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Phase 1 Bioavailability(BA)/Bioequivalence(BE) & Fed Studies

Phase 1 Bioavailability(BA)/Bioequivalence(BE) & Fed Studies. Ruth E. Stevens, PhD, MBA Chief Scientific Officer, Executive Vice President Camargo Pharmaceutical Services ACPU: October 19, 2010. Approved Product Labeling. Drug Substance. Indication. Safety. Clinical Pharmacology. DDI.

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Phase 1 Bioavailability(BA)/Bioequivalence(BE) & Fed Studies

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

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

  3. Therapeutics Pharmacokinetics Pharmacodynamics Dose Concentration Effect Pharmacokinetics

  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. Cmax AUC Note: AUC = AUC0-t and AUC0-inf Reference: Food, Drug and Cosmetic Act Section 505(j)(7) Bioequivalence

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

  6. Bioequivalence: Cmax AUC (B) A drug shall be considered to be bioequivalent to a listed drug if: • 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 • 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. AUC Note: AUC = AUC0-t and AUC0-inf Reference: Food, Drug and Cosmetic Act Section 505(j)(7) Bioequivalence

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

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

  9. **Area Under-the-Curve (AUC0-t)“Extent of Absorption” ** = Pivotal Bioequivalence PK Parameter AUC 0-t or AUC0-last: Area under the plasma concentration-time curve from time zero to the last measurable time point. Biological Matrix Concentration (ng/mL) t Time (hrs)

  10. **Area Under-the-Curve (AUC0-inf) ** = Pivotal Bioequivalence PK Parameter “Extent of Absorption” Biological Matrix Concentration (ng/mL) AUC 0-inf or AUC∞: Area under the plasma concentration-time curve from time zero to time infinity. 12 24 Time (hrs)

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

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

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

  14. Drug Elimination Half-Life, (t½) z = terminal slope Ln(2) = natural log of 2 Biological Matrix Concentration (ng/mL) t1/2 = ln(2)/z = 0.693 z ≥4 points on terminal slope to calculate z 24 12 Time (hrs)

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

  17. 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 approval 6. Additional subjects enrolled to replace dropouts

  18. 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%.

  19. Statistical Designs 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 R A N D O M I Z A T I O N Period Subjects Sequence 1 I II W A S H O U T Reference Test Sequence 2 Test Reference

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

  21. 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.

  22. 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 ruleAUC0-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.

  23. Pharmacokinetic AnalysisBA/BE & FED • Plasma/Serum and/or Whole Blood • Drug level at sampling times • 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 • Urine • Drug level at sampling intervals (Ae) • Pharmacokinetic parametersCumulative excretion (*Ae0-t)Maximum excretion rate (*Rmax)Time to maximum excretion rate (Tmax) * = Pivotal Bioequivalence PK Parameter

  24. 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}.

  25. 1.25 1.25 1.25 1.25 BE SD X 1.00 1.00 1.00 1.00 BE SD X X BE SD BE SD X 0.80 0.80 0.80 0.80 BE Confidence Intervals • For Bioequivalence, the 90% confidence interval of F’ must fall between 0.80 and 1.25. BE = Bioequivalent SD = Statistically Different

  26. 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”.

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

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

  29. Bioequivalence (BE)Excellent Concentration – Time Profile

  30. Subject by Formulation Interaction? A=TestB=Reference

  31. Cmax Plot: Text to Reference Ratio: Cmax (Test)/Cmax (Reference) = 0.98

  32. Therapeutics Pharmacokinetics Pharmacodynamics Dose Concentration Effect Pharmacokinetics

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

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

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