Differences in CYP mediated pharmacokinetics betwee

n Chinese and Caucasian populations predicted by me

chanistic physiologically-based pharmacokinetic mode

lling

Barter ZE1, Tucker GT1,2, Rowland Yeo K1

1Simcyp Limited (a Certara Company), John Street, Sheffield, UK

2Emeritus Professor, University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK

Corresponding Author: Zoe Barter, Ph.D.

Simcyp Limited (a Certara Company)

Blades Enterprise Centre,

John Street

Sheffield S2 4SU, UK

Tel: 0114 2922332

Fax: 0114 2922333

Email: [email protected]

For publication in Clinical Pharmacokinetics

Page 1 of 15 SUPPLEMENTAL DATA

Table 1. Summary of hepatic CYP abundances (pmol/mg microsomal protein) in Chinese and Caucasian extensive metabolisers. Caucasian Chinese CYP CV CV Mean n References Mean n References (%) (%)

1A2 52 67 119 Rowland Yeo et al. [1] 42 50 42 Shu et al. [2] 2B6 17 122 145 Hofmann et al. [3] 17 122 Hofmann et al. [3] 2C9 73 54 118 Rowland Yeo et al. [1] 60 67 42 Shu et al. [2] 2C19 14 106 126 Rowland Yeo et al. [1] 8 39 20 Shu et al. [4] 2D6 8 61 98 Rowland Yeo et al. [1] 5.5 61 Yue et al. [5] 3A4 137 41 52 Cubitt et al. [6] 120 33 42 Shu et al. [2]

Page 2 of 15 Table 2. Summary of gut CYP abundances in Chinese and Caucasian extensive metabolisers. A coefficient of variation of 60% was applied to all CYP abundances based on data on CYP3A4 from Lown et al. [7].

CYP Abundance (nmol per intestine) Caucasian Chinese 2C9 12.9 10.6 2C19 1.5 0.85 2D6 0.8 0.5 3A4 66.2 58.0 3A5 24.6 21.5

Page 3 of 15 Table 3. Summary of CYP genotype and corresponding phenotype frequencies in Chinese and Caucasian populations.

CYP Genotype Phenotype Frequency Caucasian Source Chinese Source *5/*5 2B6 *5/*6 PM 0.11 Lamba et al. [8] 0.05 Guan et al. [9] *6/*6 *2/*2# Myrand et al. [11]; Man et al. 2C9 *2/*3# PM 0.06 Scordo et al. [10] 0.002 [12]; Yang et al. [13] *3/*3

Man et al. [12]; Xie et al. [15]; *2/*2 Chen et al. [16]; Niu et al. [17]; 2C19 *2/*3 PM 0.02 Zackrisson et al. [14] 0.13 Zhou et al. [18]; Myrand et al. *3/*3 [11]; Wang et al.[19]

*3, *4, *5, *6, *7, *8, *11, *14, PM 0.08 Zackrisson et al. [14] 0 *15, *19, *20 Zanger et al. [20]; Cai et al. [21]; Zhou et al. [18]; Garcia- 2D6 *9, *10, *17, *29, *36, *41 IM 0 0.39 Barcelo et al. [22]; Myrand et al. [11]

duplicate EM alleles (*1/*1x2) UM 0.05 0.003

Lin et al. [23]; Myrand et al. [11]; Li et al. 3A5 *3/*3 PM 0.83 0.58 Kamdem et al. [24] [25]; Hu et al. [26]

# Alleles not present in Chinese

Page 4 of 15 Table 4. Parameter values for the model compounds used in the simulations. (fu – fraction unbound in plasma; BP – blood : plasma ratio; V max – pmol/min/pmol recombinant enzyme; Km,u - µM; CLint,u - µL/min/mg cytosolic protein or pmol CYP3A4; CL/F and CLR – L/h; Vss; volume of systemic and liver compartments (L/kg); Vsac – volume of the single adjusting compartment (L/kg); kin and kout – first order rate constant in and out of the SAC (1/h); * assumed to be the same as that of the parent compound bupropion).

