, 1.84)
3 / 2.12 / (2.02, 2.22) / 1.96 / (1.87, 2.06)
4 / 1.95 / (1.87, 2.03) / 1.82 / (1.74, 1.90)
5 / 2.05 / (1.96, 2.15) / 1.89 / (1.79, 1.99)
6 / 2.01 / (1.94, 2.09) / 1.86 / (1.78, 1.95)
7 / 2.00 / (1.91, 2.08) / 1.84 / (1.75, 1.94)
8 / 1.99 / (1.91, 2.08) / 1.84 / (1.75, 1.93)
9 / 2.01 / (1.91, 2.08) / 1.88 / (1.79, 1.98)
10 / 2.00 / (1.93, 2.08) / 1.83 / (1.76, 1.90)
11 / 1.99 / (1.91, 2.08) / 1.81 / (1.72, 1.90)
12 / 2.07 / (1.98, 2.17) / 1.91 / (1.81, 2.02)
13 / 1.99 / (1.92, 2.06) / 1.84 / (1.77, 1.92)
14 / 1.99 / (1.92, 2.07) / 1.84 / (1.77, 1.92)
15 / 2.04 / (1.97, 2.12) / 1.89 / (1.81, 1.97)
16 / 2.05 / (1.94, 2.15) / 1.85 / (1.74, 1.95)
17 / 2.04 / (1.95, 2.15) / 1.87 / (1.78, 1.96)
18 / 1.97 / (1.90, 2.05) / 1.77 / (1.69, 1.86)
19 / 1.86 / (1.79, 1.93) / 1.68 / (1.61, 1.76)
20 / 2.05 / (1.95, 2.15) / 1.88 / (1.78, 1.99)
Population (n=880) / 2.00 / 1.84
de Jong 2015 (Study 1; n=44) / 1.86 / (1.69, 2.04) / 3.15 / (2.72, 3.65)
Table S4. Fed/fasted AUC and Cmax ratios (geometric mean and 90% confidence interval) of ibrutinib for 20 simulated trials and reported by de Jong et al., 2015 (study 3). The number of simulated/reported individuals is shown in brackets.
Trial group (n=8) / Fed/fasted AUC ratio / Fed/fasted Cmax ratioGeomean (90% CI) / Geomean (90% CI)
1 / 2.16 / (1.97, 2.38) / 1.91 / (1.76, 2.08)
2 / 1.99 / (1.73, 2.31) / 1.77 / (1.49, 2.11)
3 / 1.92 / (1.81, 2.04) / 1.75 / (1.63, 1.87)
4 / 2.06 / (1.81, 2.34) / 1.90 / (1.68, 2.13)
5 / 2.00 / (1.78, 2.23) / 1.83 / (1.64, 2.05)
6 / 1.87 / (1.74, 2.01) / 1.75 / (1.58, 1.93)
7 / 1.90 / (1.62, 2.23) / 1.68 / (1.40, 2.01)
8 / 1.98 / (1.82, 2.15) / 1.90 / (1.71, 2.10)
9 / 1.94 / (1.63, 2.31) / 1.78 / (1.45, 2.17)
10 / 2.00 / (1.78, 2.23) / 1.84 / (1.64, 2.06)
11 / 2.00 / (1.84, 2.17) / 1.88 / (1.72, 2.05)
12 / 2.07 / (1.88, 2.28) / 1.91 / (1.71, 2.13)
13 / 1.96 / (1.79, 2.14) / 1.86 / (1.66, 2.08)
14 / 2.14 / (1.90, 2.41) / 2.02 / (1.81, 2.26)
15 / 2.08 / (1.86, 2.33) / 1.95 / (1.70, 2.24)
16 / 2.05 / (1.84, 2.28) / 1.92 / (1.75, 2.11)
17 / 2.10 / (1.93, 2.28) / 1.87 / (1.73, 2.04)
18 / 2.10 / (1.83, 2.41) / 1.89 / (1.60, 2.23)
19 / 2.17 / (1.89, 2.48) / 2.03 / (1.80, 2.28)
20 / 2.01 / (1.86, 2.18) / 1.88 / (1.71, 2.07)
Population (n=160) / 2.02 / 1.86
de Jong 2015 (Study 3; n=8) / 2.23 / (1.67, 2.97) / 3.52 / (2.13, 5.82)
References
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