Supplementary Material: DOI: 10.1515/dmdi-2015-0003
Literature references for reported in vitro data and calculations of pharmacokinetic
parameters
In order to obtain intrinsic secretion clearances CLint,sec,invitro (provided in Table 2 of the
manuscript), the measured apparent secretion clearances from sandwich-cultured
hepatocyte incubations (CLapp,sec,invitro) were corrected for the unbound fraction of drug in
hepatocytes (fu,hep, Supplementary Table 1) as described previously (1):
CLint,sec,invitro  CLapp,sec,invitro / f u ,hep
(1)
log( f u ,hep )  0.9161  0.2567  log D7.4
(2)
with:
Where logD7.4 refers to the drug’s distribution coefficient at pH 7.4 (Supplementary
Table 1). Similarly, the intrinsic metabolic clearances CLint,met,invitro were calculated from
reported
apparent
metabolic
clearances
from
liver
microsomal
incubations
(CLapp,met,invitro) taking the unbound fraction of drug in microsomes (fu,mic; Supplementary
Table 1) into account (1):
CLint,met ,invitro  CLapp,met ,invitro / f u ,mic
(3)
Supplementary Table 1: Physiochemical and pharmacokinetic parameters.
compounds
logD7.4
(-)
fu,hep
(-)
fu,mic
fu,p
Rb
CLapp,met,invitro
CLapp,sec,invitro
(-)
(-)
(-)
(µL·min-1·mgprot-1)
(µL·min-1·mgprot-1)
lovastatin acid
1.51
(2) a)
0.050
0.096
(3)
0.05
(2)
0.57
(4)
32.35
(2)
bld
[m]
simvastatin acid
1.88
(2)
0.040
0.051
(3)
0.06
(2)
0.57
(4)
28.80
(2)
0.02
[m]
cerivastatin
1.90
(5)
0.039
0.689
(3)
0.01
(6)
0.60
(7)
23.70
(2)
bld
[m]
fluvastatin
1.60
(8)
0.047
0.308
(9)
0.02
(6)
0.52
(7)
33.20
(2)
bld
[m]
pitavastatin
1.50
(10)
0.050
0.432
(9)
0.04
(7)
0.58
(7)
5.60
(2)
bld
[m]
atorvastatin
1.30
(5)
0.056
0.510
(1)
0.05
(1)
0.63
[-]
24.18
(1)
0.21
(1)
pravastatin
-0.40
(11)
0.154
0.880
(1)
0.52
(1)
0.54
[-]
0.60
(1)
0.11
(1)
rosuvastatin
-0.89
(10)
0.205
0.975
(3)
0.12
(9)
0.69
(9)
1.10
(12)
0.40
[m]
Notes: fu,p refers to the fraction of unbound drug in plasma, R b denotes the blood-to-plasma partition
coefficient. The literature references are shown in brackets. [-], calculated parameter. [m], parameter
determined in this study. bld, below limit of detection. a) the reported value refers to logD7.0
Literature references for clinical data
Supplementary Table 2 provides the literature references for all described clinical
pharmacokinetic parameters. All reported clearances in Supplementary Table 2
represent plasma clearances. Hepatic clearances (CLh,obs,p) were obtained from
reported total body clearances after oral (CLtot,obs,oral,p ) or i.v. (CLtot,obs,p) administration
according to equations 4-6:
CLtot,obs, p  CLtot,obs,oral, p  F
(4)
CLren,obs  Ue  CLtot,obs, p
(5)
CLh ,obs, p  CLtot,obs, p  CLren,obs, p
(6)
where F denotes the absolute oral bioavailability, CLren,obs,p refers to the renal organ
clearance, fn,ren (= CLren,obs,p/CLtot,obs,p) refers to fraction of drug excreted unchanged in
urine, and fn,h (= CLh,obs,p/CLtot,obs,p= 1- fn,ren) denotes the fractional contribution of
hepatic clearance to overall clearance (Eq. 4 in main manuscript).
