本次學術研討會中 - cde.org.t of Population... · DDI 3 Disease state 15 Body weight 19 Renal impairment 14 Hepatic impairment 8 . Applications of Population PK in ... •Evolving

本次學術研討會中

查驗中心同仁之演講內容

僅代表查驗中心之觀點

凡涉及政策方向及法規解釋適用

應依衛生主管機關之指示為準

• A four-year survey of new drug application (NDA)

• Regulatory assessment of population PK/PD analysis

• Applications of population PK/PD in regulatory decision making-case study

Topics to be covered…





A four-year survey of 79 new drug

applications for NCE (2008-2011)

A proportion of NDA included studies of PK/PD modeling of the drug

56% 44%

Yes No

A four-year survey of 79 new drug

applications for NCE (2008-2011)

Small Molecules

Yes 83%

17% No

51% 49%

No Yes Yes

Biologicals

Frequencies of different types of

population PK data

Yes No Yes Yes

Type

Gender 21

Age 22

Race 18

DDI 3

Disease state 15

Body weight 19

Renal impairment 14

Hepatic impairment 8

Applications of Population PK in

Drug Labeling





• Unfortunately, there is no absolute answer or black-and-white line

– Every model will depend on the decision made by the modeler

• Evolving Science

• Requirement on case by case basis

– Relative importance

What is acceptable?

• Selection Criteria – Minimization procedure converges

– Number of significant digits at least 3

– Covariance step terminates without any warning message

– Gradients at the last iteration are all greater than 10-3 but less than 102

– Standard errors of the estimates should be less than 50%

– No correlation between parameters greater than 0.95

Criteria for model selection

(Company A)

• Goodness of Fit Plots – WRES versus population predicted concentrations and

versus time

– Absolute weighted residuals versus individual predictions

– Histogram or quantile plots of WRES

– Population and individual predicted concentrations versus observed concentrations


(Company A) -cont’d

• Selection Criteria – A „successful minimization“ statement by the NONMEM

program

– Number of significant digits ≥ 3; if the number of significant digits is <3, reasons for acceptance of the NONMEM run are given

– Estimates of THETA not close to boundary


(Company B)

• Goodness of Fit Plots (visual inspection) – Reduction of inter- and/or intra-individual (=residual)

variability

– Reduction of the standard errors with respect to parameter estimates

– Analysis of residuals (random and uniform scatter around zero, no time dependency)


(Company B) -cont’d

• Outliers – the criterion to should be clearly pre-specified

– WRES > 5 or WRES < - 3

• Missing data value – the criterion to should be clearly pre-specified

• Co-linearity of covariates – BW, height, and body surface area (BSA)

– BW and age in infants

– High correlation of covariates (r0.5) may lead to biased in parameter estimation (Bonate et al., 1999)

Issues in Model Building

Limitation of using Population PK to

Evaluate Drug-Drug Interactions

• Only provide interaction information in 1 direction

• Information with regard to actual dose regimens of a coadministered drug (eg, size of dose, frequency of dose) is usually unavailable

Regulatory Documents

• USFDA, Guidance for Industry. Population Pharmacokinetics. 1999

• EMA, Guideline on reporting the results of population pharmacokinetic analysis. 2007

• ICH, Dose-Response Information to Support Drug Registration and other pertinent guidances. 1994

• USFDA, Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications. 2003





Case study 1 (Investigational New Drug Application; IND)

To preserve confidentiality, the name of the drug is not disclosed

• Anti-viral compound

• Phase 1 study was completed (Four dose levels of 0.05, 0.25, 0.5 and 1.25 mg/kg)

• Dose-response relationship was observed for viral load decrease

Background

• Proposed Phase 2 study design

– Dose: 0.5 mg/kg QW and 1.25 mg/kg Q2W

– Treatment period: 8 weeks

• The sponsor approached the CDE to discuss their dose selection and trial design of a phase 2 study

Background (cont’d)

• Are the proposed dose and dosing regimen reasonable for the phase 2 trial?

Regulatory Question

PK/PD Modeling

• A one-compartment model with Michaelis-Menten kinetics were selected to describe the PK

VD , Cp

Km Vmax

K0 𝑑𝐶𝑝

𝑑𝑡=𝑘0𝑉𝐷−𝑉𝑚𝑎𝑥 × 𝐶𝑝

𝐾𝑚 + 𝐶𝑝

where

Ko: Infusion rate

Vmax: Maximum elimination rate

Km: Concentration at which 50% of elimination rate occurs

VD: Volume distribution

Cp: Concentration

PK/PD Modeling

• The CDE reviewer developed a steady-state area under the curve (AUC)–viral load reduction relationship

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

0 10000 20000 30000 40000 50000 60000 70000

AUC (ug*hr/mL)

Observed

PredictedR=0.83

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

0 10000 20000 30000 40000 50000 60000 70000

AUC (ug*hr/mL)

Observed

PredictedR=0.91

PK Simulation of Multiple Dosing

Scenarios (once weekly; QW)

EC50: 4 g/ml (in vitro)

PK Simulation of Multiple Dosing

Scenarios (once weekly; Q2W)

EC50: 4 g/ml (in vitro)

Emax Sigmoid Emax

Dosage regimen Log10 viral load reduction at Week 8 (copies/ml)

