Conducting the review from

pharmacokinetic reviewer’s

perspectives

Division of Pharmaceutical Science

PK Team Leader

Yi-Lin Wang

1 1

20161117 APEC GRM Workshop

2

This presentation was not officially cleared,

and the views offered here do not necessarily

represent the official positions at MOHW,

including TFDA.

Outline

• Filing and reviewing

• Priority review and risk management

• Introduction of PK’s review points

• Case study

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Before reviewing, filing the application! 1) Clarify the status of drug application

- the applied product (dose, dosage form, labeling etc.),

- bridging study evaluation, if needed

- the global status

2) Filing based on CTD package

3) Sponsor‘s regulatory strategy

4) Minimum registration requirement

5) Timeline, and the project manager

• Team-based discussion and sharing experience

4

Filing and Reviewing

Minimum regulatory requirement in Taiwan

• Regulations for Registration of Medicinal Products

• Appendix III Documents for the Application of NCE

5 ○=necessary; △= depends on case; ╳= not necessary

• Article 38-1 Non-CPP

- Domestic Phase I trial (n≧10) and global phase III pivotal trial

simultaneously in Taiwan, Or

- Phase II trial (n≧20) and Phase III pivotal trial (n≧80) simultaneously in

Taiwan

- Post-marketed risk management plan

• Article 38-2 One-CPP

- Domestic Phase I trial (n≧10), or

- Multi-country, multi-center Phase II trial (domestic n≧20, or 10%), or

- Multi-country, multi-center Phase III trial (domestic n≧80, or 10%)

if top 10 pharmaceutical advanced countries joined the trial, and it would be submitted to

FDA or EMA, the domestic sample size could be (1) domestic n≧30 or 5% in single pivotal

trial with 200 subjects at least; or (2) n≧10 in single pivotal trial with less than 200 subjects

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NCE Regulatory requirement in Taiwan

Outline

• Filing and reviewing

• Priority review and risk management

• Introduction of PK’s review points

• Case study

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• Arrange your prioritization

- Deadline

- Application which is subject to the policy of priority review

- Application without any CPP

- Application developed from domestic industry

- Application which is subject to the policy of abbreviated

review

- Application which submit BE study as the pivotal study,

including new dosage form, global generics

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Priority review and Risk management

Outline

• Filing and reviewing

• Priority review and Risk management

• Introduction of PK’s review points

• Case study

9

Pharmacokinetics/Pharmacodynamics

• Pharmacokinetics described as what the body does to a drug,

refers to the movement of drug into, through, and out of the body—

the time course of its absorption, bioavailability distribution,

metabolism and excretion.

• Pharmacodynamics refers to the relationship between the drug

concentration at the site of action (receptor) and pharmacologic

response, including biochemical and physiologic effects that

influence the interaction of drug with the receptor.

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Clinical

response

Drug release

and dissolution

Drug in systemic

circulation Drug in tissues

Excretion and

metabolism Pharmacologic

effect

Absorption

Elimination

Toxicity Efficacy

Characteristics of drug administration route

11 https://www.pinterest.com

http://howmed.net/pharmacology/bioavailability-of-drugs/

100%

Oral: Convenient, first pass

effect occurs

Rectal: Less first pass

effect than oral route

SC: Smaller volume than

IM, may be painful

Transdermal: Usually slow

absorption, lack of first

pass effect and prolonged

duration of action

IV: most rapid

IM: Large volume may be

injected but painful method

Intrathecal: avoid BBB,

only made by technician

Inhalation: rapid onset

Oral 5-100%

Rectal 30-100%

SC 75-100%

Transdermal

80-100%

75-100%

5-100%

100%

Absorption

• Absolute bioavailability — systemic availability measured by comparing the respective AUCs

after “extravascular” and “IV” administration

— the most straightforward ways to realize the basic PK properties

12

What ‘s relative bioavailability?

