Supplement Materials to:
Case Studies for Practical Food Effect Assessments across BCS/BDDCS Class
Compounds Using In Silico, In Vitro and Preclinical In Vivo Data
METHODS
Description of Compound’s PK disposition parameters
Case Study 1: NVS732
A single intravenous (i.v.) dose of 25 mg was infused to healthy volunteers over 30 min. Blood samples
were collected at predose and up to 24 h post dosing and plasma concentrations were analyzed by LCMS/MS. The disposition parameters were determined by compartmental analysis using PKPlusTM
(Simulation Plus Inc. CA, USA). A two compartment model was best fit to the concentration-time profile
(Fig. s1a) and the calculated disposition parameters were used in the GastroPlus model (Table II).
Case Study 2: NVS406
A single i.v. dose of 75 mg was administered to healthy volunteers via infusion over 25 min. Blood samples
were collected at predose and up to 24 h post dosing and plasma concentration was analyzed by LCMS/MS. The human pharmacokinetic parameters were characterized by compartmental PK analysis using
PKPlusTM. A three compartment PK model was found to best describe the concentration-time profile (Fig.
s1b). The observed PK parameters (Table II) were then incorporated in the GastroPlus model for the
prediction of oral absorption.
Case Study 3: NVS562
Human PK profiles after i.v. dosing have not been determined and therefore the disposition parameters
had to be predicted from preclinical data. Preclinical PK studies with i.v. administration were conducted in
mice, rats, dogs, and monkeys. The observed CL was 0.11, 0.94, 0.75, and 1.5 mL/min/kg in mice, rats,
dogs, and monkeys, respectively. The observed Vss was 0.49, 3.4, 2.1, and 2.9 L/kg in mice, rats, dogs, and
monkeys, respectively. Human CL was estimated using simple allometry of the product of CL
brain
weight according to “the rule of exponents method” (ROE) from preclinical animal data (1) while the
human Vss was estimated using simple allometry with plasma protein binding correction method. The
predicted human CL and Vss are 0.015 L/h/kg and Vss 3.4 L/kg, respectively. The normalized concentrationtime curve at 1 mg/kg in humans was then projected based on the concentration-time curves from
preclinical species using Wajima et al. method (2). A two compartmental PK model was found to best
describe the projected human concentration-time curve and the calculated PK parameters were used in the
model (Table II).
Case Study 4: NVS701
Human PK profiles after i.v. doses have not been determined and therefore the disposition parameters
were predicted from preclinical data. The observed CL was 5.0, 4.3, 8.8, and 11.0 ml/min/kg in mice, rats,
dogs, and monkeys, respectively. The observed Vss was 0.52, 7.9, 2.5, and 0.67 L/kg in mice, rats, dogs,
and monkeys, respectively. Human CL was estimated using fraction unbound (fu) intercept correction
method between rat and human (1) according to ROE while the human Vss was estimated using Oie-Tozer
method (3-4). The predicted human CL and Vss are 0.10 L/h/kg and 2.1 L/kg, respectively. Further, the
human concentration-time curve was projected using Wajima et al. method (2). A two compartmental PK
model best described the projected human concentration-time curve and the calculated PK parameters were
used in the model (Table II).
Case Study 5: NVS001
A single i.v. dose of 20 mg was administered to healthy volunteers via infusion over 15 min. Blood
samples will be collected at pre-dose and up to 12 h post dosing and plasma concentration was analyzed by
LC-MS/MS. The PK parameters of was characterized by compartmental PK analysis using PKPlusTM. A
three compartment PK model was found to best describe the concentration-time profile (Fig. s1c) and
observed PK parameters are listed (Table II).