0.25 mg/kg QW 0.89 1.12

0.5 mg/kg QW 1.64 1.51

0.75 mg/kg QW 1.97 1.51

1 mg/kg QW 2.03 1.52

1.25 mg/kg QW 2.05 1.52

0.25 mg/kg Q2W 0.56 0.04

0.5 mg/kg Q2W 1.16 1.50

0.75 mg/kg Q2W 1.52 1.51

1 mg/kg Q2W 1.74 1.51

1.25 mg/kg Q2W 1.92 1.51

PD Simulation of Multiple Dosing

Scenarios (once weekly; Q2W)

• Based on these analyses, the CDE review team recommended that 0.5 mg/kg QW and 1.25 mg/kg Q2W dosing regimen for further Phase II study was acceptable

Regulatory Recommendation

Case study 2 (Bridging Study Evaluation; BSE)


• Anti-epilepsy compound

• Recommended dosage: initiated with a dose of 2 mg/day, and may be increased to 4 mg to 12 mg/day based on clinical response and tolerability

• Regulatory status: has not yet received any marketing authorization in the world

• Submission date: 2009.09

Background

• Bridging data package

– Two Phase 1 PK studies in Japanese; a single dose study (1, 2, 4, 6 and 8 mg ) and multiple dose study (2 and 4 mg QD for 14 days)

– Subgroup analysis of the Asian population (26%) in a multicenterphase III trial


• Are there ethnic difference in pharmaco-kinetics (and/or pharmacodynamics)? If so, what is the appropriate dose for Taiwanese population?

Regulatory Question

PK/PD Modeling

• A total of 526 subjects (479 were Caucasian, 28 African Americans and 19 other) were utilized.

• No Asian subjects data used

• Two-compartment model with first order absorption and lag time

CL/F=0.652

Ka=4.87; if (Fed.EQ.1) Ka=0.295

V1/F=31.3

Q=7.51

V2/F=43.5

ALAG=0.239

CL

Ka

Q V2 , C2 V1 , C1

• The Monte Carlo simulations (N=1000) was performed by CDE reviewer to examine the ethnic difference in PK

• The observed concentrations in Japanese overlaid with the predicted concentration from the final PK model

Single Dose 2 mg

Simulation

• The Monte Carlo simulations (N=1000) was performed by CDE reviewer to examine the ethnic difference in PK

• The observed concentrations in Japanese overlaid with the predicted concentration from the final PK model

Multiple Dose 2 mg

Simulation

• No significant differences in pharmacokinetics exist between the Asian and Non-Asian population

• Combining the clinical efficacy and safety results of Asian population in Phase 3 trial, the CDE review team recommended for a waive of the bridging study

Regulatory Action

• Population PK/PD analysis are a regular part of NDA submissions

• The analysis report need to be of sufficient quality so that the final model can be judged to be a good description of the data

• Modeling and simulation is playing an increasing role in drug review process and is also a very useful tool to support the regulatory decision-making

Take Home Message

• Hsiao, Chia-Ling

• Su, Li-Li

• Lin, Chia-Ying

• Wang, Yi-Lin

• Chang, Yu-Hsin

• Chang, Ya-Wen

• Lin, Chun-Chiang

Acknowledgement

Backup Slides

Case study 3 (Bridging Study Evaluation; BSE)


• Anti-cancer compound

• Recommended dosage: 250 mg/m2 q3w

• Regulatory status: EMA approved in 2005

• Submission date: 2009.08

Background

• Bridging data package

One Phase 1 PK studies in Japanese; a single dose study (200, 250, 280 and 320 mg/m2)

Subgroup analysis of the Asian population (11%) in a multicenter phase III trial


• Are there ethnic difference in pharmaco-kinetics (and/or pharmacodynamics)? If so, what is the appropriate dose for Taiwanese population?

Regulatory Question

• A logistic regression model was used to test the relationship between the PK parameter (i.e. AUC) and the worst NCI-CTC grade

• Logit P=i+i AUC

Where

i was the value of neutropenia grade

i was the main effect on the logit for a given grade i

i AUC was the AUC effect on the logit of the model

Model for Probability of response

• Significant relationship between AUC and neutropenia was confirmed

• High accuracy between observed and predicted probabilities of incidence

ANC grade Observed data; n=840

Logistic regression prediction (95% CI)

Global incidence (Gr0) 72% 79% (74-86%)

3 22% 26% (20-34%)

4 27% 21% (15-28%)

3-4 49% 47% (36-62%)

Model for Probability of response

Caucasian (n=79)

Japanese (n=18)

AUC 14000 16896 121%

Incidence (95% CI)

48.4 (40.2-56.8)

62.5 (52.7-71.5)

14.1%

Ratio (Japanese/Caucasian) Difference (Japanese−Caucasian)

Caucasian

Japanese

Model Prediction

Caucasian (n=79)

Japanese (n=18)

AUC 14000 16896 121%

Incidence (95% CI)

22.6 (16.5-30.2)

34.2 (25.5-44.2)

11.6%

Ratio (Japanese/Caucasian) Difference (Japanese−Caucasian)

Caucasian

Japanese

Model Prediction

• The predicted incidence rates of neutropenia are higher in Japanese than in Caucasians.

• Ethnically sensitive in PK and PD was observed

• In order to determine the optimal dose in Taiwanese population, the sponsor was requested to provide additional clinical data

Regulatory Action