Virtual trial, Fed vs fasted state, In vitro dissolution & IVIC correlation , Biowavier correlation.pptx

20-11-2022 © R R INSTITUTIONS , BANGALORE 1
VIRTUAL TRIAL, FED VS FASTED STATE, IN VITRO
DISSOLUTION & IN VITRO-IN VIVO CORRELATION ,
BIOWAIVER CONSIDERATION
RR COLLEGE OF PHARMACY
SUBMITTED BY: SUBMITTED TO:
PAWAN DHAMALA PROF. Mr. K MAHALINGAM
2nd SEM , M.PHARMACY
DEPARTMENT OF PHARMACEUTICS

20-11-2022 © R R INSTITUTIONS , BANGALORE
2
 VIRTUAL TRIAL
 FED vs FASTED STATE
 IN VITRO-IN VIVO CORRELATION
 BIOWAIVER CONSIDERATIONS
 REFERENCES

INTRODUCTION
• Subject participation in clinical research most critical for
successful drug development.
• Conclusions derived from the clinical trial directly impacted
by the extent of subject participation.
Biggest challenges with conventional trials:
• Patient enrollment & retention
• Protection of patient’s rights
• Compliance

Virtual Clinical Trial (VCT)
Definition:-
• New method of collecting safety and efficacy data from clinical trial
participants, from study start-up through execution to follow-up.
• Trials take full advantage of technologies (apps, monitoring devices)
and online social engagement platforms to conduct each stage with the
comfort of the patients.

Open Enrolment Centralized Data Collection

Emerging technologies that make a virtual trial possible:

1. Social Media

Clinical Trials.gov and International Clinical Trials Registry Platform
(ICTRP). These registries serve as online repositories.

International Clinical Trials Registry Platform (ICTRP)

2. Mobility
Use of next generation communication solutions such as
mobile devices (smart-phones and tablets).
Speedy and cost effective connectivity Locate nearby
trial sites.
For example, GlaxoSmithKline developed an app for
the iPhone.
Likewise, Novartis uses Clinical Trial Seek and My
Net Manage mobile apps.

3. Remote Patient Monitoring
Direct data capture is a proven cost effective measure to engage
patients and improve retention.
Mobility enabled medical devices alert staff if a patient needs urgent
medical attention.
Alere™ HealthPal, an electronic health record, such as
Microsoft's HealthVault.
Medication Event Monitoring System™ (MEMS)
Glucometers include features to register the day, date, and time of
data capture electronically captured and transferred to a
database.

4. Electronic Patient Reported Outcome Data Capture
Tools
e-PRO instruments such as e-diaries are designed for
patients to record and report well specified and reliable
observations electronically.
Less errors, provides real time access to data, enable trigger
alerts and notifications.
PROMIS (2004)

5. Interactive Response Technology
IRT provides a centralized application and database that can
provide patients with automated access.
IRT can also be used - to educate and guide patients, much
like virtual nurses, and enhance compliance.

6.E-Informed Consent
Mytrus, an innovative clinical
technology and services company, has
launched an iPad application that
explains informed consent prior to
clinical trial subject enrollment.
Mytrus uses animation and other visual
aids to simplify patient education and
informed consent processes.

Benefits of Virtual Trials

Challenges with Virtual Trials

CASE STUDY: Sanofi’s Virtual Diabetes Trial
In 2015, Sanofi announced their intention to conduct a
virtual diabetes trial – named VERKKO.
 First clinical trial using electronic informed consent to be
approved by EMA.
Instead of testing a drug, as Pfizer’s trial did, Sanofi’s
European study tested a 3G capable wireless glucose meter in
diabetes patients.
60 patients — all recruited through Facebook.

The results exceeded expectations in many areas:
o74 individuals registered interest, 60 enrolled.
oThe average age of patients was 56 years old.
oPatient satisfaction had a score of 4.52 out of 5.
Improvements observed v/s the comparator study:
o9% drop-out rate - same as the comparator study.
oCompliance improved 18%.
o66% less time in study coordination activities.

