This document summarizes the development of the drug Rivaroxaban. It discusses clinical trial simulations that were used in developing Rivaroxaban to determine safe dosages and evaluate its effectiveness for reducing risks of blood clots. Simulation studies incorporating patient data and models were used to predict Rivaroxaban's effects in different populations and help design later phase clinical trials. The trials showed Rivaroxaban was more effective than other drugs in reducing risks of blood clots in patients with atrial fibrillation or undergoing hip or knee replacement surgery. Rivaroxaban was approved for use in many countries based on the positive results of the clinical trials.

1. 1Challenge
Team
Presented for
CRA Helwan
[RIVAROXABAN A SCIENTIFIC LEAP IS
IT THE BEGINNING OF A NEW ERA ?]
Author: challenge team
Team Leader: Dina serag
Team:,Ahmed salem ,Heba Mahmoud, Hala mahmoud, Mohamed assad ,
sara mahmoud ,Aya hamid, amina bashar, Hosam Eldin Ahmed,
Ahmed Mohamed, Hadeer Abd Alaziz, Resam Hesham

2. 2
Abstract— Clinical trial simulation is the
application of old technologies to a new problem.
That problem being how to maximize the
information content obtained during the drug
development process with an intent to have the
greatest chance of success in a clinical trial.
Under that paradigm, some summary measure of the
pharmacokinetics across animal species, such as
mean clearance and volume of distribution, is used
to predict what the pharmacokinetics will be in
humans. From this, point a single estimate of the
pharmacokinetics in humans is estimated without
regard to error or variability.
Simulation may be used to provide a better grasp on
the variability in pharmacokinetics in humans and
possibly provide a better point estimate for the
pharmacokinetic in humans as well.
Researchers at the Duke Clinical Research Institute
have been accused of withholding clinical data used
to evaluate the blood thinner drug Xarelto .
Xarelto was tested at Duke in a 2011 clinical trial
known as the ROCKET AF trial (current
Commissioner of the FDA) found Xarelto to be
more effective than the standard prescription of
warfarin in reducing the likelihood of ischemic
strokes in patients with atrial fibrillation, or
abnormal heart rhythms[1]
..
INTRODUCTION
simulations may be based on allometry and are
of value in setting a safe starting dose.
The allometric relationship between actual
pharmacokinetic parameters andbody mass in the
pre-clinical species enables the extrapolation to
species that have a larger body mass ( as human)
aiding the selection of a safe starting dose with
acceptable pharmacological activity.
In its simplest form, a clinical trial simulation is
the study of the effects of a drug in virtual patient
populations using mathematical models that
incorporate information on physiological systems.
 STEPS OF CLINICAL TRIAL
SIMULATION
First step:
Its use is based on knowledge of biology and
population as well as specific information on the
drug , Such simulations require data on the physico
chemistry of the drug, in vitro metabolic stability
(eg. in human hepatocyte) and information related
to drug absorption and active transport.
The scenarios can be unlimited number of
initiatives that you may want to try in order to get
the trial the finish sooner with the lower cost profile
for optimal simulation clinical trial optimizer builds
on CTS[2].
NOTE:
Methods used in this type of simulation may
involve use of dose versus clearance regression
models, simple superposition models and
compartmental models.
Second step:
Decisions on which dose and dose regimen to use
for Phase 2a and 2b clinical trials may be facilitated
by simulations that are derived from data collected
from clinical trials in small numbers of healthy
volunteers or patients. Such work seeks to
understand the relationship between drug dose,
pharmacokinetic profile and drug response and
simulate potential treatment scenarios.
By describing these relationships in a mathematical
model, the effect of different doses of drug and
drug regimens may be simulated Such simulations
were used to inform the dose and regimen for the
subsequent Phase 2 trials.
Key words: simulation / Disease Modelling / Rivaroxaban/ factor Xa /population pharmacokinetics/ cohort
/ retrospective / prospective / clinical simulation/RECORD program

