In-Jin Jang M.D., Ph.D. Clinical Pharmacology Unit, Clinical Trial Center Seoul National University Hospital (SNUH) & Seoul National University College

In-Jin Jang M.D., Ph.D.In-Jin Jang M.D., Ph.D.

Clinical Pharmacology Unit, Clinical Trial CenterClinical Pharmacology Unit, Clinical Trial Center

Seoul National University Hospital (SNUH) & Seoul National University Hospital (SNUH) &

Seoul National University College of MedicineSeoul National University College of Medicine

Experience in Korea on Experience in Korea on Bridging StudiesBridging Studies

SNUH-CTC Recent Changes in Korean Regulations for Clinical

Trials 1999

Elimination of compulsory conduction of local clinical trial in Korea as a condition of registration (For the products with < 3yr market experience or, For the products only marketed in the original developing country)

Introduction of Bridging Study System; Dec. 1999 Bridging study waiver until June 2001

Allowance for conducting the multi-national, multi-center trials

2002 Separation of IND system and NDA system. Began to collect user-fee but not providing

consultation about the clinical trial designs yet.

SNUH-CTC

Track for “marketing approval without domestic/Korean bridging data”; 8 drugs

1 for life-threatening condition, 4 orphan drugs, 1 diagnostic, 1 topical drug, 1 antibiotic without domestic/Korean clinical

data on the basis of ethnic insensitivity and in vitro

microbiological sensitivity test of domestic clinical isolates

2 failed to register without domestic bridging data

Insulin analogue and one more endocrine drug

Bridging Data Generation : Experiences in Korea (1)

SNUH-CTC

Track for single pharmacokinetic study for bridging data generation; 11 drugs

Three products were approved with single Korean pharmacokinetic clinical trial data.

Actos, Avandia, Gastrointestinal (GI) drug GI drug study was done in Koreans living in an other cou

ntry Three sponsors finished PK studies

ED, IBS, antimuscarinic More than 5 sponsors are planning to do PK base

d bridging data generation BPH/alopecia, diuretic, vascular, antihyperlipidemic, hor

monal agent


SNUH-CTC

Track for phase 3 clinical study for bridging data ; 11 drugs, (12 indications) None approved yet Open trial: 3, Blinded trial: 9 Placebo control: 2, Active control: 7 Sample size: 30 (open) ~ 284 (142 x 2) Therapeutic class

Analgesics (1), Antibiotic (1), Erectile dysfunction (1), Endocrine (3), Glaucoma (1), Antipsychotic (1), Respiratory (1), Rheumatic (2)


SNUH-CTC

Multi-national phase 2/3 clinical study for bridging data ; 19 drugs, (23 trials) None approved yet Open trial: 7, Blinded: 12 Placebo control: 8, Active control: 12 Sample size: 16, 30/630, 98, 20/700, et

c. Therapeutic class

Antibiotic (3), Anticancer (7), Antifungal (1), Antihypertensive (2), Antiviral (2), ED (1), Dementia (1), Gastrointestinal (2), Osteoporosis (2), Thrombolytic (1), CNS (1)


Clinical Trial Center / Clinical Pharmacology UnitClinical Trial Center / Clinical Pharmacology Unit

Seoul National University Hospital Seoul National University Hospital

(SNUH)(SNUH)

Pharmacokinetics of XX prolonged release capsPharmacokinetics of XX prolonged release capsules in Japanese, Caucasian and Korean healthules in Japanese, Caucasian and Korean healthy volunteers, with a tolerability assessment in thy volunteers, with a tolerability assessment in th

e Japanese subjects.e Japanese subjects.A multiple-dose, placebo-controlled sequential A multiple-dose, placebo-controlled sequential

dose-escalation studydose-escalation study

SNUH-CTCStudy

Summary Objectives: Objectives: show similarity in steady state AUC for the show similarity in steady state AUC for the active moiety (sum of the unbound parent drug and active moiety (sum of the unbound parent drug and metabolite1) between Japanese versus Caucasians and metabolite1) between Japanese versus Caucasians and Japanese versus Korean subjects Japanese versus Korean subjects

