Patient-centered drug delivery system: Use of big data for ...€¦ · Patient-centered drug...

Patient-centered drug delivery system:

Use of big data for clinical unmet

needs

Beom-Jin Lee, Ph.D.

Professor and Dean of College of Pharmacy

Ajou University

Suwon, Korea

Platform technology A few successful case: OROS, OCAS, SODAS, Geomatrix.. Sensitive to system design, drug type, formulation and excipients,

races and patient pathophysiology Therapeutically acceptable to satisfy clinical unmet needs from

patients

Evolution of Drug Delivery Technology

Patient-centered (therapeutic-based) DDS according to patient medical unmet needs: pathophysiology, clinical benefits and treatments

Material basis and formulation

The number of older adults

(aged over 65years)

• In Europe, 87 million in

2010 -> 123 million in

2030

• In the UK, older adults aged

80+ will represent 9% of the

population in 2050 compared

with 4.8% in 2012

Americans have been living

longer, meaning that the

demarcation of 65 as "old" is

more distant from the

average life expectancy.

www.ajou.ac.kr

Population of geriatric patient

Figure. Age composition of american

Physiological changes on aging(ADME in the geriatrics)

Absorption Distribution Metabolism Elimination

Amount of saliva ↓ Cardiac output ↓ Liver function (through

decrease in blood flow) ↓

Kidney size ↓

Gastric acid production ↓ Renal blood flow ↓ Cyp P450 enzyme levels ↓ Renal blood flow ↓

Gastro-intestinal surface ↓ Hepatic blood flow ↓ Overall drug metabolism ↓ Number of functional

nephrons ↓

Active transport

mechanism ↓

Albumin water levels ↓ Tubular secretion ↓

Gastric pH ↑ Volume of distribution for

water soluble drugs ↓

Overall glomerular filtration

rate (GFR) ↓

Gastric emptying time ↑ Body fat/water ratio ↑

Learning from practice to meet patient centricity

2015-10-27

• The Guidance for Industry Q8(R2) Pharmaceutical Development”

request: “In all cases, the product should be designed to meet

patients’ needs and the intended product performance”

• Lack of suitable formulations, pharmaceutical packs and

administration devices to meet their needs.

A. Swallowing considerations

B. Dosage form and pharmaceutical product design Dosage form design: The size, shape, color, surface structure, taste

and smell of the product should be considered to improve the ease of

swallowing

Packaging and labelling: Tamper-resistant product

C. Medication schedule and management factors Dosing frequency: Controlled release system

Dealing with polypharmacy: Fixed-dose combination

Medicines requirement for pediatrics & geriatrics

Patient-centric drug delivery

The development of drug products that address unmet needs within

specific target populations.

Patient-centric formulations and dosage forms can positively impact

the quality life of patients Improving or maintaining therapeutic efficacy

Diminishing the negative aspects of taking medication

Patient populations

Geriatric Pediatric Dysphasic Those affected by debilitating

mental or physical illnesses Life-threatening diseases (CV,

cancer, DM)

Primary objectives

Ease of administration Improved compliance to the dosing

regimen Improved palatability Optimized dosage form needs Reduction in the number of daily doses Satisfaction of clinical unmet needs

Specialized Patient Needs

[Expected levels of concern for patients]

Optimal patient

dosing needs

Geriatric Pediatric Dysphasic Mentally III

Ease of swallowing ++++ ++++

++++

++++

Reduced pill

burden

++++

++

++

++

Convenient dosage

form

++ ++++

+ +

Pleasant taste ++

++++

+ +

Identification, mix-

up prevention

++++

++

+ ++

Moynihan, H., Crean, A. (2009) Physicochemical Basis of Pharmaceuticals. Chapter 1, Oxford University Press.

Higher ++++>+++>++>+ Lower

2015-10-27

Big Data in Pharma Industry

Definition: Big data is a set of techniques and technologies that require new forms of integration to uncover large hidden values from large datasets that are diverse, complex, and of a massive scale. Big Data is used in the singular and refers to a collection of data sets so large and complex, it’s impossible to process them with the usual databases and tools. Because of its size and associated numbers in complexity, Big Data is hard to capture, store, search, share, analyze and visualize. The phenomenon came about in recent years due to the sheer amount of machine data being generated today – thanks to mobile devices, tracking systems, RFID (definition to follow), sensor networks, social networks, Internet searches, automated record keeping, video archives, e-commerce, etc.