3. 3
This step occur by model some results which
contain:
"Dose type, no. of patient group, no. of visits,
frequency of visit, total no. of patient , trial
duration"
Cases change the model:
Drug-drug interaction studies
Special patient population studies
the assessment of drug clearance in special patient
populations, such as the renally impaired,
hepatically impaired, children, the elderly and
specific ethnic groups, is a substantial component of
a clinical pharmacology programme [3]
.
EX:
The simulation in Figure shows that as hepatic
impairment increases, the clearance of the drug
decreases, suggesting that the administered dose
may need to be decreased in this patient population.
The information gained from the simulation can
be used to aid the design of hepatic impairment
studies and help to maintain the safety of patients
with different degrees of hepatic impairment in
other studies.
Third step:
Proof of Concept
Clinical Proof of Concept (PoC) is a key decision
making point in the drug development process.
Initial proof that the concept may be efficacious in a
clinical setting is obviously a key trigger point for
major investment and a decision that the sponsor
needs to take with some confidence that this will be
supported by future clinical trials[3]
.
Three critical questions need to be
addressed in the PoC clinical trial:
1--How much drug needs to be delivered to the
target and for how long ?
2- How to determine if the drug is achieving
the desired pharmacological activity and clinical
activity ?
3- Which patients will respond to treatment?
By identifying those patients who will achieve the
most benefit from a given therapy, thereby avoiding
the patients who will not gain from exposure to the
drug.
We can answer these questions by using Disease
Modelling:
Our computer representations of diseases based on
experimental clinical data and human
pathophysiological concept.
They provide a quantitative link between various
factors changes in symptoms and disease
biomarkers overtime .
The underlying progression of the disease and the
variability between patients this is what the disease
model enables us to correlate short term effects on
disease biomark with long-term effects on clinical
endpoints home
such as how early tumour shrinkage translates into
progression-free survival..in a cancer study
Fourth step:
phase 3 trial was able to study what tactical
improvements could be made to improve the
performance of their delivery. [4]
Some videos to support our ideas:
1-https://www.youtube.com/watch?v=ZlUC6sA6uzI
2- https://vimeo.com/64332443
3- https://www.youtube.com/watch?v=Hhd2U94QM60

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The following is an examples for a practical application:
Gooley et al. used simulation to find an optimal dose of T-cells to be used in bone marrow
transplantation patients with HLA-mismatched unrelated donors.
The goal was to find a dose such that the risk of moderate to severe graft- versus host-disease was
less than 15% with no more than a 5% rejection rate.
Their simulation showed that using a standard dose-escalation scheme used for oncotic agents, there was an
unacceptably high risk of an erroneous dose
Conclusion.
Clinical trials program of rivaroxaban:[5]
In vitro and phase I clinical studies showed that rivaroxaban was well tolerated in healthy human
subjects, with predictable, dose proportional PK and PD up to total daily doses of 60 mg. with a mean
terminal half-life of 7–11 hours
phase II studies were performed in patients undergoing THR( Total hip replacement) or TKR( total knee
replacement) to investigate the efficacy and safety of rivaroxaban.