Case Study 6: NVS169 and NVS113
Human PK profiles after i.v. doses have not been determined for both compounds and therefore the
disposition parameters were predicted from preclinical data. Preclinical PK studies with i.v. doses were
conducted in rats and dogs, NVS169 showed moderate CL (34 mL/min/kg) and moderate Vss (2.1 L/kg) in
rats while exhibited low CL (4.0 mL/min/kg) and low Vss (0.3 L/kg) in dogs. Using a single species scaling
method from rats as a conservative estimation, human CL and Vss were predicted to be 0.38 L/h/kg and 1.3
L/kg, respectively. A two compartment model was assumed for NVS169 to describe human PK profiles and
the calculated PK parameters were used in the model (Table II). For NVS113, Preclinical PK studies with
i.v. doses were conducted in rats, dogs, and monkeys. The observed CL was 1.4, 0.56 and 0.57 mL/min/kg
in rats, dogs, and monkeys, respectively. The observed Vss was 0.59, 0.28, and 0.59 L/kg in rats, dogs, and
monkeys, respectively. The human CL was estimated using allometric scaling according to ROE (1) while
the human Vss was estimated using Oie-Tozer method (3, 4) from the above three preclinical species. The
predicted human CL and Vss are 0.018 L/h/kg and Vss 0.4 L/kg, respectively. Similar, the human
concentration-time curve was then projected using Wajima et al. method (2). A two compartmental PK
model best described the projected human concentration-time curve and the calculated PK parameters were
used in the model (Table II).
SUPPLEMENTARY TABLES
Supplementary Table S1: Relative transporter expressions used in GastroPlus Simulation.
Transporters
Duodenum
Jejunum 1
Jejunum 2
Ileum 1
Ileum 2
Ileum 3
Caecum/Colon
P-gpa
0.538
0.645
0.723
0.77
0.838
0.908
1
0.33
0.33
0.33
1
1
1
0.33
OATP2B1
a
b
b
From (5)
From (6)
Supplementary Table S2: Simulated AUC values of NVS562 with mean precipitation time (MPT) generated from in vitro or in vivo data
Formulation
SEDDS
Tablet
Mean Precipitation Time (s)
AUC0-last (ng∙h/mL)
Fed state
Calculated from in
vitro data
Optimized
from
clinical in vivo data
Predicted using
in vitro MPT
Predicted using
in vivo MPT
Observed
Fasted
Fed
Fasted
3564
3478
2210
6000
6000
3500
13670
12810
5728
14230
13210
6909
14100
14260
7480
Fed
3231
6000
9722
10320
11900
LEGENDS OF SUPPLEMENTARY FIGURES
Supplementary Figure S1. Mean observed plasma concentration (solid circle) and fitted
plasma concentration time curve (black line) after a single i.v. infusion dose of (a) 25 mg of
NVS732, (b) 75 mg of NVS406, or (c) 20 mg of NVS001 in healthy volunteers.
Supplementary Figure S2. Mean observed food effect after oral administration of 3 mg/kg
of NVS001 in fasted (black) and non-fasted primates (gray).
SUPPLEMENTARY FIGURES
Figure S1.
Figure S2.
REFERENCES FOR SUPPLEMENTAL DOCUMENTS
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2.
Wajima T, Yano Y, Fukumura K, Oguma T. Prediction of human pharmacokinetic profile in animal scale
up based on normalizing time course profiles. J Pharm Sci. 2004;93(7):1890-900.
3.
Oie S, Tozer TN. Effect of Altered Plasma-Protein Binding on Apparent Volume of Distribution. J
Pharm Sci. 1979;68(9):1203-5.
4.
Lombardo F, Obach RS, Shalaeva MY, Gao F. Prediction of volume of distribution values in humans for
neutral and basic drugs using physicochemical measurements and plasma protein binding data. J Med Chem.
2002;45(13):2867-76. DOI: 10.1021/Jm0200409.
5.
Mouly S, Paine MF. P-glycoprotein increases from proximal to distal regions of human small intestine.
Pharm Res. 2003;20(10):1595-9.
6.
Meier Y, Eloranta JJ, Darimont J, Ismair MG, Hiller C, Fried M, et al. Regional distribution of solute
carrier mRNA expression along the human intestinal tract. Drug Metab Dispos. 2007;35(4):590-4. DOI:
10.1124/dmd.106.013342.