Article Figures & Data
Figures
- Fig. 1.
Mean simulated using hepatocyte CLint data (solid line) and observed (data points) concentrations of FMO substrates after administration of a single dose to humans for nine FMO substrates. The gray lines around the solid black line represent simulated individual trials matched to a clinical study. Lower and upper gray lines represent the 90% confidence interval of the respective simulations.
- Fig. 2.
Forest plot showing the PBPK modeling performance of FMO substrates. Predictions are expressed as ratios of predicted over observed AUC. The dashed line represents the identity (predicted/observed ratio), the gray shaded represents the 0.5–2.0 ratio window, and the blue shaded area represents the 0.67- to 1.50-fold ratio. Mean AUC using hepatocytes (blue squares); mean AUC using HLM (red circles); mean AUC using rFMO with no scaling (green triangles), with error bars represented as percentile range (fifth and 95th percentiles).
- Fig. 3.
Determination of rFMO scalar for itopride and its application to tozasertib as an example. (A–C) Model fit without rFMO scalar, with rFMO tissue scalar, and with rFMO ISEF scalar for itopride, respectively. (D–F) Tozasertib model without rFMO scalar, with rFMO tissue scalar, and with rFMO ISEF scalar, respectively.
- Fig. 4.
Correlations for the PBPK model–predicted clearance using human hepatocytes, HLM, and rFMO with ISEF scalar and tissue-specific scalar.
Tables
Drug Age Range Number of Subjects Male/Female Numbers Dose (Route) Dosage Regimen/PK Duration Comments Reference yr Benzydamine 41–51 6 6/0 5 mg (i.v.) Single/48 hours Caucasian healthy volunteers Humphries et al. (2015) Benzydamine 18–51 12 6/6 50 mg (oral) Single/48 hours Caucasian healthy volunteers Humphries et al. (2015) Itopride — 6 6/0 50 mg (oral) Single/24 hours Japanese healthy volunteers Yoon et al. (2014) Itopride 24–31 5 5/0 150 mg (oral) Single/24 hours Japanese healthy volunteers Katagiri et al. (2006) Tozasertib 22–80 27 14/13 4, 8, 16, 32, 45, 64, and 96 mg/m2 (i.v.) Single, 24-hour infusion Oncology patients Traynor et al. (2011) Tamoxifen 29–71 29 4/25 20 mg (oral) Multiple, PK at SS Oncology patients AstraZeneca internal dataa Tamoxifen 41–64 24 0/24 30 mg (oral) Single Healthy volunteers Fuchs et al. (1996) Moclobemide 21–30 12 12/0 150 mg (i.v.), 20 minute infusion Single Healthy volunteers Raaflaub et al. (1984) Moclobemide 21–30 12 12/0 100 mg (oral) Single Healthy volunteers Schoerlin et al. (1987) Imipramine 23–64 8 8/0 100 mg (oral) Single Caucasian healthy volunteers Albers et al. (2000) Imipramine 22–37 11 5/6 50 mg (i.v.) and 100 mg (oral) Single Caucasian healthy volunteers Brøsen and Gram (1988) Clozapine 21–30 18 18/0 100 mg (oral); twice daily Single Asian healthy volunteers Tassaneeyakul et al. (2005) Clozapine 30–32 2 2/0 200 and 600 mg (oral) Multiple, PK at SS Caucasian schizophrenic patients Takano et al. (2006) Olanzapine 28–50 10 10/0 10 mg, oral Single Schizophrenic patients Elshafeey et al. (2009) Olanzapine 19–41 24 24/0 10 mg (oral) Single Healthy volunteers Chiu et al. (2004) Ranitidine 21–23 6 6/0 20 mg (i.v.) and 100 mg (oral) Single Healthy volunteers McNeil et al. (1981) Ranitidine 19–32 12 12/0 100–400 mg (oral) Single and multiple Healthy volunteers Garg et al. (1985) SS, steady-state. —, data not available or not reported.
↵a Clinical trial NCT02093351: To assess safety and effect of olaparib on the pharmacokinetics of anastrozole, letrozole, and tamoxifen, and their effect on olaparib, in patients with advanced solid cancer (2017).