5. 5
Influence of demographic factors on the
pharmacokinetics of rivaroxaban:
Simulations of rivaroxaban "plasma
concentration−time" profiles after a 10 mg od
dose were performed to represent typical patients
with extreme demographic characteristics (aged
90years; with moderate-to-severe renal
impairment [CrCL of 30 ml/min]; underweight
[40 kg]; and 90 years old and underweight) at the
upper and lower limits of the studied population
to provide further insights into the expected
average
influence of these covariates on rivaroxaban
exposure.
Those were plotted for comparison alongside the
plasma concentrations for the average population.
Plasma concentration–time profiles for each
simulated typical ‘extreme’patient fell within the
predicted 90% confidence intervals of the average
patient in these studies. [6]
The later studies for the approved indication of
10 mg rivaroxaban once daily in patients
undergoing elective hip or knee replacement
surgery
that no dose adjustment is required in mild
(creatinine clearance 50–80 mL/min) or moderate
(CrCl 30–49 mL/min) renal impairment, and
should be used with caution in patients with
severe renal impairment (CrCl 15–29 mL/min).
The drug is not recommended
in patients with CrCl <15 mL/min .
Collectively, these studies demonstrated an
optimal dose range of 5_20mg per day, and
indicated that rivaroxaban 10mg once daily had
the optimum balance of efficacy and safety,
relative to enoxaparin 40mg once daily.
suggesting that this dose should be investigated
further.
On the basis of the results of the Phase II studies,
rivaroxaban 10mg once daily was selected for
investigation in the Phase III ReCoRD
programme, which comprised four large studies
involving patients undergoing elective tHR or
tKR and investigate the efficacy and safety of
Venous Thromboembolism prophylaxis.
RECORD1 and 2: total hip replacement surgery
RECORD1: Both treatments continued for 35+/-
4days
RECORD2: ‘Xarelto’ continued for 35+/-4
days; enoxaparin for 12+/- 2 days
RECORD3 and 4: total knee replacement
surgery
RECORD3: Both treatments continued for
12+/-2 days RECORD4:
Both treatments continued for 12+/-2 days
RECORD4:
Both treatments continued for 12+/-2 days
(‘Xarelto’ 10mg against enoxaparin 30 mg
injected subcutaneously twice-daily, which is the
U.S.-approved treatment regimen for
enoxaparin).
Xarelto’ demonstrated superior efficacy for the
primary endpoint over enoxaparin in the four
RECORD trials , including head-to-head
comparisons (RECORD1, 3 and 4,)
and a comparison of extended-duration (5
weeks) ‘Xarelto’ with short-duration (2 weeks)
enoxaparin (RECORD2).
The results from this study demonstrate that
extended duration prophylaxis with 10 mg

6. 6
XARELTO od for 35 days provided clinically
meaningful decreases in Total VTE, Major VTE,
and symptomatic VTE in THR patients without
an increased risk of bleeding.
this trial also showed no evidence of
compromised liver function in patients receiving
rivaroxaban for up to 6 months[7]
.
Bayer HealthCare has submitted regulatory
filings in more than 10 countries; ‘Xarelto’
received its first marketing approval in Canada on
September 15, 2008, for the prevention of (VTE)
in patients who have undergone elective total hip
or total knee replacement surgery..
On July 30, 2008, the new drug application
(NDA) for ‘Xarelto’ was
submitted for approval to the U.S. Food and
Drug Administration (FDA). [8]
PROSPECTIVE AND
RETROSPECTIVE COHORT
STUDIES[9]
Cohort studies can be classified as prospective or
retrospective based on when outcomes occurred
in relation to the enrollment of the cohort.
 Prospective Cohort Studies:
The baseline information is collected from all
subjects in the same way using exactly the same
questions and data collection methods for all
subjects.
The investigators design the questions and data
collection procedures carefully in order to obtain
accurate information about exposures before
disease develops in any of the subjects.
After baseline information is collected, subjects
in a prospective cohort study are then followed
"longitudinally," i.e. over a period of time,
usually for years, to determine if and when they
become diseased and whether their exposure
status changes.
In this way, investigators can eventually use the
data to answer many questions about the
associations between "risk factors" and disease
outcomes.
For example, one could identify smokers and
non-smokers at baseline and compare their
subsequent incidence of developing heart
disease.
Alternatively one could group subjects
based on their body mass index (BMI) and
compare their risk of developing heart disease
or cancer.
.
*Key Concept: The distinguishing feature of a
prospective cohort study is that at the time
that the investigators begin enrolling subjects and
collecting baseline exposure information, none of
the subjects has developed any of the outcomes
of interest.
 Retrospective Cohort Studies:
Retrospective studies are conceived after some
people have already developed the outcomes of
interest.
The investigators jump back in time to identify a
cohort of individuals at a point in time before
they have developed the outcomes of interest, and
they try to establish their exposure status at that
point in time.
They then determine whether the subject
subsequently developed the outcome of interest.
It would be more efficient to use employee health
and employment records over the past two or
three decades as a source of data. In essence, the
investigators are jumping back in time to identify
the study cohort at a point in time before the
outcome of interest occurred.