Big Data : Raising the Table Stakes for Master Data Management, IMS Health

“We swim in a sea of data … and the sea level is rising rapidly.” Pew Research Center’s Internet & American Life Project - July 2012

Big Data Advantages in Pharma R&D

• Better disease understanding • Better design of products, trials &

treatments • Real-world patient data • Customized drug development • Identification of undiagnosed patients • Detection of serious adverse events • Prediction of hospital re-admissions • Improved HO & medical forecasting

• Comparative effectiveness • Track of patient pathway & drug

switches • Prediction of disease trends & locations • Patient sentiments & feedbacks • Improved communications • Healthy pipeline & better products • Reduced cost, enhanced quality &

efficiency

Detecting adverse/side effects and finding clinical unmet needs for patient centricity

• Cases using big data in Korea : Accessibility of EMR in general hospital (Ajou University Hospital); Drug safety monitoring (adverse effects) and decision making in drug discovery & development

• History - Use of big data for evidence-based drug safety monitoring and decision making: Detecting adverse effects of medicines (thalidomide, cisapride, rofecoxib)

10

Next-Gen Pharma R&D with Big data

Pharmaceutical and life sciences companies that focus on research, clinical trials,

and managing the business historically use data warehouses and business

intelligence tools to report on and analyze this data.

- Big Data solutions help improve the efficiency of the drug discovery and

development process and to provide support for transnational approaches to

research(discovery, non-clinical safety, PK/PD, clinical data)

Accelerated Clinical Trials and

Drug Discovery

Monitoring and Improving

Patient Adherence

Improving Operational

Efficiency

By combining shared research data from

the marketplace with clinical data,

genetic / genomic profiles, patient

adherence, and population data,

research outcomes can be recognized

faster, clinical trials can become

streamlined, and new medicines can be

discovered faster and at lower cost. Once

consumers have access to the drugs,

social media can be monitored to better

understand drug effectiveness and

possible side effects.

When drugs are prescribed by

physicians, there is often a question

of how often the prescriptions are

filled and whether they are taken in

the way that the drug was designed

for and as the physician intended.

As sensors become more prevalent in

drugs and monitoring devices, the

industry is becoming better

equipped to monitor patient

adherence.

Predictive analytics has typically been

applied to data residing in a data

warehouse. Applying analytics to a Big

Data solution enables us to analyze a

wider variety of data sources thus

improving the accuracy of our

predictions.

Predicting the success of a drug trial

early is critical to determining if a

drug’s development should be

continued and can greatly reduce

wasted time and cost.

Linkage of big data and patient centricity

BA improvement, durability

Better response, tolerance

Taste, route & frequency

of administration

Pricing, Cost,

patent, Treatment

GI irritation,

toxicity (heart, kidney)

Bleeding, Sugar level

Technology (CR, Sol, BBB)

Dosage forms

(Nano, beads, matrix)

Big Data

(Collection &

Analysis)

Korea United Pharm. Brief History

1987 Establishment 1992 Acquired KGMP approval for the plant

2000 Established API Plant 2001 10 Mil. Dollar Export Award

2004 Completed Korea United Pharm Int’l, JSC. in Vietnam 2004 Completed United Douglas Pharm. Inc. in Alabama

2009 / 2010 Forbes Asia’s 200 Best Under a billion for 2 years

2011 Established New Plant (cGMP) 2012 Designated Korea Innovative Pharmaceutical Company

2013

Out-licensing of IMDs to other companies 2014 Selected on the list of World Class 300 project

