Ruth E. Stevens, PhD, MBAChief Scientific Officer, Executive Vice President

Camargo Pharmaceutical ServicesACPU: October 19, 2010

Phase 1 Bioavailability(BA)/Bioequivalen

ce(BE)& Fed Studies

Approved Product Labeling

2

Pharmacokinetics

(BA/BE/FED)

Clinical Pharmacology

Drug Substance

Indication

Safety

DDI

Reproductive

Pharmacokinetics

Therapeutics

Concentration

Pharmacokinetics

Dose Effect

Pharmacodynamics

PHARMACOKINETICS: What the body does to the drug (Absorption, Distribution, Metabolism and Excretion (ADME)).

PHARMACODYNAMICS: What the drug does to the body (Therapeutic Effects, Side Effects).

Bioavailability

For the purpose of this subsection:

(A) The term “bioavailability” means the rate and extent to which the active ingredient or therapeutic ingredient is absorbed from a drug and becomes available at the site of drug action.

Cmax

AUC

Note: AUC = AUC0-t and AUC0-inf

Reference: Food, Drug and Cosmetic Act Section 505(j)(7) Bioequivalence

Comparative Bioavailability Study (Rate and Extent of Absorption)

A = Test; 1x/dayB = Reference; 3x/day

Y axis-Linear Scale

Y axis-Log Scale

Bioequivalence:

(B) A drug shall be considered to be bioequivalentbioequivalent to a listed drug if:(i) the rate and extent of absorption of the drug do not shown a

significant difference from the rate and extent of absorption of the listed drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses; or

(ii) the extent of absorption of the drug does not show a significant difference from the extent of absorption of the listed drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses and the difference from the listed drug in the rate of absorption of the drug in intentional, is reflected in its proposed labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug.

Reference: Food, Drug and Cosmetic Act Section 505(j)(7) Bioequivalence

Cmax

AUC Note: AUC = AUC0-t and AUC0-inf

AUC

Bioequivalent Products - Concentration – Time

ProfilesRate & Extent =

“SAME”Y axis-Linear Scale

Y axis-Log Scale

LOQ = Limit of Quantitation orLQC = Last Quantifiable Concentration

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LOQ

Time (hrs)

Area Under-the-Curve (AUC)

“Extent of Absorption”

**Area Under-the-Curve (AUC0-t)

“Extent of Absorption”

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AUC 0-t or AUC0-last: Area under the plasma concentration-time curve from time zero to the last measurable time point.

t

** = Pivotal Bioequivalence PK Parameter

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AUC 0-inf or AUC∞: Area under the plasma concentration-time curve from time zero to time infinity.

**Area Under-the-Curve (AUC0-inf)** = Pivotal Bioequivalence PK Parameter

“Extent of Absorption”

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**Maximum Observed Concentration, Cmax

“Rate”

Cmax

Value read off Y-axis

** = Pivotal Bioequivalence PK Parameter

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Time (hrs)12 24

Tmax

Time to Maximum Concentration, Tmax

Value read off X-axis

“Rate”

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z or Kel: slope≥4 timepoints

Terminal Elimination Rate Constant z (lambda, lambda z or Kel) Rate & Extent of Absorption

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z = terminal slopeLn(2) = natural log of 2

Drug Elimination Half-Life, (t½)

t1/2 = ln(2)/z = 0.693 z

≥4 points on terminal slope to calculate z

Major Elements of Study Designs

[BA, BE, Fed](Example: Immediate-Release

Products)1. Subject Selection

• Number of subjects: typically 24-36• Major objective: minimize intersubject variation conducted in healthy

subjects, 18-50 years old, ± 10% (range 10%-20%) of ideal body weight.• Populations traditionally excluded

• Elderly: stress, blood loss, chronic disease and polypharmacy, PK effects of altered organ function

• Patients: stress, blood loss, concurrent medications, special diets, PK effects of disease states

• Some Exceptions to When Patients are Enrolled Instead of Healthy Subjects: studies with pharmacodynamic or clinical end points, cytotoxic drugs

• Females are no longer excluded

2. Meal – Office of Generic Drugs [Egg McMuffin]Thirty minutes before dosing, subjects are served a high-fat content meal consisting of:

• One fried egg• One slice of American cheese• One slice of Canadian bacon• One buttered English muffin• One serving of hash brown potatoes• 180mL of orange juice• 240mL of whole milk

Major Elements of Study Designs - Fed State(Example: Immediate-Release Products)

Grams No. of Calories Percent of Total Calories

Protein 33 132 15.4%

Fat 55 280 35.3%

Carbohydrate 58 232 27%

0.001

0.010

0.100

1.000

10.000

0 5 10 15 20 25 30 35 40

Time (hr)

A

B

Major Elements of Study Designs[BA, BE, Fed](Example: Immediate-Release Products)

3. Exclusion CriteriaMajor organ, systemic, or mental disease, hypersensitivity to drug product or class recent participation in investigational drug studies, recent blood donation, recent exposure to enzyme-inducing or inhibiting agents abnormal diets or recent significant weight loss.

4. RestrictionsNo Rx medications within two weeks or OTC products within two days of study start.No alcohol for 48 hours prior to dosing and during sampling no xanthine-containing products for 48 hours prior to dosing and during sampling.No strenuous exercise or immobilization (except during sleeping times); normal activity for four hours post-dose.