7. 7
Key Concept: The distinguishing feature of a
retrospective cohort study is that the investigators
conceive the study and begin identifying and
enrolling subjects after outcomes have already
occurred.
INTERVENTION STUDIES
(CLINICAL TRIALS)
Intervention studies (clinical trials) are
experimental research studies that compare the
effectiveness of medical treatments, management
strategies, prevention strategies, and other
medical or public health interventions.
Their design is very similar to that of a
prospective cohort study. However, in cohort
studies exposure status is determined by genetics,
self-selection, or life circumstances, and the
investigators just observe differences in outcome
between those who have a given exposure and
those who do not.
In clinical trials exposure status is assigned by the
investigators.
In summary, the characteristic that distinguishes a
clinical trial from a cohort study is that the
investigator assigns the exposure status in a
clinical trial, while subjects' genetics, behaviors,
and life circumstances determine their exposures
in a cohort study.
Key Concept:
Common features of both prospective and
retrospective cohort studies.
1. None of the subjects have the outcome of
interest at the beginning of the follow-up period
(In retrospective cohort studies the follow-up
period begins in the past.)
2. The groups being compared differ in their
exposure status.
One measures and compares the incidence of the
outcome in order to determine whether there is an
association between the exposure and the
outcome.
CONCLUSIONS
In our vision of a very different future, clinical
trial simulations will be the principle scientific
activity as well as this will go well beyond the
success and efficiency of actual development
activities. It will impact the selection and training
of scientific personnel involved in drug
development ,virtual clinical trials may reduce
overall cost of drug development by reducing the
total number of trials, especially ones that are
prone to failure or that are unnecessary.
It help in calculate accurate doses specially in
patients with kidney problem.
Rivaroaban could be one of the drugs
developed in the new era of CTS.
An era that we can avoid the sever but not
frequent problem showed in 2014.

8. 8
 REFERENCES
[1] M. R. Patel, A. S. Hellkamp, and K. A. A. Fox,
“Point-of-Care Warfarin Monitoring in the
ROCKET AF Trial,” N. Engl. J. Med., vol. 374, no.
8, pp. 785–788, Feb. 2016.
[2] A. Bedding, G. Scott, N. Brayshaw, L. Leong, E.
Herrero-martinez, M. Looby, and P. Lloyd,
“Clinical trial simulations – an essential tool in drug
development,” Abpi, 2014.
[3] R. Gieschke and J. L. Steimer, “Pharmacometrics:
modelling and simulation tools to improve decision
making in clinical drug development,” Eur. J. Drug
Metab. Pharmacokinet., vol. 25, no. 1, pp. 49–58,
2000.
[4] P. L. Bonate, “Clinical trial simulation in drug
development,” Pharm. Res., vol. 17, no. 3, pp. 252–
256, 2000.
[5] F. Misselwitz, S. D. Berkowitz, and E. Perzborn,
“The discovery and development of rivaroxaban,”
Ann. N. Y. Acad. Sci., vol. 1222, no. 1, pp. 64–75,
2011.
[6] V. Laux, D. Ph, E. Perzborn, D. Kubitza, and F.
Misselwitz, “Preclinical and Clinical Characteristics
of Rivaroxaban : A Novel , Oral , Direct Factor Xa
Inhibitor,” vol. 1, no. 212, pp. 515–523, 2007.
[7] M. Repka, N. Langley, and J. DiNunzio, AAPS
Advances in the Pharmaceutical Sciences Series.
2013.
[8] A. K. Kakkar, B. Brenner, O. E. Dahl, B. I.
Eriksson, P. Mouret, J. Muntz, A. G. Soglian, ??kos
F. Pap, F. Misselwitz, and S. Haas, “Extended
duration rivaroxaban versus short-term enoxaparin
for the prevention of venous thromboembolism
after total hip arthroplasty: a double-blind,
randomised controlled trial,” Lancet, vol. 372, no.
9632, pp. 31–39, 2008.
[9] “Prospective and Retrospective Cohort Studies.”
[Online]. Available:
http://sphweb.bumc.bu.edu/otlt/MPH-
Modules/EP/EP713_AnalyticOverview/EP713_Ana
lyticOverview3.html.
.