-compare one drug product (e.g. tablet) to

a recognized standard (e.g. solution or

suspension)

AUCoral

AUCiv

Concentration-time profile

13 http://en.wikipedia.org/wiki/Pharmacokinetics

Absorption

Distribution Elimination

Dose-proportionality

• A proportional increase in exposure (Cmax and AUC) of a

drug after a corresponding increase in dose

• At least 3 different doses covering the propose therapeutic

dose range

Linear Pharmacokinetic

Cmax or AUC vs. Dose Dose-proportional

CL, Vd, T1/2 vs. Dose Not changed

Nonlinear Pharmacokinetic

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Review point of absorption in NDA

• Single dose PK study to determine parameters, such as

Cmax, Tmax, AUC, T1/2, bioavailability (%F)

• Multiple dose PK study for accumulation ratio (R)

• Dose proportionality or linearity

Proper assessments to demonstrate dose-concentration

relationship ex. Power model, graphic, dose normalization

• Food effect

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Food effect

Effect of food on GI drug absorption

- Delay in gastric empty

- Stimulation of bile flow

- Change GI pH

- Increase splanchnic blood flow

- Change luminal metabolism of a drug substance

- Physical or chemical interaction with a dosage form or a drug

substance

Especially lipid-soluble drug!

Food effect bioavailability study should be conducted in all NCE drug

which was given as oral dosage form.

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In principle, food effect study should

- be randomized, balanced, single dose, two-treatment (fed vs. fasted),

two period, two-sequence, crossover design

- n≧12 healthy subject (or pt’s)

- use drug product intended to be marketed

- cover the maximum therapeutic dose, if no safety concern

- conduct with high-fat and high calorie meal (~1000 cal)

- support the food condition of Phase III pivotal trial

- support the proposed labeling, including sprinkle study, special

vehicle (crushed into suspension, nasogastric tube feeding)

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Food effect

*USFDA Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies

Changing dosage form/formulation/API form in development phase

should consider whether to replicate food effect study or not !

Atorvastatin

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Atorvastatin NDA020702 USFDA assessment report

Vd>> 40-50 L Concentrated in tissue

Interstitial Fluid

(21%)

Plasma (4%)

Intracellular Fluid

(35%) To

tal b

od

y w

eig

ht

(10

0%

)

Vd=15-18 L

To

tal b

od

y w

ate

r (60

%)

Distribution

• Movement of drug from the central compartment (blood) to

peripheral compartments (tissues)

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Tissue

Extracellular

Fluid (25%)

Distribution-Vd

• The apparent volume of distribution, Vd, is defined as the

volume of fluid required to contain the total amount, Q, of drug

in the body.

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Vd

Vd

Vd

Drug

Drug

Drug

Plasma Conc.

Plasma Conc.

Plasma Conc.

Tissue

Tissue

Tissue

Review point of distribution in NDA

• Volume of distribution

• In vitro plasma protein binding (%) at various species

• In vitro plasma protein binding (%) over the level of clinical

therapeutic dose range

• 14C-labeled autoradiography (rodent only)

• Blood-brain barrier and

brain drug accumulation

• Placenta transfer, milk secretion

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Metabolism (biotransformation) • In drug development, sponsor should identify enzymes involved in

the metabolism, not only CYP450, but other enzymes responsible

for acetylation, methylation and etc.

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CYP3A4/5 is responsible for about 50% of the drugs metabolized by

CYP450 enzymes, followed by CYP2D6 (20%), CYP2C9/19 (15%), with

the rest metabolized by CYP1A2, CYP2A6, CYP2E1, and other unidentified

P450 enzymes.

Evans WE, 1999, Science

Review point of metabolism in NDA

• First pass effect

• Liver microsomal stability-species comparison

• Metabolic pathway and metabolite(s) identification

• Potency and extent of active metabolite

• Substrate and/or inhibitor for human CYP isozymes

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Clearance

• Clearance is a measure of drug elimination from the body without

identifying the mechanism or process. (Unit: L/hr or mL/min)

• Clearance (CL)

= Metabolism + Biliary secretion+ Renal secretion +other

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= Incomplete absorption

+ Parent in bile

+ Metabolite in bile

+ Metabolite from gut

Metabolism

Metabolism Urine

Dose

Feces

Bioavailability Gut first pass

effect

Bile

Review point of elimination in NDA

• Elimination pathway of drug, clearance, and T1/2

• Mass balance study

• Determine excretion routes and extent of 14C-labeled

NCE, urine, feces, bile. Determine % residue after X

days of dosing

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How about the DDI potential in transporter ?

