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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
Bridging Data Generation : Experiences in Korea (2)
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)
Bridging Data Generation : Experiences in Korea (3)
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)
Bridging Data Generation : Experiences in Korea (4)
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
Day 1 incl. outliers
0.77 0.50 1.18
Substance Period Ratio90 C.I. Lower bound
90 C.I. Upper bound
Active (M1+P)
Day 7 incl. outliers
0.90 0.78 1.03
Metabolite1
Day 7 incl. outliers
0.84 0.71 0.98
Parent drug
Day 7 incl. outliers
0.80 0.51 1.26
Point estimate and 90 % C.I. for AUC0- ratios in Japanese/Caucasian
SNUH-CTC
Substance Period Ratio90 C.I. Lower bound
90 C.I. Upper bound
Active (M1+P)
Day 1 incl. outliers
0.77 0.67 0.89
Metabolite1
Day 1 incl. outliers
0.81 0.72 0.92
Parent drug
Day 1 incl. outliers
0.50 0.39 0.65
Substance Period Ratio90 C.I. Lower bound
90 C.I. Upper bound
Active (M1+P)
Day 7 incl. outliers
0.72 0.62 0.83
Metabolite Day 7 incl. outliers
0.70 0.59 0.82
Parent drug
Day 7 incl. outliers
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
22 10 mg10 mg88 Active, 10mg tabletActive, 10mg tablet
22 Placebo, 10mg tabletPlacebo, 10mg tablet
33 20 mg20 mg88 Active, 20mg tabletActive, 20mg tablet
22 Placebo, 20mg tabletPlacebo, 20mg 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
SNUH-CTC
Trial Simulation Platform
5 dose group (0, 7.5, 15, 30, 45 mg, N=500), 300 replications
SNUH-CTC
-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.