Parameter Description Unit Parameter Value Benzydamine Itopride Tozasertib Tamoxifen Moclobemide Imipramine Clozapine Olanzapine Ranitidine Physicochemical dataa 309.4 358.4 464.6 371.5 268.7 280.4 326.8 312.4 314.4 MW Molecule weight g/mol log P/log D Octanol: buffer partition coefficient 4.24/2.34 2.12/0.72 4.3/3.36 6.8/4.62 2.17/1.65 5.03/2.51 3.5/2.96 3.5/2.15 0.67/−0.78 pKa/type Dissociation constant 9.3/base 8.8/base 8.3/base 8.8/base 6/base 9.4/base 7.75/base 7.2/base 8.2/2.7 diprotic base BP Blood-to-plasma partition ratio 0.76 0.72 0.94 0.89 0.84 0.93 0.825 0.73 0.90 Fu Fraction unbound in plasma 0.146 0.262 0.0873 0.00035 0.638 0.261 0.0925 0.327 0.912 Absorption Ka Absorption rate constant 1/h 1.21 4, lag time of 0.4 hours — 0.39 1.12 1 2.2.2 1.36 0.38 Fu,gut Unbound fraction of drug in gut enterocytes. Either default of 1 or predicted value used 1 0.192 1 1 1 1 1 1 1 Pcaco-2 Caco-2 permeability × 10−6 cm/s Mech-eff model — — Mech-eff model 64.4 Mech-eff model PSA/HBD PSA/HBD PSA/HBD Peff,man Human jejunum permeability × 10−4 cm/s 8.71 5 — 4.09 6.95 8.56 7.87 7.83 0.94 Distribution Vss Distribution volume at steady-state after IV or predicted using Method 2 l/kg 0.966 6.3 5.6 15.7 3.59 17.1 1.6 5.1 1.50 Vss Distribution model l/kg Minimal PBPK model Full PBPK Full PBPK Full PBPK Full PBPK Minimal PBPK Minimal PBPK Minimal PBPK Full PBPK Elimination CLint-HLM Human liver microsomal protein in vitro intrinsic clearance µl/min/mg protein 18 18 61 4 3 14 18 <3 <3 CLint- Hepatocytes Hepatocytes in vitro intrinsic clearance µl/min per 106 cells 9 11 29 4 3 9 5 2 0.6 Fm (% FMO) Fraction metabolized contribution % 53 96 38 28 38 21 23 23 26 CLint - rFMO FMO in-vitro intrinsic clearance and remaining metabolic CL was accounted via major metabolizing enzyme via HLM in enzyme kinetics or via rCYP if P450 contribution known µl/min/pmol protein or µl/min/mg protein for HLM FMO1 = 0.44,FMO3 = 0.29,FMO5 = 0.001,CYP2D6 = 8.5 FMO1 = 0.79,FMO3 = 0.118,FMO5 = 0.0.052,CYP3A4 = 0.87 FMO1 = 0.24,FMO3 = 0.48,FMO5 = 0,CYP3A4 = 39 FMO1 = 0.083,FMO3 = 0,FMO5 = 0,CYP3A4 = 3.6 FMO1 = 0.018,FMO3 = 0.031,FMO5 = 0.003,CYP3A4 = 2.9 FMO1 = 0.163,FMO3 = 0.013, FMO5 = 0.001,CYP1A2 = 0.058,2C19 = 2.36,2D6 = 47,3A4 = 0.021,Additional HLM CL = 1.52 FMO1 = 0.031,FMO3 = 0,FMO5 = 0,CYP3A4 = 11.1 FMO1 = 0.04,FMO3 = 0.006,FMO5 = 0,CYP3A4 = 2.31 FMO1 = 0.011,FMO3 = 0.003,FMO5 = 0.028,CYP3A4 = 2.22 Systemic clearance Systemic absolute CL or oral CL l/h 9.66b 88c 87b 8c 63.7b 54c 32c 26c 7.56b Renal clearance Renal CL l/h 0.24 1.5 — — — — — — 24.6 Fu,mic Unfound fraction in microsomes 0.35 1.05 0.18 0.02 0.98 0.31 0.30 0.73 0.97 Fu,inc Unfound fraction in hepatocytes 0.74 0.88 0.21 0.003 0.87 0.65 0.33 0.86 0.98 HBD, hydrogen bond donor; PSA, polar surface area; rCYP, recombinant cytochrome P450; Vss, volume of distribution at steady state. —, data not available or not reported.