5. Informed Consent, IRB approval6. Additional subjects enrolled to replace dropouts

Major Elements of Study Designs[BA, BE, Fed] (Example: Immediate-Release Products)

7. Design• Overnight fast of at least 10 hours, fasting continued for four hours post

dose, then standardized meals.• Dose administered with 240 mL of water; fluids restricted within ± 1

hour of dosing.• Two-way crossover:

Subject randomizationWashout period between treatments (7-10 drug half-lives)Potencies of test and reference products within ± 5%.

Period 1 Period 2

Sequence 1 Treatment 1

Treatment 2

Sequence 2 Treatment 2

Treatment 1

Crossover Studies:Subject receives each of the formulations one at a time in different time periods. Designed to eliminate individual differences.2 x 2 Crossover Designs

RANDOMIZATION

WASHOUTTest Reference

TestReference

SubjectsSequence 1

Sequence 2

Period

I II

Statistical Designs

Intra-subject Variability (Estimated): variability within a subject

Test

Reference

EstimatedIntra-subject Variability

Period I

Period II

Statistical Designs: Crossover Study

(Subject Acts as Own Control)

1

Major Elements of Study Designs[BA, BE, Fed]

(Immediate-Release Products Example, Fasting Study)

8. Sampling (plasma, serum, whole blood)• Sufficient sampling during absorption phase to define

adequately to ascending portion of the curve; avoid first nonzero concentration as the Cmax.

• Intensive sampling around the time of the expected Cmax.

• Sampling duration of at least 3 to 6 drug half-lives (NDA) or 7-10 drug half-lives (ANDA) or longest half-life of any analyte.

Major Elements of Study Designs[BA, BE, Fed] (Immediate-Release Products Example, Fasting Study)

9. Pharmacokinetic Parameters• Area Under the Curve (AUC)

AUC0-t: Time of the last quantifiable concentration Calculated by the trapezoidal rule

AUC0-inf: Extrapolated to infinity= AUC0-t + Ct/Kel

• Peak concentration (Cmax) and time to Cmax (Tmax) are obtained directly from the observed data

• Terminal elimination rate constant (Kel, λz) and half-life, t1/2 = ln(2)/Kel.

Pharmacokinetic AnalysisBA/BE & FED

1. Plasma/Serum and/or Whole Blooda. Drug level at sampling timesb. Pharmacokinetic parameters

*AUC0-t Last quantifiable concentration*AUC0-inf Infinity*Cmax Peak concentrationTmax Time to peak concentrationKel Terminal elimination rate constantt1/2 Elimination half-life

CL/F Clearance Vd Volume of Distribution

2. Urinea. Drug level at sampling intervals (Ae)b. Pharmacokinetic parameters

Cumulative excretion (*Ae0-t)Maximum excretion rate (*Rmax)Time to maximum excretion rate (Tmax)

* = Pivotal Bioequivalence PK Parameter

Statistical Requirements: Bioequivalence

Two one-sided tests procedure (also called the 90% confidence interval approach)

– The July 1, 1992 Statistical Procedures Guidance requires 90% confidence interval limits from 80% to 125% based upon log transformed AUC0-t, AUC0-inf and Cmax data.

– Result must be between Lower Bound 80% and Upper Bound 125% {Ln 80 – 125}.

BE Confidence Intervals

• For Bioequivalence, the 90% confidence interval of F’ must fall between 0.80 and 1.25.

0.80

1.00

1.25

0.80

1.00

1.25

0.80

1.00

1.25

0.80

1.00

1.25BESD

BESD BE

SDBESD

X

X XX

BE = Bioequivalent SD = Statistically Different

Statistical Designs - BESubject-By-Formulation Interaction• A statistical term, meaning that the difference

between the subject-specific means for the test product and the reference product is not the same for all subjects in the population.

• The possibility of subject-by-formulation interaction is one of the main concerns in the discussions of “bioequivalence”.

0.01

0.10

1.00

10.00

100.00

1000.00

0 5 10 15 20 25 30 35 40

Time (hr)

Treatment=A

0.01

0.10

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Time (hr)

Treatment=B

Side-by-Side Spaghetti Plots: FASTED

Test Product (n=108) Reference Product (n=108)

Phase 1: BA/BE (and/or FED)

Concentration – Time Profiles

0

1

2

3

4

5

6

0 5 10 15 20 25 30 35 40

Time (hr)

A

B

0.001

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Time (hr)

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B

Y axis-Linear Scale

Y axis-Log Scale

Bioequivalence (BE)Excellent

Concentration – Time Profile

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

0 5 10 15 20 25 30 35 40

Time (hr)

A

B

Subject=78

Subject by Formulation Interaction?

A=Test B=Reference

0

2

4

6

8

10

0 5 10 15 20 25 30 35 40

Time (hr)

A

B

Subject=17

0

5

10

15

20

25

30

35

0 2 4 6 8 10 12 14 16

Time (hr)

A

B

Subject=18

Cmax Plot: Text to Reference

Ratio: Cmax (Test)/Cmax (Reference) = 0.98

Pharmacokinetics

Therapeutics

Concentration

Pharmacokinetics

Dose Effect

Pharmacodynamics

PHARMACOKINETICS: What the body does to the drug (Absorption, Distribution, Metabolism and Excretion (ADME)).

PHARMACODYNAMICS: What the drug does to the body (Therapeutic Effects, Side Effects).

Conclusion: What is in your Drug Product Labeling?

34

Pharmacokinetics

(BA/BE/FED)

Clinical Pharmacology

Drug Substance

Indication

Safety

DDI

Reproductive

Thank YouACPU CommitteeDr. Charles PierceDr. Punkaj DesaiDr. William Sietsema