Supplementary Table 2: Clinical data information.
compounds
CLtot,obs,p
[mL/(min∙kg)]
lovastatin acid
CLh,obs,p
CLren,obs,p
[mL/(min∙kg)]
([mL/(min∙kg)]
[mL/(min∙kg)]
(13)
144.00
[-]
16.53
[-]
330.69
cerivastatin
2.04
[-]
fluvastatin
3.88
[-]
pitavastatin
2.02
[-]
atorvastatin
3.73
[-]
pravastatin
10.60
[-]
rosuvastatin
11.64
(17)
simvastatin acid
7.20
CLtot,obs,oral,p
fn,ren
fn,h
(-)
F
(-)
(-)
6.48
[-]
0.72
[-]
0.10
(2)
0.90
0.05
(2)
(14)
14.39
[-]
2.15
[-]
0.13
(6)
0.87
0.05
(6)
3.40
(2)
2.04
[-]
0.00
[-]
0.00
(7)
1.00
0.60
(6)
16.17
(15)
3.65
[-]
0.23
[-]
0.06
(15)
0.94
0.24
(6)
3.97
(2)
2.02
[-]
0.00
[-]
0.00
(7)
1.00
0.51
(6)
26.62
[-]
3.69
(1)
0.04
[-]
0.01
(16)
0.99
0.14
(16)
58.89
[-]
5.62
(1)
4.98
[-]
0.47
(16)
0.53
0.18
(16)
58.20
[-]
8.40
[-]
3.24
(17)
0.28
[-]
0.72
0.20
(2)
Notes: Clearance values were corrected for the average human body weight assuming 70 kg. The
literature references are shown in brackets. [-], calculated parameter
In the main manuscript all pharmacokinetic parameters are referring to blood, in order to
compare with predicted hepatic blood clearances. Consequently, plasma-based
parameters in Supplementary Table 2 were converted to the respective blood
parameters by the following equation:
Rb  f u , p / f u ,b  CLp / CLb  Cb / C p
(7)
Where Rb (Supplementary Table 1) denotes the blood-to-plasma partition coefficient, fu,p
(Supplementary Table 1) and fu,b (provided in Table 2 of the manuscript) denote the
fraction of drug unbound in plasma (p) and blood (b), respectively, CLp and CLb refer to
clearance values and Cp and Cb to concentrations obtained in plasma and blood,
respectively.
DDI predictions taking into account inhibition of renal secretion
The degree of change in AUC caused by drug-drug interaction following oral (p.o.)
administration can be expressed as follows:
Fa  Fg ,i  Fh ,i  D
AUC po,i
AUC po
CLh ,i  CLren,i
Fa  Fg  Fh  D

(8)
CLh  CLren
where Fa, Fg and Fh represent the fraction absorbed, fraction of drug escaping gut-wall
metabolism and fraction of drug escaping hepatic extraction and D represents the
administered dose. The corresponding parameters in the presence of a perpetrator drug
are denoted “i”.
Assuming that: (i) the substrate is not metabolized and/or transported in the intestine
(Fg = 1), and (ii) Fa does not change in the presence of inhibitor, the AUC po,i/AUCpo ratio
can be described as follows:
AUC po,i
AUC po

Fh ,i  (CLh  CLren )
Fh  (CLh ,i  CLren,i )
(9)
Eq. 9 was be applied for the two statins in our dataset (pravastatin, rosuvastatin), which
are subject to concomitant hepatic as well as renal process inhibition by CsA. The
corresponding input parameters assuming 80% process inhibition on hepatic and renal
clearance and DDI anticipations are summarized in Supplementary Table 3:
Supplementary Table 3: Hepatic and renal elimination contributions in clinics in absence and presence
of a 80% process inhibitor.
compounds
CLh,obs
Fh
CLren,obs
CLh,i,pre
Fh,i
CLren,i,pre
AUCpo,i/
AUCpo
[mL/(min∙kg)]
(-)
[mL/(min∙kg)]
[mL/(min∙kg)]
(-)
[mL/(min∙kg)]
(-)
pravastatin
10.4
(1)
0.50
[-]
9.2
[-]
2.08
[-]
0.90
[-]
1.84
[-]
9.0
rosuvastatin
12.2
(17)
0.42
[-]
5.2
(7)
2.44
[-]
0.88
[-]
1.04
[-]
10.5
Notes: All clearance parameters represent human blood clearances. [-], calculated parameter.
Assuming a 90% inhibition on both processes the data are as follows:
Supplementary Table 4: Hepatic and renal elimination contributions in clinics in absence and presence
of a 90% process inhibitor.
compounds
CLh,obs
[mL/(min∙kg)]
Fh
(-)
CLren,obs
CLh,i,pre
[mL/(min∙kg)]
[mL/(min∙kg)]
Fh,i
(-)
CLren,i,pre
AUCpo,i/
AUCpo
[mL/(min∙kg)])
(-)
pravastatin
10.4
(1)
0.50
[-]
9.2
[-]
1.04
[-]
0.95
[-]
0.92
[-]
19.0
rosuvastatin
12.2
(17)
0.42
[-]
5.2
[15]
1.22
[-]
0.94
[-]
0.52
[-]
22.4
Notes: All clearance parameters represent human blood clearances. [-], calculated parameter.
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