Study design:Study design: Parallel group Parallel group Age/weight matching of the Caucasian and Korean Age/weight matching of the Caucasian and Korean

groups to Japanesegroups to Japanese Single-dose and 5-day multiple dose administrationSingle-dose and 5-day multiple dose administration

Dosage and subjectsDosage and subjectsTreatment Treatment definitiondefinition

JapaneseJapanese CaucasianCaucasian KoreanKorean

ActiveActive PlaceboPlacebo ActiveActive ActiveActive

x mgx mg 1212 33 1212 1212

2x mg2x mg 1212 33 1212 1212

3x mg3x mg 1212 33 1212 1212

SNUH-CTC

Substance Period Ratio90 C.I. Lower bound

90 C.I. Upper bound

Active (M1+P)

Day 1 incl. outliers

0.91 0.80 1.03

Metabolite1

Day 1 0.93 0.82 1.05

Parent drug


0.77 0.50 1.18


90 C.I. Upper bound

Active (M1+P)


0.90 0.78 1.03

Metabolite1


0.84 0.71 0.98

Parent drug


0.80 0.51 1.26

Point estimate and 90 % C.I. for AUC0- ratios in Japanese/Caucasian

SNUH-CTC


90 C.I. Upper bound

Active (M1+P)


0.77 0.67 0.89

Metabolite1


0.81 0.72 0.92

Parent drug


0.50 0.39 0.65


90 C.I. Upper bound

Active (M1+P)


0.72 0.62 0.83

Metabolite Day 7 incl. outliers

0.70 0.59 0.82

Parent drug


0.52 0.39 0.70

Point estimate and 90 % C.I. for AUC0-24 ratios in Japanese/Korean

In-Jin Jang M.D., Ph.D.In-Jin Jang M.D., Ph.D.

Clinical Pharmacology Unit /Clinical Trial CenterClinical Pharmacology Unit /Clinical Trial Center

Seoul National University Hospital (SNUH)Seoul National University Hospital (SNUH)

Phase I Study of YY, Placebo-controlled, Double-Phase I Study of YY, Placebo-controlled, Double-blind, Group-comparison, Dose-escalation study blind, Group-comparison, Dose-escalation study

to Investigate Safety, Tolerability, and to Investigate Safety, Tolerability, and Pharmacokinetics after Single Oral Dosing of Pharmacokinetics after Single Oral Dosing of

5mg, 10mg and 20mg in Healthy Subjects5mg, 10mg and 20mg in Healthy Subjects

SNUH-CTC

Study Summary Study designStudy design

Placebo-controlled, single ascending dose, Placebo-controlled, single ascending dose, parallel group parallel group

Double-blind, randomized studyDouble-blind, randomized study

Dosage and subjectsDosage and subjects

StepsSteps DosageDosage Number of Subject Number of Subject Drugs Drugs

11 5 mg5 mg88 Active, 5mg tabletActive, 5mg tablet

22 Placebo, 5mg tabletPlacebo, 5mg tablet





SNUH-CTC Pharmacokinetics

Plasma concentration profiles of Study Drug after single oral dosing of 5, 10 and 20 mg under fasting condition

Geometric mean; Geometric SD

Time after administration (hr)

0 4 8 12 16 20 24

Pla

sm

a D

rug

co

nce

ntr

atio

n (

ug

/L)

0.1

1

10

100 5 mg (n=8)10 mg (n=8)20 mg (n=8)

SNUH-CTC Korean vs. CaucasianKorean vs. CaucasianStudy

Number 000 000

Race

Korean Caucasian

(n=8) (n=8) (n=8) (n=24) (n=24)

Dose (mg) 5 10 20 10 20

Tmax (h) b0.5

(0.5~0.75)

0.5(0.5~0.7

5)

0.5(0.5~1.0

)

0.884(0.50~1.

5)

0.992(0.48~1.

5)Cmax

(㎍ /L)9.70/1.4

017.14/1.

7641.55/2.

197.03/1.7

318.5/1.5

2AUC

(㎍ *h/L) 17.92/1.

4135.26/1.

6593.49/1.