The Future of Virtual Clinical Trials
Potential concerns about the inadvertent disclosure of
patient data are likely to increase with virtual data
collection practices.
Recruitment and retention of patients with low computer
literacy is a major concern that can greatly impact the trial
and data that it generates.
Perhaps virtual studies will augment rather than replace
traditional study practices and workflows.
Virtualizing aspects of the study may be done when the
circumstances call for it.

Can be used in rescue studies, where traditional models
have failed (e.g. for geographically dispersed groups or rare
disease populations).
Virtual studies will lend themselves well to sensors and
diagnostics, which will continue to increase in importance
as the technology evolves.
Generation of ‘big data’.
It is not an easy road, but likely to offer significant benefits
for certain studies & select populations.

Fed Vs. fasted state
The presence of food may affect drug absorption via a variety of
mechanism by impacting GI tract physiology (e.g. food induced
changes in gastric emptying time, gastric pH, intestinal fluid
composition), drug solubility, dissolution and drug permeation.
o For e.g.- lipophilic drugs often show increased systemic exposure with food
and this phenomenon is attributed to improved solubilization due to higher bile
salt and lipid concentration.
o While, negative effects are mostly seen by the hydrophilic drugs, where food
impedes permeation.

One of the frequently used approaches to assess the effect of food on oral
drug absorption involves animal studies. However, the fact that
physiological factors are species dependent, the magnitude of food effect
of given compound is usually different across the species. Thus,
complicating the prediction of food effect on humans.
 One alternative to animal experiments is to simulate food effects on
humans using physiologically based absorption model (for e.g.
GastroPlus) . These advanced model are built based on the prior
knowledge of GI physiology in the fasted and fed states.
o These model are able to describe the kinetics of drug transit, dissolution
and absorption on the basis of drug specific features such as permeability,
solubility, Ionization constant, metabolism and dose data etc.

Several studies have confirmed the usefulness of the in silico
modeling approaches to assess food effects on oral drug
absorption.
oFor e.g.- incorporation of biorelevant solubility and degradation
data in the GastroPlus absorption model to predict plasma
profile in fed, fasted and high fat condition. The biorelevant
solubility were measured at different media (simulates gastric,
intestinal and colonic fluids) under fed and fasted condition,
and the food effect of each drug was estimated by comparing
AUC or Cmax between both conditions.
o The predicted and observed plasma concentration time profiles
and food effect were compared for a range of doses to assess
the accuracy of simulation.

Significance:- The biorelevant solubility tests, in conjunction with physiologically based
absorption modelling, can be used to predict food effect caused by solubility and
dissolution rate limitations or degradation.
• An important issue is related to formulation dependent food effect, incorporated gastric
emptying time and different drug in vivo solubilities under fasted and fed states into the
generated CBZ (Carbamazepine) absorption model and observed that;
 Co-administration of CBZ IR suspension with food resulted in decreased Cmax and
prolonged tmax, probably due to a prolonged gastric emptying time. while,
Co-administration of CBZ IR tablets and CBZ XR capsules with food resulted in
increased Cmax and earlier tmax in comparison with the PK parameters obtained under
fasted state.
A possible explanation of this phenomenon was that the presence of a high fat meal
induced the increase in bile salts concentration in the GIT, thus enhancing the
dissolution rate of low soluble CBZ from the IR tablets and XR capsules.

In vitro-in vivo correlation (IVIVC)
There are two approaches enabling the GastroPlus generated drug
specific absorption model to be used to assess the relationship between
the in vitro and in vivo data :
i. Convolution approach
ii. Deconvolution approach
Once an IVIVC is developed, an in vitro dissolution test can be used to
identify changes that may affect the efficacy and safety of the drug
product. In addition, biowaiver justification could be discussed in terms
of whether dissolution from the dosage form is expected to be the rate-
limiting factor for drug in vivo absorption.

i. Convolution approach : To predict the plasma dissolution
profile. A set of in vitro data representing different
dissolution scenario is used as the input function in
GastroPlus software to estimate the expected drug plasma
concentration time profiles. The obtained profiles compared
with the mean drug plasma concentration profile observed
in vivo, in order to establish an IVIVC.
ii. Deconvolution approach : To estimate the in vivo
dissolution profile. The GastroPlus generated in vivo
dissolution profile is plotted against the in vitro obtained
dissolution profile, so that ‘bioperformance’ dissolution
conditions can be identified.

