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Ruth E. Stevens, PhD, MBA Chief Scientific Officer, Executive Vice President Camargo Pharmaceutical Services ACPU: October 19, 2010 Phase 1 Bioavailability(BA)/Bioequivalence(BE)

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Presentation on theme: "Ruth E. Stevens, PhD, MBA Chief Scientific Officer, Executive Vice President Camargo Pharmaceutical Services ACPU: October 19, 2010 Phase 1 Bioavailability(BA)/Bioequivalence(BE)"— Presentation transcript:

1 Ruth E. Stevens, PhD, MBA Chief Scientific Officer, Executive Vice President Camargo Pharmaceutical Services ACPU: October 19, 2010 Phase 1 Bioavailability(BA)/Bioequivalence(BE) & Fed Studies

2 Approved Product Labeling 2 Pharmacokinetics (BA/BE/FED) Clinical Pharmacology Drug Substance Indication Safety DDI Reproductive

3 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).

4 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. C max AUC Note: AUC = AUC 0-t and AUC 0-inf Reference: Food, Drug and Cosmetic Act Section 505(j)(7) Bioequivalence

5 Comparative Bioavailability Study (Rate and Extent of Absorption) A = Test; 1x/day B = Reference; 3x/day Y axis-Linear Scale Y axis-Log Scale

6 Bioequivalence: bioequivalent (B) A drug shall be considered to be bioequivalent 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 C max AUC Note: AUC = AUC 0-t and AUC 0-inf AUC

7 Bioequivalent Products - Concentration – Time Profiles Rate & Extent = “SAME” Y axis-Linear Scale Y axis-Log Scale

8 LOQ = Limit of Quantitation or LQC = Last Quantifiable Concentration Biological Matrix Concentration (ng/mL) LOQ Time (hrs) Area Under-the-Curve (AUC) “Extent of Absorption”

9 ** Area Under-the-Curve (AUC 0-t ) “Extent of Absorption” Biological Matrix Concentration (ng/mL) Time (hrs) AUC 0-t or AUC 0-last : Area under the plasma concentration-time curve from time zero to the last measurable time point. t ** = Pivotal Bioequivalence PK Parameter

10 Biological Matrix Concentration (ng/mL) Time (hrs) 1224 AUC 0-inf or AUC ∞ : Area under the plasma concentration-time curve from time zero to time infinity. **Area Under-the-Curve (AUC 0-inf ) ** = Pivotal Bioequivalence PK Parameter “Extent of Absorption”

11 Biological Matrix Concentration (ng/mL) Time (hrs) 12 24  **Maximum Observed Concentration, C max “Rate” C max Value read off Y-axis ** = Pivotal Bioequivalence PK Parameter

12 Biological Matrix Concentration (ng/mL) Time (hrs) 12 24 T max Time to Maximum Concentration, T max Value read off X-axis “ Rate ”

13 Biological Matrix Concentration (ng/mL) Time (hrs) 12 24 z or K el : slope ≥4 timepoints Terminal Elimination Rate Constant z (lambda, lambda z or K el ) Rate & Extent of Absorption

14 Biological Matrix Concentration (ng/mL) Time (hrs) 12 24 z = terminal slope Ln(2) = natural log of 2 Drug Elimination Half-Life, (t ½ ) t 1/2 = ln(2)/ z = 0.693 z ≥4 points on terminal slope to calculate z

15 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

16 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) GramsNo. of CaloriesPercent of Total Calories Protein3313215.4% Fat5528035.3% Carbohydrate5823227%

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18 Major Elements of Study Designs [BA, BE, Fed] (Example: Immediate-Release Products) 3. Exclusion Criteria Major 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. Restrictions No 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 approval 6. Additional subjects enrolled to replace dropouts

19 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 randomization Washout period between treatments (7-10 drug half-lives) Potencies of test and reference products within ± 5%. Period 1Period 2 Sequence 1Treatment 1Treatment 2 Sequence 2Treatment 2Treatment 1

20 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 RANDOMIZATIONRANDOMIZATION WASHOUTWASHOUT Test Reference Test Reference Subjects Sequence 1 Sequence 2 Period III Statistical Designs

21 Intra-subject Variability (Estimated): variability within a subject Test Reference Estimated Intra-subject Variability Period I Period II Statistical Designs: Crossover Study (Subject Acts as Own Control) 1

22 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 C max. Intensive sampling around the time of the expected C max. 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.

23 Major Elements of Study Designs [BA, BE, Fed] (Immediate-Release Products Example, Fasting Study) 9. Pharmacokinetic Parameters Area Under the Curve (AUC) AUC 0-t : Time of the last quantifiable concentration Calculated by the trapezoidal rule AUC 0-inf :Extrapolated to infinity = AUC 0-t + C t /K el Peak concentration (C max ) and time to C max (T max ) are obtained directly from the observed data Terminal elimination rate constant (K el, λz) and half-life, t 1/2 = ln(2)/K el.

24 Pharmacokinetic Analysis BA/BE & FED 1.Plasma/Serum and/or Whole Blood a.Drug level at sampling times b.Pharmacokinetic parameters *AUC 0-t Last quantifiable concentration *AUC 0-inf Infinity *C max Peak concentration T max Time to peak concentration K el Terminal elimination rate constant t 1/2 Elimination half-life CL/F Clearance Vd Volume of Distribution 2.Urine a.Drug level at sampling intervals (Ae) b.Pharmacokinetic parameters Cumulative excretion (*Ae 0-t ) Maximum excretion rate (*R max ) Time to maximum excretion rate (T max ) * = Pivotal Bioequivalence PK Parameter

25 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 AUC 0-t, AUC 0-inf and C max data. –Result must be between Lower Bound 80% and Upper Bound 125% {Ln 80 – 125}.

26 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 1.25 BE SD BE SD BE SD BE SD X XX X BE = BioequivalentSD = Statistically Different

27 Statistical Designs - BE Subject-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”.

28 Side-by-Side Spaghetti Plots: FASTED Test Product (n=108)Reference Product (n=108)

29 Phase 1: BA/BE (and/or FED) Concentration – Time Profiles Y axis-Linear Scale Y axis-Log Scale

30 Bioequivalence (BE) Excellent Concentration – Time Profile

31 Subject by Formulation Interaction? A=Test B=Reference

32 C max Plot: Text to Reference Ratio: Cmax (Test)/Cmax (Reference) = 0.98

33 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).

34 Conclusion: What is in your Drug Product Labeling? 34 Pharmacokinetics (BA/BE/FED) Clinical Pharmacology Drug Substance Indication Safety DDI Reproductive

35 Thank You ACPU Committee Dr. Charles Pierce Dr. Punkaj Desai Dr. William Sietsema


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