8828.8/1.6

270.0/1.5

3

T 1/2 (h) 3.49/1.44

3.31/1.32

3.51/1.33

4.76/1.51

4.80/1.36

Vz/F (L/kg) 21.54/1.61

19.78/1.57

16.63/1.56

29.6/1.77

24.6/1.50

CL/F (L/h)278.9/1.

41283.6/1.

65213.9/1.

88347/1.62 286/1.53

SNUH-CTC

Korean vs. CaucasianKorean vs. Caucasian

Dose of Study Drug (mg)

5 10 15 20

AUC

(ug*

h/L)

0

20

40

60

80

100

120

KoreanCaucasian

Dose of Study Drug (mg)

5 10 15 20

Cmax

(ug/

L)

0

10

20

30

40

50

KoreanCaucasian

Evaluation of Safety and Pharmacokinetics of Single Dose of Rosiglitazone in Healthy Korean Volunte

ers

In-Jin Jang, MD, PhDIn-Jin Jang, MD, PhD

Clinical Trial Center / Clinical Pharmacology Unit Clinical Trial Center / Clinical Pharmacology Unit

Seoul National University Hospital (SNUH)Seoul National University Hospital (SNUH)

SNUH-CTC

Point Estimates and 90% Confidence Intervals in Korean : Caucasian Volunteers for AUC(0-inf) (ng.h/mL), Cmax (ng/mL), and T1/2 (h) Endpoint Comparison Dose

(mg) Point

Estimate 90%

Confidence Interval AUC(0-inf) K:W1 2 1.48 (1.25, 1.74) 4 1.48 (1.24, 1.77) 8 1.61 (1.36, 1.90) Cmax K:W1 2 1.36 (1.16, 1.60) 4 1.37 (1.15, 1.63) 8 1.37 (1.16, 1.60) T1/2 K-W2 2 1.41h (0.82h, 2.00h) 4 0.69h (0.06h, 1.32h) 8 0.86h (0.27h, 1.44h) 1 presented as the ratio of geometric means. 2 presented as the arithmetic mean difference K Korean Volunteers (each dose group : n= 8)

W Caucasian Volunteers (2mg n=51; 4mg n=25; 8mg n=53)

SNUH-CTC

Pharmacokinetic parameters of Avandia in Caucasian and Korean healthy subjects

Ratio (Korean/ Caucasian) Geometric Mean

Equivtest NONMEM Pharmacokinetic Parameters Korean

male (n=24)

Caucasian male (n=79)

Point Estimate 90% CI Point

Estimate

Dose normalized

AUCinf (hrㆍng/mL)

512.77 344.21 1.49 1.38~1.61 1.47

Dose normalized

Cmax (ng/mL)

90.13 68.03 1.32 1.22~1.42 1.29

T1/2 (hr) 4.56 3.63 1.25 1.13~1.35 1.29

SNUH-CTC Pharmacokinetic parameters of Aisan and Caucasian healthy subjects single-dose (4mg or 8mg) oral administration Rosiglitazone

Dose Parameter Korean Chinese Taiwanese Japanese Caucasian

N 8 12 12 6 25

Mean 345.3 445.86 384.1 326.90 260.2

SD 60 67.71 59.3 46.58 75.6 Cmax ng/ml

Ratio 1.33 1.7 1.47 1.25 1

Mean 1960 2177.8 2078 1724 1374

SD 525 506.8 433 335.16 545 AUC0-inf h·ng/ml

Ratio 1.43 1.58 1.51 1.25 1

Mean 4.35 3.92 4.18 4.04 3.65

SD 1.020 0.75 0.43 0.39 1.08

4mg

T1/2 H

Ratio 1.19 1.07 1.14 1.04 1

N 8 12 12 6 25

Mean 765.2 832.58 724.3 746.85 558.2

SD 185.22 170.96 135.7 147.37 127.5 Cmax ng/ml

Ratio 1.37 1.49 1.29 1.34 1

Mean 4508 4505 4024 3619 2792

SD 1342 959 956 573 660 AUC0-inf h·ng/ml

Ratio 1.61 1.61 1.44 1.29 1

Mean 4.67 3.76 4.19 3.63 3.81

8mg

T1/2 H SD 0.64 0.61 0.57 0.42 0.93

ACTOSACTOS®®

PK/PD Modeling and PK/PD Modeling and Simulation for BridgingSimulation for Bridging

