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

Prepared By: Pawan Dhamala
M.Pharmacy(Pharmaceutics)
RR College of Pharmacy

1. 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 COMPUTER AIDED DRUG DELIVERY SUBMITTED BY : SUBMITTED TO: PAWAN DHAMALA PROF. Mr. K MAHALINGAM 2 nd SEM , M.PHARMACY DEPARTMENT OF PHARMACEUTICS

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

3. 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 20-11-2022 © R R INSTITUTIONS , BANGALORE 3

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5. 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. 20-11-2022 © R R INSTITUTIONS , BANGALORE 5

6. 20-11-2022 © R R INSTITUTIONS , BANGALORE 6 Open Enrolment Centralized Data Collection

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8. 20-11-2022 © R R INSTITUTIONS , BANGALORE 8 Emerging technologies that make a virtual trial possible:

9. 1. Social Media 20-11-2022 © R R INSTITUTIONS , BANGALORE 9

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12. Clinical Trials.gov and International Clinical Trials Registry Platform (ICTRP). These registries serve as online repositories. 20-11-2022 © R R INSTITUTIONS , BANGALORE 12

13. International Clinical Trials Registry Platform (ICTRP) 20-11-2022 © R R INSTITUTIONS , BANGALORE 13

14. 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. 20-11-2022 © R R INSTITUTIONS , BANGALORE 14

15. 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. 20-11-2022 © R R INSTITUTIONS , BANGALORE 15

16. 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) 20-11-2022 © R R INSTITUTIONS , BANGALORE 16

17. 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. 20-11-2022 © R R INSTITUTIONS , BANGALORE 17

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20. 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. 20-11-2022 © R R INSTITUTIONS , BANGALORE 20

21. Benefits of Virtual Trials 20-11-2022 © R R INSTITUTIONS , BANGALORE 21

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23. Challenges with Virtual Trials 20-11-2022 © R R INSTITUTIONS , BANGALORE 23

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25. 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. 20-11-2022 © R R INSTITUTIONS , BANGALORE 25

26. The results exceeded expectations in many areas: 74 individuals registered interest, 60 enrolled. The average age of patients was 56 years old. Patient satisfaction had a score of 4.52 out of 5. Improvements observed v/s the comparator study: 9 % drop-out rate - same as the comparator study. Compliance improved 18%. 66 % less time in study coordination activities. 20-11-2022 © R R INSTITUTIONS , BANGALORE 26

27. 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. 20-11-2022 © R R INSTITUTIONS , BANGALORE 27

28. 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. 20-11-2022 © R R INSTITUTIONS , BANGALORE 28

29. 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. 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. While , negative effects are mostly seen by the hydrophilic drugs , where food impedes permeation . 20-11-2022 © R R INSTITUTIONS , BANGALORE 29

30. 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 . 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. 20-11-2022 © R R INSTITUTIONS , BANGALORE 30

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32. Several studies have confirmed the usefulness of the in silico modeling approaches to assess food effects on oral drug absorption. For 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 . The predicted and observed plasma concentration time profiles and food effect were compared for a range of doses to assess the accuracy of simulation. 20-11-2022 © R R INSTITUTIONS , BANGALORE 32

33. 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. 20-11-2022 © R R INSTITUTIONS , BANGALORE 33

34. 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. 20-11-2022 © R R INSTITUTIONS , BANGALORE 34

35. 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. 20-11-2022 © R R INSTITUTIONS , BANGALORE 35

36. 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 ”. 20-11-2022 © R R INSTITUTIONS , BANGALORE 36

37. 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. 20-11-2022 © R R INSTITUTIONS , BANGALORE 37

38. 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; 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. 20-11-2022 © R R INSTITUTIONS , BANGALORE 38

39. 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. 20-11-2022 © R R INSTITUTIONS , BANGALORE 39

40. 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. 20-11-2022 © R R INSTITUTIONS , BANGALORE 40

41. REFERENCES Computer Applications in Pharmaceutical Research & Development by Sean Ekins Computer-aided applications in pharmaceutical technology by Jelena Djuris . www.google.com 20-11-2022 © R R INSTITUTIONS , BANGALORE 41

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