Compound Molecular fu BP Enzyme Pathway Vmax Km,u CLint CL/F CLR References Weight

Hydroxy Posner et al. [27]; Palovaara et al. 255.7 0.16* 0.82* 5 bupropion [28]; Loboz et al. [29]; Kharasch et al. [30]; Kustra et al. [31]

CYP2D6 2-hydroxylation 17.5 1.6 Ciraulo et al. [32]; Abernethy et Desipramine 1.5 al. [33]; Von Moltke et al. [34]; Additional 9 Romiti et al. [35]; Senggunprai et cytosolic al. [36]

Alprazolam CYP3A4 0.019 Lin et al. [37]; Fleishaker et al. [38]; Smith et al. [39]

Compound Vss Vsac kin kout (1/h) References (L/kg) (L/kg) (1/h)

Midazolam 0.85 0.24 0.36 0.29 Kupferschmidt et al. [40]

Page 5 of 15 Table 5. Summary of data relating to clinical studies used as comparators for predictions, and observed and predicted geometric clearances (with and without weight correction; 95% CI in brackets) in healthy Chinese and Caucasian subjects. Hydroxybupropion data are expressed as AUC0-∞ ng/ml.h.

% Weight Dose Observed CL Predicted CL Observed CL Predicted CL CYP Compound Ethnicity n Age (y) Route Reference Female (kg) (mg) (L/h) (L/h) (L/h/kg) (L/h/kg) 105.9 83.9 1.56 1.14 Caucasian 19 30 68 ± 10 25 ± 4 900 p.o. (84.2 – 133.1) (64.9 – 108.5) (1.23 – 1.99) (0.87 – 1.42) Bartoli et al. 1A2 Phenacetin 76.7 53.3 1.25 0.85 [41] Chinese 20 40 61 ± 6 26 ± 5 900 p.o. (57.5 0 102.3) (41.4 – 68.8) (0.93 – 1.67) (0.67 – 1.08) 80 22 12.7 12.4 0.15 0.16 Caucasian 9 0 150 p.o. Hydroxy (60-99) (19-23) (10.1 – 16.6) (8.8 – 17.9) (0.11 – 0.19) (0.11 – 0.23) 2B6 Loboz et al. [29] bupropion# 64 22 15.2 13.2 0.15 0.20 Chinese 9 0 150 p.o. (53-76) (20-32) (11.4-21.2) (9.1 – 19.4) (0.11 – 0.22) (0.13 – 0.29) Not 26 0.92 0.87 0.012 0.011 Madsen et al. Caucasian 14 0 500 p.o. given (21-30) (0.71 – 1.19) (0.62 – 1.23) (0.009 – 0.015) (0.08 – 0.016) [42] 2C9 Tolbutamide 0.90 0.65 0.014 0.010 Chinese 10 30 63 ± 7 35 ± 4 500 p.o. Chen et al. [43] (0.79 – 1.01) (0.42 – 1.01) (0.013 – 0.016) (0.007 – 0.016) 46.4 49.0 0.60 0.62 Andersson et al. Caucasian 12 0 68-86 22 – 32 20 p.o. (35.3 – 61.0) (32.0 – 76.0) (0.46 – 0.79) (0.40 – 0.98) [44] 2C19 Omeprazole 11.4 24.1 0.19 0.36 Chinese 12 0 61 ± 1 23 ± 2 20 p.o. Hu et al. [45] (8.8 – 14.9) (19.0 – 30.7) (0.14 – 0.24) (0.29 – 0.46) Not 111.6 100.4 1.57 1.41 Caucasian 16 50 22-58 100 p.o. given (89.9 – 138.5) (73.6 – 137.2) (1.22 – 2.01) (1.03 – 1.93) Rudorfer et al. 2D6 Desipramine Not 65.0 52.0 1.15 0.85 [46] Chinese 14 50 19-55 100 p.o. given (50.1 – 84.3) (38.7 – 70.1) (0.91 – 1.45) (0.64 – 1.13) 31.0 25.0 0.44 0.33 Meta-analysis Caucasian 39 31 64 18 – 41 1 - 5 i.v. (28.4 – 33.9) (20.4 – 30.8) (0.40 - 0.48) (0.27 – 0.40) n=4 studies 65 25.0 19.1 0.39 0.29 Chinese 22 0 20-28 5 i.v. Yang et al. [47] (57-75) (23.6- 26.6) (16.7 – 21.9) (0.36 – 0.41) (0.25 – 0.33) 3A4 Midazolam 111.2 103.1 1.59 1.36 Meta-analysis Caucasian 65 37 70 18 – 41 1 - 15 p.o. (99.3 – 124.5) (64.8- 165.2) (1.42 – 1.77) (0.88 – 2.13) n=7 studies 42.3 85.7 0.65 1.27 Meta-analysis Chinese 76 0 62 19 – 31 7.5 - 15 p.o. (37.7 – 47.4) (51.2– 143.7) (0.58 – 0.73) (0.76 – 2.13) n=4 studies

