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ISSN: 0363-9045 (print), 1520-5762 (electronic)
Drug Dev Ind Pharm, Early Online: 17
! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2014.991399
RESEARCH ARTICLE
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Centre of Excellence-Biostudies, Integrated Product Development Organization, Dr. Reddys Laboratories, Hyderabad, Andhra Pradesh, India
Abstract
Keywords
Prediction of the in vivo performance of the drug product from the in vitro studies is the major
challenging job for the pharmaceutical industries. From the current regulatory perspective,
biorelevant dissolution media should now be considered as quality control media in order to
avoid the risk associated. Physiological based pharmacokinetic models (PBPK) coupled with
biorelevant dissolution medium is widely used in simulation and prediction of the plasma drug
concentration and in vivo drug performance. The present investigation deals with the
evaluation of biorelevant dissolution media as well as in vivo drug performance by PBPK
modelling using STELLA simulation software. The PBPK model was developed using STELLA
using dissolution kinetics, solubility, standard gastrointestinal parameters and post-absorptive
disposition parameters. The drug product selected for the present study includes Linezolid filmcoated immediate-release tablets (Zyvox), Tacrolimus prolonged-release capsules (Advagraf),
Valganciclovir tablets (Valcyte) and Mesalamine controlled-release capsules (Pentasa) each
belonging to different biopharmaceutics classification system (BCS). The simulated plasma drug
concentration was analyzed and pharmacokinetic parameters were calculated and compared
with the reported values. The result from the present investigation indicates that STELLA
when coupled with biorelevant dissolution media can predict the in vivo performance of the
drug product with prediction error less than 20% irrespective of the dosage form (immediate
release versus modified release) and BCS Classification. Thus, STELLA can be used for in vivo
drug prediction which will be helpful in generic drug development.
Introduction
Prediction of in vivo pharmacokinetics of drug products is one of
the major challenges for both innovator and generic pharmaceutical industries. Accurate to approximate prediction of in vivo
behavior of drug product will reduce failure rate in drug product
development as well as huge resources involved in the same.
Prediction of pharmacokinetics from in vitro and in silico tools
has been used since few decades and is based on the certain
physicochemical and biopharmaceutical properties of drug molecules and in vitro release rates. In vitro dissolution tests using
suitable media, i.e. biorelevant media has proven to be successful
methodology for in vivo performance prediction of drug products1,2. Recent literature reflects the wide use of simulated gastric
fluids or so-called biorelevant media for better in vivo drug
performance prediction3,4. Physiologically based pharmacokinetic
(PBPK) models predict the plasma concentration time profile
from the in vitro dissolution and in silico data inputs5,6. PBPK
modeling takes into account the factors influencing the absorption, distribution and elimination7,8. The insights given by the
History
Received 29 May 2014
Revised 4 September 2014
Accepted 12 November 2014
Published online 12 December 2014
PBPK models are integrative and far better than that of noncompartmental or compartmental analysis. A report by Parrott
et al.9,10 suggests that PBPK models are superior to the other
empirical methods for interspecies scaling and prediction of
human pharmacokinetics. Prediction of pharmacokinetic behaviour of the drug products from the physicochemical and dissolution data assists the generic pharmaceutical companies to select
the optimized formulation when the qualitative and/or information
is unavailable. Currently, regulatory governing bodies are also
utilizing the PBPK models for better understanding of the drug
products11,12. Therefore, the generic pharmaceutical industries
are also utilizing the same concept of PBPK modelling using
dissolution specifications (of both test and reference listed drug)
for the pharmacokinetics prediction in order to avoid the
resources and time spent on the pilot biostudies.
Among the various in silico software packages for building
PBPK models (GastroPlus , PKSim , SimCyp and MatLab),
STELLA (Structural Thinking, Experimental learning
Laboratory with Animation) has been proven as useful
approach to simulate the in vivo behavior of orally administered
drugs13,14. It is an icon-based model building and simulation
tool that was first introduced in the 1980s. In contrast to
commercially available PBPK models available, through the use
of a graphical interface, the user constructs and runs the
simulation by building a graphical representation of the model
using STELLA 13 (Figures 1 and 2). STELLA is user
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S. Chakraborty et al.
Figure 1. General model structure used to simulate the pharmacokinetic profiles of the selected drugs using STELLA .
Figure 2. STELLA model map used to
simulate the plasma profiles of the selected
drugs. SI, small intestine; Vfluid, volume of
co-administered fluid; API, active pharmaceutical ingredient.
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DOI: 10.3109/03639045.2014.991399
S. Chakraborty et al.
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W 3 Xs Wt zW 3 Cs C
dt
Vp2=3
where Wt is the amount dissolved at time t; W is the amount of
drug remaining to be dissolved; Xs is the amount of drug which
saturates the volume V of the dissolution medium, Cs is the
solubility of drug, C is the concentration of the dissolved drug
at time t; is the particle density, is the shape factor, N is the
number of the particles to be dissolved and z is the dissolution
parameter which is constant equivalent to D N1/3/d2/3.