26 Clinical Pharmacology & Therapeutics 94, 3-9, July 2013

Drug-drug interaction

• In vitro test In vivo evaluation

Metabolism-based In vivo trial will be needed if

(1) “Drug” is a substrate of an enzyme responsible for ≧25% of its systemic clearance

(2) Based on in vitro data, “Drug” is an interacting drug of an enzyme, ex. CYP3A4 inhibitor

Transporter-based ex. Modulation of P-gp (substrate? Inhibitor? Inducer?)

Displacement-based

Only important in drug with a high extraction ratio and narrow therapeutic index that is

given parenterally

• Combination therapy in clinical

• Other concerns

- Oral contraception, gastric pH change, delayed gastric empty

- Potential DDI as other drug with same mechanism

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Special Populations

• Gender

• Body weight

• Age (pediatrics, geriatrics)

- 91.7.23 小兒族群的藥動學試驗基準

- 90.08.07 年老病患的藥品臨床試驗基準

- USFDA/ EMA guidance

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Comparison of pharmacokinetic outcomes for diazepam in a younger man (A)

and an older man (B).

Clinical Pharmacology and Therapeutics 27:301–312, 1980

• When renal impairment study is not needed? - Drug is excreted entirely via liver with no involvement of the renal

- Drug with wide therapeutic index and mainly excreted via hepatic

- The drug is gaseous or volatile, and primarily eliminated through the lungs

- Intended only for single-dose

• Study design - Full PK study or Reduced PK study

- Classification of renal impairment

- Matching demographic characteristics in control and test group (n=6~8_

- Need multiple dosing? Need detect fu in renal impaired population?, Need detect metabolite?

- Population pharmacokinetic approach

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Renal impairment study

92.08.03 腎功能不全病患之藥動學試驗基準

Cockcroft-Gault (C-G) equiation

Estimated glomerular filtration rate (eGFR)

Hepatic impairment study

30 90.8.23 肝功能不全病患的藥動學試驗基準

• When hepatic impairment study is not needed? - Drug is excreted entirely via renal with no involvement of the liver

- Drug with wide therapeutic index and <20% metabolized in the liver

- The drug is gaseous or volatile, and primarily eliminated through the lungs

- Intended only for single-dose

• Study design - Full PK study or Reduced PK study

- Classification of hepatic impairment, ex Child-pugh, GSP, MEGX etc.

- Matching demographic characteristics in control and test group (n=6~8)

- Need multiple dosing? Need detect fu in hepatic impaired population?, Need

detect metabolite?

- Population pharmacokinetic approach

Special population & Drug-drug interaction

• Special population and drug-drug interaction studies should be

evaluated in all NCE or NME.

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Special population Drug-drug interaction

“Support and Cover” the maximum therapeutic absorption extent (Cmax and AUC), if

there’s no safety concern

1. Conducting dedicated study with final drug product/ formulation would be better.

If not, relative BA, or modeling/simulation would be a good bridging tool.

2. Population PK analysis, and subgroup analysis in pivotal study were supportive

• Gender

• Elderly, pediatric population

• Hepatic /Renal impaired classification

• Obese, smoking (if needed)

• Genetic polymorphism (if needed)

• Available dose strength for dose

adjustment

• In vitro DDI

• In vivo DDI

• Enzyme substrate/inducer/inhibitor

• Transporter substrate/inducer/inhibitor

• Metabolite investigation (≧25% of parent drug

AUC)

• Drug- therapeutic protein

Outline

• Filing and reviewing

• Priority review and risk management

• Introduction of PK’s review points

• Case study

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Drug Anti-C® 150 mg tablet

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Regulatory Status: new chemical entity

Back ground information

• A hepatitis C virus (HCV) NS3/4A protease inhibitor

• Indication: adults with chronic hepatitis C virus (HCV) infection

• Usage regimen: 150 mg tablet taken once daily with food in combination

with peginterferon alfa and ribavirin

• Global status: US FDA, EMA, Canada (at least 2 CPP)

BSE: needed

Review focus

General pharmacokinetic properties of Anti-C in target patients

Reasonable dosing regimen

Drug-drug interaction

Dose recommendation for special population

Drug Anti-C Study Finding

(1) Caco-2 permeability a P-gp substrate, a low permeability compound

(2) Protein binding High PPB drug, >99.8 % over therapeutic range

Blood: plasma ratio=61~69% (most in plasma)