Globally Registered Countries & Products

Number of Exported products : 416 Number of registered countries : 32

Hongkong Indonesia Malaysia Mongolia Pakistan

Singapore Thailand

Uzbekistan India

Costa Rica El Salvador

Ecuador Guatemala Nicaragua

Peru Chile Cuba

Colombia Uruguay

Venezuela Honduras

Dominica

Panama

Nigeria Kenya Egypt Ghana Yemen Syria Iran

Belarus Georgi

144

132

49

60

31

Product Partner Business Region

License Out Russia Kazakhstan Ukraine

Uzbekistan Belarus Venezuela

License Out China

Co-marketing S. Korea

Co-marketing S. Korea

IMDs Partnering

Case I: Aceclofenac

: Physicochemical & biopharmaceutical properties

Molecular formula C16H13Cl2NO4

Molecular weight 354.19

Dose 100 mg

Protein binding >99%

Peak time after oral

administration 1 ~ 3 h

Elimination half life Approximately 4 h

Solubility Insoluble in water, soluble in alcohol

Major route of eliminat

ion About two-thirds of a dose is excreted in the

urine mainly as hydroxymetabolites

Adverse effect Gastro-intestinal disturbances,

nausea, diarrhoea

Aceclofenac : 89796-99-66

http://upload.wikimedia.org/wikipedia/commons/0/05/Aceclofenac.png

Unmet needs Patient compliance (QD), Gastric adverse effects, Low solubility, Rapid onset & maintaining plasma concentration

Applied Technology Controlled release system - Bilayered matrix types, Solubilization (IR/CR)

Solution Q.D, Dual-controlled/Bilayered (dosing design), No food effect

Design of patient-centered aceclofenac DDS

Bilayered tablets with instant release & sustained release for 24 hrs

Generations in Solubility Enhancement

Beom-Jin Lee et al., EJPB (2013)

Aceclofenac

Release profiles of poorly soluble drug according to four generations

Beom-Jin Lee et al., EJPB(2013)/PR (2012)

Modulation of micro-environmental pH and controlled release system

Formulations & dissolution profiles

Time (min)

0 15 30 45 60

Dis

solu

tion r

ate

(%

)

0

20

40

60

80

100F25

F26

F27

F28

F29

Time (min)

0 15 30 45 60

Dis

solu

tion r

ate

(%

)

0

20

40

60

80

100F30

F31

F32

F33

F34

Time (min)

0 15 30 45 60

Dis

so

lutio

n r

ate

(%

)

0

20

40

60

80

100

F35

F36

F37

F38

F39

F40

Time (min)

0 15 30 45 60

Dis

solu

tion r

ate

(%

)

0

20

40

60

80

100

F41

F42

F43

F44

F45

Time (hr)

0 5 10 15 20 25

Diss

olut

ion

rate

(%)

0

20

40

60

80

100

120

F8

F9

F10

F11

F12

Time (hr)

0 5 10 15 20 25

Diss

olut

ion

rate

(%)

0

20

40

60

80

100

120

F13

F14

F15

F16

Time (hr)

0 5 10 15 20 25

Diss

olutio

n ra

te (%

)

0

20

40

60

80

100

120

F27

F28

F29

F30

SR layer IT layer

Time (h)

0 5 10 15 20 25

Dis

solu

tio

n A

mo

un

t (m

g)

0

50

100

150

200

Airtal

Clanza CR

Time (hr) 1 12 24

Airtal® 92.3

Clanza® CR 86.3 137.4 195

Amount of drug dissolved (mg)

Dissolution Profile of optimized formulation

Alkalizer (Na2CO3)

Hydrogen ion

(pHm) controlled system

(Electronic microscopy image, x

5000000) (pHm) images in dissolution media

pH 1.2

pH 6.8

Release-modulating mechanism: Microenvironmental pH (pHm) and swelling system

Preclinical Test in Beagle Dogs

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32

Pla

sma

level

( ㎍

/mL

)

Time (h)

mean (n = 6)

AIRTAL® TAB 100 mg

CLANZA CR TAB 200 mg

0.1

100.0

0 4 8 12 16 20 24 28 32Pla

sma

level

( ㎍

/mL

)

Time (h)

mean (n = 6) AIRTAL TAB 100 mg

CLANZA CR TAB 200 mg

Reference Test

Cmax 54.47 ± 6.86 60.65 ± 25.34

Tmax 1.64 ± 1.34 3.750 ± 4.168

t1/2 4.44 ± 0.79 4.191 ± 0.720

AUC(0-t) 258.99 ± 60.18 428.7 ± 163.6

AUC(0-inf) 263.93 ± 60.75 433.9 ± 164.2

AUC(0-t)/AUC(0-inf),% 98.1 98.5

F* (%) - 82.2

Confirming the SR pattern

* F : Relative Bioavailability to Airtal® 200mg; Bioavailabity (%) = (AUC∞ , Test / AUC∞ Ref x 2 ) x 100