Dissolution inputs are introduced into the model by assuming
the dissolution kinetics as the first-order kinetics, according to the
defined equation. Sink conditions are assumed for the dissolution
in the intestine. When in vitro dissolution was considered to occur
according to the equation and the dose administered in vivo was
the same as the dose tested in vitro, the z-value for the in vivo
dissolution process, z vivo, was identical to z vitro27. The
corresponding z-value is calculated for each drug product in
the respective dissolution media and is tabulated in Table 1. The
simulation of plasma drug concentration for each drug from the
dissolution media is done for doses 600 mg, 5 mg, 2*450 mg and
5*500 mg for Linezolid film-coated IR tablets, Tacrolimus PR
capsules, Valganciclovir tablets and Mesalamine CR capsules,
respectively.
Linezolid
Tacrolimus
Valganciclovir
Mesalamine
Linezolid
Dissolution medium
0.01 N HCl
pH 6.8 phosphate buffer
Tacrolimus
pH 4.5 OPA with 0.005% HPC
pH 4.5 OPA with 0.05% SLS
0.1 N HCl 0.05% SLS
pH 4.5 acetate buffer with 0.05% SLS
pH 6.8 phosphate buffer with 0.05% SLS
Valganciclovir 0.1 N HCl
pH 6.8 phosphate buffer
Mesalamine
Fasting gradient media
0.1 N HCl
pH 7.2 phosphate buffer
0.01 N HCl
pH 6.8 phosphate buffer
4.5 pH OPA with 0.005% HPC
4.5 pH OPA with 0.05% SLS
0.1 N HCl 0.05% SLS
4.5 pH acetate buffer with 0.05% SLS
6.8 pH phosphate buffer with 0.05% SLS
0.1 N HCl
pH 6.8 phosphate buffer
FaSSGF
FaSSIF (6.5)
FaSSIF pH 7.0
pH 7.2 phosphate buffer
pH 7.5 phosphate buffer
SCoF
4.38
2.53
0.007
0.068
0.002
0.082
0.079
602.9
625.9
6.20
4.52
15.32
9.87
11.35
5.25
Drug
Drug
Dissolution medium
Solubility
(mg/mL, at
37 0.5 C)
z-Value
(mL/mg2/3/h)
0.890
0.952
0.280
0.425
0.239
0.525
0.511
0.758
0.815
0.525
0.925
0.345
Drugs
Linezolid
Tacrolimus
Valganciclovir
Mesalamine
V/F
mg/(ng/mL)
k10
(h1)
k12
(h1)
k21
(h1)
Bioavailability
(fraction)
0.004
1.3125
0.0518
0.0075
0.165
0.0223
0.1823
3.1048
0.1392
2.3125
0.251
5.6037
0.1257
1.7529
0.1295
9.1986
1
0.22
0.594
0.29
k10, elimination rate constant; k12, distribution rate constant for drug
transfer from first to second compartment; k21, distribution rate constant
for drug transfer from second to first compartment.
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DOI: 10.3109/03639045.2014.991399
Figure 3. Dissolution profile of the selected drug products in the respective dissolution media. (A) Linezolid film-coated IR tablets, (B) Tacrolimus PR
capsules, (C) Valganciclovir tablets and (D) Mesalamine CR capsules.
Table 4. The observed (reported) and simulated (predicted using STELLA ) pharmacokinetic parameters of the drugs in selected dissolution medium.
Drug (BCS Class)
Linezolid film-coated IR tablets
Tacrolimus PR capsules
Valganciclovir tablets
Mesalamine CR capsules
Cmax (ng/mL)
AUC0t (ng*h/ml)
AUC01 (ng*h/ml)
Reported values
pH 6.8 phosphate buffer
Reported values
6.8 pH phosphate buffer with 0.05% SLS
Reported values
0.1 N HCl
pH 6.8 phosphate buffer
Reported values
Fasting gradient media
13.68
15.03
11.57
9.82
4630
4450.23
4519.01
537.93
575.13
112
142.21
290.81
284.83
24 400
25 265
25 576.50
4831.05
5285.82
112.60
149.05
318.15
363.90
24 900.00
25 711.87
26 208.73
5401.84
6533.92
S. Chakraborty et al.
Conclusions
The present investigation indicates that the dissolution testing in
appropriate media, coupled with simulation software STELLA ,
can predict the plasma drug concentration of the selected drug
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Figure 4. Observed and simulated (using STELLA ) plasma drug concentration of the drugs. (A) Linezolid (600 mg tablets), (B) Tacrolimus (5 mg
capsules), (C) Valganciclovir (2*450 mg tablets) and (D) Mesalamine (2*500 mg capsules).
Table 5. The percentage prediction error in the observed (reported) and simulated (predicted using STELLA ) pharmacokinetic parameters of the
drugs in selected dissolution medium.
% Predicted
error (Cmax)
% Predicted
error (AUC0t)
% Predicted
error (AUC01)
0.01 N HCl
6.8 pH phosphate buffer with 0.05% SLS
0.1 N HCl
pH 6.8 phosphate buffer
Fasting gradient media
9
15
4
2
7
6
2
4
3
9
16
14
3
5
21
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DOI: 10.3109/03639045.2014.991399
Acknowledgements
Authors would like to thanks Dr. Reddys Laboratory for providing
assistance and support to publish this work. Also the authors acknowledge
the scientific inputs provided by Dr Hemant P. Joshi.
Declaration of interest
All the authors are employees of Dr. Reddys laboratory and
report no conflicts interest. The authors alone are responsible for
the content and writing of this article.
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