For e.g. ; for the establishment of IVIVC the predictive in vitro
dissolution data of CBZ formulation obtained under different
conditions for different CBZ product, which were submitted to the
FDA, and made a selection of the representative in vitro dissolution
profile, which were compared with the GastroPlus predicted CBZ
in vivo dissolution profile under fed and fasted states.
The first data collected for CBZ IR suspension; and collected in
vitro dissolution data demonstrated that the in vitro dissolution
was slower than the simulated in vivo dissolution in fed state but,
faster than in vivo dissolution in the fasted state.
 This indicates that the employed in vitro dissolution test
conditions for CBZ IR suspension could not be considered
“biorelevant”.

• The second data collected for CBZ IR tablets, in vitro dissolution
profiles obtained in 900ml media containing 0.1% SLS, using
USP Apparatus 2 with paddle speed 75rpm, were close to the in
vivo dissolution in the fed state.
• The third data collected for CBZ XR tablets, dissolution profile
obtained in 900ml buffered (pH 1.1, 4.5 and 6.8) using USP
Apparatus 1 at 100rpm, correlated well with in vivo dissolution
under fed condition .
The CBZ IR and XR tablets dissolution profile data showed the
“biorelevance” or bioequivalence between the in vitro and in vivo
data and provided a comparatively good IVIVC.

Biowaiver Considerations
• The term biowaiver refers to the situations in which in vivo BE studies
can be substituted with the relevant in vitro data.
• The main premise, when adopting the biowaiver concept was;
1) To reduce cost and time
2) To offer benefits in terms of ethical consideration
• The most common type of biowaiver adopted by the regulatory authorities
includes the application of the BCS based scheme or the application of
IVIVC.
• According to the FDA, biowaiver for IR drug products may be requested
solely in the case of highly soluble and highly permeable substances (BCS
class 1) when the drug product is (very) rapidly dissolving and exhibits
similar dissolution profile to the reference product. While, the IVIVC based
approach has been narrowed down to application for XR products.

• The EMA and WHO issued guidelines widened the eligibility for
biowaiver to some BCS class 3 (eligible if very rapidly dissolving) and
BCS class 2 ( eligible if the dose to solubility ratio at pH 6.8 is 250ml or
less and high permeability is at 85%).
• Also, it was pointed out that the biowaiver concept concerning to BCS 2
and BCS 3 drugs should further be relaxed (e.g. BCS class 2 drugs eligible
for biowaiver under assumption that the drug dissolved completely during
the GI passage) and ( BCS class 3 drugs eligible if rapidly dissolving).
For e.g. ; In CBZ study the biowaiver justification for this BCS class 2 drug
was elaborated. The GastroPlus generated CBZ-specific absorption model
was use to predict drug plasma concentration-time profiles based on
different in vitro dissolution rates as input function.
The result revealed that high dissolution rate (i.e.>85% of drug dissolved
in < 10 mins) were not related to the significant increase in Cmax in
comparison to the in vivo observed values.

Thus, indicating that the predicted plasma concentration profile
were rather insensitive to the differences in drug input kinetics.
Conclusion : It was concluded that there is a rationale for
considering CBZ biowaiver. But, other factors such as narrow
therapeutic index and vital indication are the limitation for
granting marketing authorization based in vitro data alone.

• Computer Applications in Pharmaceutical Research & Development
by Sean Ekins
• Computer-aided applications in pharmaceutical technology by Jelena
Djuris.
• www.google.com

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