Single Dose and Food Effect Study Multiple Dose Study

Study Design 3 treatment, 3 period 2x2 cross-over

Study Purpose

To Assess the Pharmacokinetics and Food Effect

of Aceclofenac Controlled Release Tablets

Following Sing-Dose Administration Compared

with the Immediate Release Tablets in Healthy

Male Subjects

To Assess the Pharmacokinetics of

Aceclofenac Controlled Release Tablets

Following Multiple-Dose

Administration Compared with the

Immediate Release Tablets in Healthy

Male Subjects

Subjects 42 healthy male adults 30 healthy male adults

Dosing Groups 6 groups of 7 people 2 groups of 15 people

Dose, Route

- Clanza® CR 200mg qd for 1day (fasted), po

- Clanza® CR 200mg qd for 1day (fed, High fat), po

- Airtal 100 mg bid for 1 day (fasted), po

- Clanza® CR 200 mg qd for 7 days,

po

- Airtal® 100 mg bid for 7 days, po

Primary Endpoint PK parameters: Cmax, AUCt

Safety Parameters AE, Vital Sign, EKG, Physical examination, Clinical Laboratory test

Start date August 24, 2009 October 7, 2009

End date October 13, 2009 November 16, 2009

PK analysis center & CRO for Clinical Trial: Hopkins Bio Research Center

Summary of Clinical Study Synopsis

2015-10-27 25

Clanza® CR tablet - Clinical Trials in humans

• Clinical equivalence between Clanza® CR (q.d.) vs. Airtal® (b.i.d., Almiral)

• All clinical data requirements are fulfilled

Single dosing PK and food effects study

Randomized, open-label, single dose, 3-treatment, 3-period

Repeated (multiple) dosing PK study

Randomized, open-label, repeated dose, 2-Way crossover

Post-marketing comparative clinical trials

Patients with chronic back pain and chronic knee

osteoarthritis

Experiment

Sample preparation process

Centrifuge (14,000 rpm, 10 min)

Supernatant 800 ㎕

Injection 50 ㎕

ACN 700 ㎕ + Calibration standard, QC sample or Plasma sample 500 ㎕

+ IS (Flufenamic acid, 80 µg/mL) 50 ㎕

Vortexing (10 s)

Instrument conditions

(1) Instrument: HPLC-UV (Agilent 1200 series)

(2) Column: C18 CAPCELL PAK (4.6 X 250 mm, 5 μm, Shiseido, Japan)

(3) Mobile phase: Acetonitrile / 0.1M acetate buffer (pH 6.4) = 40 / 60 (v/v)

(4) Flow rate: 1.0 mL/min

(5) Detector: UV 280 nm

(6) Run time: 9 min

★ Sample amount; single study 4612ea, multiple study 2296ea

Total average n=41

0

1

10

100

0 4 8 12 16 20 24

Tim e (h)

Plasma level ( g/mL)

Reference drug (fasted)

Test drug (fasted)

Mean Plasma Concentrations Following Single Oral Administration

Bioequivalence Test (Single Dose, Fasting State)

Items AUCt Cmax

90% confidence interval log 0.9975 ≤ δ ≤ log 1.0634 log 0.9144 ≤ δ ≤ log 1.0280

PK parameters Reference

(fasted)

Test

(fasted)

Cmax (μg/mL) 10.26 ± 1.81 10.61 ± 2.07

AUCt (h∙μg/mL) 42.33 ± 8.35 41.05 ± 7.66

AUC∞ (h∙μg/mL) 43.22 ± 8.62 43.31 ± 7.89

Tmax (h) 1.7 ± 0.7 1.5 ± 0.7

Λz (1/h) 0.39 ± 0.14 0.16 ± 0.07

T1/2 (h) 2.1 ± 0.9 5.0 ± 2.1

Confirming the SR pattern

Total average n=41

0

1

10

100

0 4 8 12 16 20 24

Time (h)

Pla

sma leve

l (g/m

L)

Test drug (fasted)

Test drug (fed)

Mean Plasma Aceclofenac Concentrations Following Single Oral Administration

Bioequivalence Test (Single Dose, Fed State)

Items AUCt Cmax


PK parameters Test drug

(fasted)

Test drug

(fed)