(3) In vitro metabolism Primarily occurs via CYP3A4, CYP2C8 and CYP2C19 may involved

Major metabolite: M2 (6% of parent drug AUC)

(4) Absorption Absolute absorption: 62% (Oral vs. IV)

(5) Mass balance Oral 300 mg 14C-labeled

Urinary: 0.039% of total dose

Feces: 91.2% (31% unchanged form, 25.9% oxidation metabolite)

Anti-C was the predominant circulating species in plasma

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91.2% = Incomplete absorption (fraction of

unabsorbed at intestine) + Parent/metabolite in

bile (40% via rat biliary excretion test) +

Metabolite from gut (CYP3A)

Dose

Feces

Bioavailability Gut first pass

effect

Bile

Metabolism

Metabolism Urine 0.039%

62%

Study Finding

(6) Distribution WBA: the mucosa of large and small intestine, liver, bile duct, pancreas

Placenta transfer was negligible in rat, but milk secretion might occurred.

(7) Food study Cmax ↑50%, AUC↑50%, 65% and delayed Tmax 4~6 hr (taken with food)

(8) Multiple

dose

Nonlinear PK at dose range of 10~700 mg

- Monotherapy PK (Anti-C)

- Combine therapy PK (Anti-C+peginterferon alfa and ribavirin)

Tmax 6 hr, Cmax= 3.64±2.89 μg/mL. AUC24=59.62±5.56 μg*hr/mL

Css=1.6±1.1 μg/mL; CL/F= 6.45 L/hr, Accumulation factor: 3.2

(9) Renal

impairment

No dose adjustment for all renal impaired population. WHY??

- Severe renal impairment study (eGFR <30 mL/min vs. ≧80 mL/min), no effect

- Protein binding rate remained unchanged can not removed by dialysis

- Limited excretion via kidney

(10) Hepatic

impairment

Mild: No dose adjustment

Moderate: 50% dose reduction was recommended (QD QOD)

Severe: not recommended.

-Moderate and severe hepatic impairment study (Child-Pugh classification and

METAVIR score)

- 2.44, and 5.22-fold increase of AUC in moderate, and severe impaired

population, respectively

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Drug Anti-C

• Based on In vitro DDI and the criteria of DDI guidance

(1) Anti-C is a substrate of CYP3A4 (major), 2C8 and 2C19

(2) Substrate of P-gp

(3) Substrate of OATP1B1

(4) Moderate inhibitor of 3A4 (potential) and CYP2A6, 2C8, 2C19

(5) Inhibitor of OATP1B1

(6) Inhibitor of P-gp

• In vivo DDI

(1) Drug-drug interaction trial with CYP3A4 moderate inhibitors, inducer

(3) DDI trial with OATP perpetrator with single dose cyclosporine (or rifampin)

(5) DDI trial with OATP1B1 substrate, ex. rosuvastatin

(4)+(5) DDI trial with drug which is substrate of both CYP3A4 and OATP1B1, ex simvastatin

(6) DDI trial with P-gp substrate, ex. digoxin

(1)+(2)+(4)+(6) DDI trial with erythromycin, a P-gp inhibitor and moderate CYP3A4 inhibitor

additional: DDI with narrow therapeutic index, ex. warfarin, tacrolimus

PBPK modeling

(1) + (3) simulated DDI with rifampicin, a potent OATP inhibitor and CYP3A4 inducer

(1) simulated DDI with strong CYP3A4 inhibtor

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Drug Anti-C

IC50≧150 mg Cmax

Labeling: avoid use with CYP3A4 strong inhibitor, inducer

Acknowledgement

• Ywan-Feng Li

• Shi-Ying Yang

• Yu-Chuan Chou

• Chia-Hsun Tsai

• Hsiao-Hua Chou

• Hui-Chong Hong

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• Li-Feng Hsu

• Ya-Wen Chang

• Yi-Chi Li

• Mei-Hsien Kuan

• Chien-Lung Tu

• Chia-Hui Huang

THANKS FOR YOUR

ATTENTION

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