Page 6 of 15 3.10 3.41 0.040 0.034 3A4 Alprazolam Caucasian 14 0 77 20-30 0.5 i.v. (2.79 – 3.46) (2.66 – 4.40) (0.036 – 0.045) (0.034 – 0.055) 2.48 2.70 0.036 0.040 Chinese 14 0 69 25-35 0.5 i.v. (2.05 – 3.00) (2.34 – 3.11) (0.030 – 0.044) (0.035 – 0.045) Lin et al. [37] 3.78 4.10 0.049 0.052 Caucasian 14 0 77 20-30 0.5 p.o. (3.29 – 4.33) (3.07 – 5.51) (0.043 – 0.056) (0.039 – 0.069) 2.97 3.19 0.043 0.047 Chinese 14 0 69 25-35 0.5 p.o. (2.65 – 3.34) (2.71 – 3.75) (0.038 – 0.049) (0.040 – 0.055)

Page 7 of 15 A B 200 C D 200 200 200

180 180 150 150 ) ) ) ) g g m m

160 k c k

160 ( c ( (

(

t t t t h h h 100 100 h g g g i g i i i e e 140 e e 140 H W H W 50 50 120 120

100 100 0 0 20 30 40 50 60 70 20 30 40 50 60 70 140 150 160 170 180 190 130 140 150 160 170 180 Age (y) Age (y) Height (cm) Height (cm)

E F 200 G H 200 200 200

180 180 150 150 ) ) ) g ) k g m m (

160 160 c k c t ( ( (

h t t t 100 g h h h 100 i g g g e i i i e 140 e e

140 W H H W 50 50 120 120

0 100 100 0 130 140 150 160 170 180 20 30 40 50 60 70 20 30 40 50 60 70 140 150 160 170 180 190 Height (cm) Age (y) Age (y) Height (cm)

Fig. 1 Simulated ( ) (A - male n=500, B - female n=500) and observed (x) (E – male n=3832, F – female n=4286) relationships between height and age and simulated ( ) (C - male n=500, D - female n=500) and observed (x) (G – male n=3832, H – female n=4286) relationships weight and height in a general Chinese population.

Page 8 of 15 A B C D 200 200 200 200

150 180 180 150 ) ) g ) g k ) ( k

m ( t 160 m c 160 t h ( c

100 h ( g t 100

i g t h i e h g e i g W i e 140 W e

140 H H 50 50 120 120

100 0 100 0 20 30 40 50 60 70 140 150 160 170 180 190 20 30 40 50 60 70 140 150 160 170 180 190 Age (y) Height (cm) Height (cm) Age (y) E F G H 200 200 200 200

180 150 150 180 ) ) g ) g k ( k

m ) (

160 t

c t h ( m 100

160 h g t c 100 i ( g h

i e t g e i h W e g W

i 140 H e 140 H 50 50 120 120 0 100 0 100 140 150 160 170 180 190 20 30 40 50 60 70 140 150 160 170 180 190 20 30 40 50 60 70 Height (cm) Age (y) Height (cm) Age (y)

Fig. 2 Simulated ( ) (A - male n=563, B - female n=31) and observed (x) (E – male n=563, F – female n=31) relationships between height and age and simulated ( ) (C - male n=563, D - female n=31) and observed (x) (G – male n=563, H – female n=31) relationships weight and height in a cohort of healthy Chinese volunteers.

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