Cmax (μg/mL) 10.61 ± 2.07 10.34 ± 2.27

AUCt (h∙μg/mL) 41.05 ± 7.66 41.61 ± 7.71

AUC∞ (h∙μg/mL) 43.31 ± 7.89 43.22 ± 7.69

Tmax (h) 1.5 ± 0.7 2.7 ± 1.2

Λz (1/h) 0.16 ± 0.07 0.21 ± 0.06

T1/2 (h) 5.0 ± 2.1 3.9 ± 2.5

No food effect

Items AUCt Cmax



PK parameters Reference drug

(fasted)

Test drug

(fasted)

Cmax (μg/mL) 3.24 ± 0.42 3.55 ± 0.56

AUCt (h∙μg/mL) 31.57 ± 4.51 29.10 ± 5.62

AUC∞ (h∙μg/mL) 34.87 ± 5.46 32.18 ± 6.59

Tmax (h) 2.61 ± 0.77 2.48 ± 0.78

Λz (1/h) 0.18 ± 0.03 0.12 ± 0.03

T1/2 (h) 3.86 ± 0.60 6.14 ± 1.46

Metabolic Bioequivalence Test (Single Dose)

Total average n=41

0

1

10

0 4 8 12 16 20 24

Tim e (h)

Plasma level (

g/mL)

Referene drug (fasted)

Test drug (fasted)

Active Metabolite (4-OH Aceclofenac)

Bioequivalence Test with Multiple Dosing

Items AUCt Cmax


PK parameters Reference drug Test drug

Css,max (μg/mL) 10.00 ± 2.25 10.08 ± 1.96

Css,min (μg/mL) 0.02 ±0.07 0.07 ±0.11

AUCt (h∙μg/mL) 39.28 ± 6.68 37.99 ± 5.88

AUC∞ (h∙μg/mL) 39.60 ± 6.83 39.79 ± 5.93

Tmax (h) 1.8 ± 0.9 1.7 ± 0.9

Λz (1/h) 0.46 ± 0.15 0.16 ± 0.07

T1/2 (h) 1.7 ± 0.7 5.1 ± 2.4

Total average n=29

0

1

10

100

0 4 8 12 16 20 24

Time (h)

Pla

sm

a level (g/m

L)

Reference drug

Test drug

Mean Plasma Concentrations Following Multiple Dosing Administration

Bioequivalence Test (Multiple Dose, Metabolite)

Pharmacokinetic

parameters

Reference

drug Test drug

Css,max (μg/mL) 2.89 ± 0.78 3.17 ± 0.68

Css,min (μg/mL) 0.27 ± 0.18 0.08 ± 0.13

AUCt (h∙μg/mL) 26.53 ± 7.17 22.56 ± 5.73

AUC∞ (h∙μg/mL) 28.41 ± 8.09 24.53 ± 6.07

Tmax (h) 5.4 ± 5.4 2.4 ± 0.9

Λz (1/h) 0.22 ± 0.05 0.13 ± 0.04

T1/2 (h) 3.3 ± 0.7 5.6 ± 1.6

Total average n=29

0

1

10

100

0 4 8 12 16 20 24

Time (h)

Pla

sm

a level (g/m

L)

Reference drug

Test drug

Items AUCt Cmax


Mean Plasma Concentrations Following Multiple Dosing Administration

Active Metabolite (4-OH Aceclofenac)

Information synopsis of Clanza® CR tablet

•World’s first once daily formulation of aceclofenac (200mg film coated),

satisfying medical unmet needs

•Best choice for the treatment of chronic pain management

•Improved patient compliance, taking once daily with and without food

: Reach MEC rapidly and maintain effective plasma concentration over

24 hrs due to the modified drug release profile from two-layered tablet

•Safety and efficacy

: Reduced side effects of upper gastrointestinal bleeding and

cardiovascular system

: Rapid onset of pain relief and safety for long term therapy

•Approval from Korea FDA on Apr. 14, 2010

Case II: Cilostazol Advanced Antiplatelet agent with reduced adverse events

Composition Cilostazol 200mg

Description White, oblong, controlled release tablet

Indication It is used in the treatment of ischemic symptoms including ulcer, pain and coldness of the extremities in chronic arterial occlusion. It is also indicated in preventing recurrence of cerebral infarction except cardiogenic cerebral embolism

Dosage & Administration

Adults: The recommended dose is 200 mg daily, taken as one dose(every 24 hours) Take this drug in the fasted state

