2. References Figure 1 in Main Text 3

Supplementary Material for “Key to opening kidney for in vitro-in vivo extrapolation entrance in health and disease: Part II Mechanistic models and in vitro-in vivo extrapolation”

Contents

1. Table S-I 2

2. References figure 1 in main text 3

3. References 4

1. Table S-I

Table S-I. Calculation of AUC ratio for renal transporter mediated DDIs using static model, and comparison with published predictions using PBPK model and observed values

PBPK Study / Posada et al, 2015 (1) / Hsu et al, 2014 (2) / Hsu et al, 2014 (2) / Hsu et al, 2014 (2) / Li et al, 2014 (3)
Victim Drug / Pemetrexed / Oseltamavir carboxylate / Cidofivir / Cefuroxime / Veliparib
CL (L/h) / 5.6 (4) / 19 (2) / 12.8 (2) / 11 (2) / 34.0 *
fe a / 0.8 (4) / 1 * / 0.89 * / 1 * / 0.7 (5)
CLR (L/ h) a / 4.48 * / 19 (2) / 11.4 (2) / 11 (2) / 23.8 (5)
fu,p,victim / 0.19 (4) / 0.97 (2) / 0.9 (2) / 0.67 (2) / 0.49 (5)
CLR,filt (L/ h) b / 1.4 / 7.0 / 6.5 / 4.8 / 3.5
CLRsec (L/ h) b / 3.1 / 12.0 / 4.9 / 6.2 / 20.3
Perpetrator drug
(transporter) / Ibuprofen
(OAT3) / Probenecid
(OAT3) / Probenecid
(OAT3) / Probenecid
(OAT3) / Cimetidine
(OCT2)
Inhibitor Cmax (µM) / - / 280.7 (6) / 520.7 (7) e / 243.7 (7) / 9.4 (8)
fu,p, inhibitor / - / 0.1 (2) / 0.1 (2) / 0.1 (2) / 0.81 (9)
Inhibitor Cmax,u (µM) / 1.6 (4) / 28.1 f / 52.1 f / 24.4 f / 7.6 f
Ki (µM) / 2.1 (4) / 0.1 – 100 (2) g / 0.1 – 100 (2) g / 0.1 – 100 (2) g / 0.25 – 373 (3, 10) h
DDI index c / 0.74 / 0.3 - 281 / 0.5 – 521 / 0.2 - 244 / 0.02 - 30.3
AUC Ratio
Static (11) / 1.3 / 1.2 – 2.7 / 1.2 - 1.6 / 1.1 - 2.3 / 1.0 - 2.4
PBPK d / 1.2 / 1.2 – 2.3 / 1.1 – 1.4 / 1.2 – 2.2 / 1.3
Observed / 1.2 (4) / 2.5 (2) / 1.3 (2) / 1.4 (2) / ND

a Data for plasma or IV clearance (CL), renal clearance (CLR) or fraction of drug recovered unchanged in urine (fe)were collated where available. Where data not available, values were calculated assuming fe = CLR/ CL, indicated by *; b Filtration clearance (CLR,filt) calculated assuming glomerular filtration rate of 7.2 L/ h. Secretion clearance (CLR,sec) calculated assuming negligible reabsorption (CLR,sec = CLR – CLR,filt); c DDI index is calculated as Cmax,u/ Ki; d data extracted from figures using GetData graph digitiser where necessary (http://www.getdata-graph-digitizer.com/); e Cmax of probenecid after 2 g SD; f Inhibitor Cmax,u calculated using reported Cmax and fu,p; g Range of Ki values represents sensitivity analysis performed in PBPK study (2). In vitro Ki values range from 1.3 – 32 µM (2, 10); h OCT2 Ki of cimetidine SimCYP default compound file is 0.25 µM, which was obtained by fitting to recover clinically observed transporter mediated DDIs. Reported cimetidine IC50 values for OCT2 range from 110 – 373 µM (10); ND - Clinical DDI study not reported

2. References figure 1 in main text

2.1 References for Figure 1

(12-30).

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