In-Jin Jang MD PhDIn-Jin Jang MD PhDClinical Trial Center/Clinical Pharmacology UnitClinical Trial Center/Clinical Pharmacology Unit

Seoul National University HospitalSeoul National University Hospital

KFDA CPAC2002.2.22

SNUH-CTC

Dose Pioglitazone Placebo

15 mg30 mg45 mg

6 Male + 3 Female6 Male + 3 Female6 Male + 3 Female

2 Male + 1 Female2 Male + 1 Female2 Male + 1 Female

A Single Dose, Dose-Escalation Study to Assess the Pharmacokinetic Characteristics and Safety/Tolerability of Piogl

itazone in Healthy Korean Subjects

SNUH-CTCDirect AUC Comparison Direct AUC Comparison

Koreans vs. WesternKoreans vs. Western

SNUH-CTC Predicted Glucose Response - Predicted Glucose Response - AUC Relationships AUC Relationships in Korean in Korean

PopulationsPopulationsGlucose -AUC relationships from global data supports 15 and 30 mg as efficacious doses

in Koreans

SNUH-CTC

Parameter Estimate StdErr %SE--------- ------ ------ ----THETA #1 KA 2.50 0.883 35.32THETA #2 CL 3.16 0.145 4.59THETA #3 V2 29.3 1.29 4.40THETA #4 orig -0.416 0.0403 9.69OMEGA #1 CL 0.109 0.0151 13.85SIGMA #1 - 0.181 0.0140 7.73$PK PJ=0 IF(PROJ .EQ. 7110115) PJ=1 KA=THETA(1) TVCL=THETA(2)*(1 + PJ*THETA(4)) CL =TVCL*EXP(ETA(1)) TVV =THETA(3) V =TVV S2 =V$ERROR IPRED = F W=IPRED+0.000001 IRES=DV-IPRED IWRES=IRES/W Y = F*EXP(ERR(1))

Korean & US Combined PK by NONMEM

SNUH-CTC

Simulation Plan

Korean Study

Dose AUC

US Study

Dose AUC ResponseEmaxModel

Response

Actual US Results

Comparison

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Trial Simulation Platform

5 dose group (0, 7.5, 15, 30, 45 mg, N=500), 300 replications

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-5.0 -4.6 -4.2 -3.8 -3.4 -3.0 -2.6 -2.2 -1.8 -1.4 -1.0 -0.6 -0.2

Distribution of 300 Mean Changes in FBG (mM) of Korean 15mg Group

0

5

10

15

20

25

US 30mg Group Mean Effect = -1.749

20.5 percentile

Median = -1.975

SNUH-CTC

-5.0 -4.6 -4.2 -3.8 -3.4 -3.0 -2.6 -2.2 -1.8 -1.4 -1.0

Distribution of 300 Mean Changes in FBG (mM) of Korean 30 mg Group

0

5

10

15

20

25

US actual trial 45mg GroupMean Effect = -3.0745

53.2 percentile

Median = -3.04

SNUH-CTC

0 30 45 60

0.0 7.5 15.0 30.0 45.0

-10

-50

5

Pre

dic

ted

CF

BG

Dose For Korean patients (mg/day)

Dose For US patients (mg/day)

USKorean

Pre

dic

ted

Mea

n C

hang

e F

rom

Bas

elin

e

Overlapping of Effect Range

SNUH-CTC

ConclusionConclusion Bridging concept is actively applied but regulatory

experience is still limited in Korea. No official bridging study has been requested by K

orean regulatory body until now. Differences in pharmacokinetics among ethnic gro

ups (even between Japanese and Korean) were frequently observed.

Mechanisms and clinical implications of such PK differences should be explored and reflected in local label on scientific bases.

Need sponsors’ cooperation and changes in attitude (strategy ?) toward more scientific and informative clinical development in Korea.

Documents

In-Jin Jang M.D., Ph.D. Clinical Pharmacology Unit, Clinical Trial Center Seoul National University Hospital (SNUH) & Seoul National University College