Unmet Needs • Improved drug compliance by taking once-a-day tablet. • Designing double-controlled release tablet with improved dissolution • Reduced adverse events of cilostasol by maintain a plasma concentration in a

controlled manner

34

Cilostasol

Drug Information / Patient profile

• Patient compliance is the key issue for the target patient

60 years old and above: > 76%

Daily dosing regimen: Mostly 2 tablets per day (> 68%)

Concomitant drugs: Mostly once daily regimen

1st Statins (44%), 2nd Aspirin (32%), 3rd Metformin (24%), 4th

ARB (24%), 5th CCB (24%)

Co-morbidity: Diabetes (14%), Stroke (13%), Hypertension (10%)

Time (min)

0 200 400 600 800 1000 1200 1400

Dis

solu

tion (

%)

0

20

40

60

80

100

C5 (Carbomer)

F5 (Carbomer + HPMC)

H5 (HPMC)

Time (min)

0 200 400 600 800 1000 1200 1400

Dis

solu

tion (

%)

0

50

100

150

200

Reference drug (Pletal(R))

Tested drug (F5)

Time (min)

0 200 400 600 800 1000 1200 1400

Sw

ell

ing

(%

)

0

200

400

600

800

1000

1200

1400

1600

H5 (HPMC)

F5 (HPMC + Carbomer)

Formulations & dissolution profiles

Dissolution rate of reference drug and tested drug in SLS 0.3%(w/v) in water

Carbomer Gastric fluid (pH 1.0~2.0)

Intestinal fluid

(pH 6.0~8.0)

Cilostazol

HPMC

HPMC Control Carbomer Control

Erosion Diffusion

Water Uptake

Sol state Gel state

Swelling

Neutralized

Sol-gel transition of carbormer according to pH value

Release-modulating mechanism: Sol-Gel proces

37

Cilostan® CR – Formulation strategies

• Maintain effective plasma concentrations over 24 hours for

better patient compliance and continued control of the disease

HPMC Control

pH-independent

in stomach

CARBOMER Control

pH-dependent

in intestine

CilostanCR

Double Controlled

Release system

Reference drug Test drug

Cmax /dose (ng/mL) 0.87 ± 0.28 0.62 ± 0.12

Tmax (h) 2.75 ± 0.61 4.17 ± 0.41

T1/2 (h) 7.25 ± 6.18 8.34 ± 1.56

AUCt (h∙ng/mL) 307.63 ± 86.14 683.77 ± 90.68

AUC∞ (h∙ng/mL) 333.72 ± 88.73 720.93 ± 95.01

AUC(0-t)/AUC(0-inf),% 92.41 ± 7.59 94.88 ± 3.28

F* (%) - 108.0

* F : Relative Bioavailability to Pletaal® 200mg

Bioavaility (%) = (AUC∞ , Test / AUC∞ Ref x 2 ) x 100 Concentration-time profile of Aceclofenac after oral administration at a

dose of tablet of test (Cilostan® CR TAB 200 mg) and reference (Pletaal®

TAB 100 mg) formulation to male beagle dogs

mean (n =6)

0

50

100

150

0 6 12 18 24 30 36 42 48

Time (h)

Pla

sm

a level (n

g/m

L)

.

Pletaal TAB 100mg

CILOSTAN CR TAB 200mg

Preclinical Test in Beagle Dogs (Oral)

Enhanced bioavailability due to the solubility and controlled release

39

Cilostan® CR – Clinical trial

Clinical equivalence between Cilostan CR® (q.d.) vs. Pletaal

(b.i.d., Otsuka)

All clinical data requirements are fulfilled

• Single Dose Pharmacokinetic Study: Randomized, Open-label, Single

dose, 2-Treatment, 2-Period, 2-Way Crossover

•Repeated Dose Pharmacokinetic Study: Randomized, Open-label,

Repeated dose, 2-Treatment, 2-Period, 2-Way Crossover

•Food Effect Study: Randomized, Open-label, Single dose, 2-Treatment,

2-Period, 2-Way Crossover Study under fed conditions


Items AUCt Cmax



(fasted)

Test drug

(fasted)

Cmax (ng/mL) 1512 ± 498 1569 ± 697

AUCt (h∙ng/mL) 30031 ± 15604 27764 ± 15501

AUC∞ (h∙ng/mL) 31195 ± 17064 30710 ± 19639

Tmax (h) 3.70 ± 1.88 4.03 ± 1.59

Λz (1/h) 0.14 ± 0.05 0.10 ± 0.05

T1/2 (h) 8.96 ± 5.25 12.95 ± 8.10

Cilostazol

10

100

1000

10000

0 12 24 36 48 60 72

Pla

sm

a l

evel (n

g/m

L)

.