↵a Source: AstraZeneca experimental data (Jones et al., 2017).
↵b From intravenous study using references shown in Table 3 for a respective drug.
↵c From oral study using references shown in Table 3 for a respective drug.
Drug Dosing Regimen Dose Observed AUC (S.D.) Observed Cmax (S.D.) Observed CL (S.D.) Predicted AUC with Hep (S.D) Predicted Cmaxa with Heps (S.D) Predicted CL (S.D.) Reference for the Observed Data mg ng⋅h/ml ng/ml l/h ng⋅h/ml ng/ml l/h Benzydamine Intravenous 5 540 (112) 68 (19) 9.6 594 (191) 74 (18) 8.89 (3.2) Baldock et al. (1991) Benzydamine Oral 50 4994 (1190) 546 (177) 9.8 4245 (1748) 398 (126) 9.4 (3.2) Baldock et al. (1991) Itopride Oral 50 750 (123) 280 (49) NR 1440 (424) 353 (61) 37.6 (11) http://www.meppo.com/pdf/drugs/2845-GANATON-1415104080.pdf Itopride Oral 150 2170 (349) 930 (50) 55–88 1940 (442)b 1061 (184) 81 (18) Katagiri et al. (2006) Tozasertib IV 4212 77,673 (18,560) 3547 (1113)a 53.6 (17.6) 85,135 (20,883) 3480 (797) 47 (11) Traynor et al. (2011) Tamoxifen Oral (multiple doses) 20 2336 (699) 134.8 (35.5) 7.68 (2.2) 1938 (488) 94 (22) 11 (4) AstraZeneca internal datac Tamoxifen Oral 30 3370 (701) 63.6 (11.1) NR 2379 (580) 58 (15) 14 (4) Fuchs et al. (1996) Moclobemide Intravenous 150 3807 2100 39.4 (5.9) 4180 (738) 3825 (376) 36(6) Raaflaub et al. (1984) Moclobemide Oral 100 1570 823 63.7 1859 (459) 531 (138) 57 (18) Schoerlin et al. (1987) Imipramine Intravenous 1 28 (12–22) (0.35–0.60) 39.5 (33.6–63) 16 (4) 0.9 (0.3) 65 (13) Nguyen et al. (2016) Imipramine Oral 100 985 (662) 63.2 (40) 126 (88) 1663 (614) 46 (17) 69 (28) Albers et al. (2000) Clozapine Oral 100 3994 (2144) 185 (132) 31.81 (16) 5465 (2097) 493 (179) 21 (9) Tassaneeyakul et al. (2005) Olanzapine Oral 10 823 (480);AUC0–120 h 21.4 (14) 13 (4.6) 623 (197) 20 (6) 18 (7) Chiu et al. (2004) Ranitidine Intravenous 20 488 (40) 615 43 (3.7) 470 (99) 891 (108) 49 (14) McNeil et al. (1981) Ranitidine Oral 100 1726 (418) 342 (122) NR 1551 (388) 280 (48) 68 (17) McNeil et al. (1981) heps, hepatocytes; NR, not reported. —, data not available or not reported.
↵a Cmax = concentration at the end of infusion.
↵b AUC0–4 h to match the reported AUC.
↵c Clinical trial NCT02093351: To assess safety and effect of olaparib on the pharmacokinetics of anastrozole, letrozole, and tamoxifen, and their effect on olaparib, in patients with advanced solid cancer (2017).
Data Supplement
- Supplemental Data -
Supplementary Table 1 - Human in vitro data for FMO substrates (Jones et al., 2017)
Supplementary Table 2 - Options used to define the elimination within PBPK platform (Simcyp V16)
Supplementary Figure 1 - Forest plot showing the physiologically based pharmacokinetic modeling performance of FMO substrates using rFMO data with and without scalar (tissue specific or ISEF) in the model
Supplementary Table 3 - Simulated mean (SD) PK parameters for FMO substrates using HLM or rFMO with ISEF or tissue specific scalar data
Supplementary Table 4 - Paediatrics simulations for Itopride using rFMO data
Supplementary Table 5 - Mass Spectrometer parameters for FMO substrates
Supplementary Text
- Supplemental Data -