Time (h)

Total average, n=30

Reference drug

Test drug

Bioequivalence Test (Single Dose, Fasting State)

Highly improved and sustained over a 24-

hour period in a controlled manner.

Mean Plasma Concentrations Following multiple Oral Administration

Items AUCt Cmax

90% confidence interval log 0.8326≤ δ ≤ log 0.9556 log 0.9216 ≤ δ ≤ log 1.0728

Reference drug

(fasted)

Test drug

(fasted)

Cmax (ng/mL) 1852.74 ±

608.32

1814.82 ±

479.18

AUCt (h∙ng/mL) 27831.47 ±

11677.61

24448.60 ±

7840.82

AUC∞ (h∙ng/mL) 33631.4 ± 18295.0 33287.6 ± 11450.9

Tmax (h) 9.4 ± 6.1 4.1 ± 1.6

Λz (1/h) 0.1134 0.0597

T1/2 (h) 6.1 ± 2.9 11.6 ± 3.9

Cilostazol

0

500

1000

1500

2000

2500

96 100 104 108 112 116 120

Pla

sma level (n

g/m

L)

Time (hr)

Total average, n=30 대조약

시험약

Bioequivalence Test (Multiple Dose, Fasting State)

Mean Plasma Concentrations Following single Oral Administration

Items AUCt Cmax



(fasted)

Test drug

(fasted)

Cmax (ng/mL) 1968.6 ± 25.1 2715.4 ±758.9

AUCt (h∙ng/mL) 31686.8 ±

10327.8

26933.2 ±

10491.1

AUC∞ (h∙ng/mL) 31923.8 ± 10352.7 27424.5 ± 10526.5

Tmax (h) 9.5 ± 6.2 5.0 ± 1.1

Λz (1/h) 0.1193 0.0769

T1/2 (h) 5.8 ± 1.9 9.0 ± 4.2

Cilostazol

0

1000

2000

3000

0 12 24 36 48 60 72

Pla

sma level (n

g/m

L)

Time (hr)

Total average, n=30 대조약

시험약

Bioequivalence Test (Single Dose, Fed State)

• Formulation strategies: Dual-controlled release cilostazol tablet which

exhibits a stable release pattern without any variation in the percentage

eluted depending on the pH in the stomach in addition to an effect

whereby release of the drug is delayed, by using a release-controlling

polymer consisting of a mixture of hydrophilic polymer and a pH-

dependent polymer

• Dual-controlled release system prevents the rapid release of API in the

tablet to ensure a long retention time and avoid adverse effects such as

headache, flushing

• No significant PK difference in AUCi / dose, Cmax / dose and t 1 / 2 but

significant difference in Tmax

44

• The World’S One and Only

Cilostazol controlled release 200mg tablet (white elliptical /

oval)

•Improved patient compliance

One 200mg tablet, once daily (Pletaal, twice daily)

•Safe and Effective

Reduced side effects of headache & tachycardia

•Korea FDA Approval

Approval from Korea FDA on Feb. 28, 2013

• Approved indications

Peripheral Artery Occlusive Disease (PAOD) Cerebral

Infarction

Cilostan® CR - Drug Information / Patient profile

Summary and Conclusions

• Patient-centric drug products have been designed to meet the clinical unmet

needs for geriatric and pediatric patients who have different pathophysiology,

taking into account their specific characteristics in terms of age, physiology,

morbidity/comorbidity and functional impairments.

• Patient-centric drug product development provides more medical & clinical

benefits for targeted patient population and their specific needs with a safe and

patient-friendly administration and good quality management.

• Patient-centric drug products are based on the combination of existing or new

formulation and drug delivery technologies, along with efficient, highly flexible,

and innovative manufacturing technologies and platforms

• In the meanwhile, use of big data gives a privilege for patient centricity and

pharma industry to help improve the efficiency of the drug discovery and

development process.

Thank you for your kind attention!

Patient-centered drug delivery system: Use of big data for ...€¦ · Patient-centered drug...

Documents

Transcript of Patient-centered drug delivery system: Use of big data for ...€¦ · Patient-centered drug...