Bioavailability and Bioequivalence Studies: General Considerations for Oral Drugs

Bioavailability & Bioequivalence studies General Considerations for Orally Administered Drugs

CONTENTS Background Methods to document BA & BE Comparison of BA measures in BE studies Documentation of BA & BE Special Topics

SERUMCONC. vsTIME Elimination phase Absorption phase 6 Maximum safe concentration 5 Average serum concntration (mcg/ml) Cmax 4 Therapeutic range 3 2 Minimum effective concentratio 1 Duration of action 0 4 5 6 7 8 9 0 1 2 3 10 11 12 Time after drug administration (h)

BACKGROUND Bioavailability is defined in 320.1 as: the rateandextentto which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site ofaction.

PHARMACO-KINETICPERSPECTIVE Estimate of the relative fraction of the dose in systemic circulation (vs Solution, suspension or Intravenous) ADME information Nutrients effect on absorption Dose proportionality Linearity of Pharmacokinetics

REGULATORYOBJECTIVE The performance of the formulations used in the clinical trials provide evidence of safety andefficacy (21 CFR 320.25(d)(1)). Focus on using relative BA (referred to as product quality BA) and, in particular, BE studies as a meansto document productquality. In vivo performance in terms of BA/BE, can be considered to be one aspect of product quality that provides a link to the performance of the drugproduct used in clinical trials and to the database containing evidence of safety andefficacy.

BIO-EQUIVALENCE the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designedstudy

BIO-EQUIVALENT??

REQUIRED FOR INDs/ NDAs ANDAs Post Approval Changes

BE forINDs/NDAs Toestablish links between: (1) early and late clinical trial formulations; (2) formulations used in clinical trial and stability studies, if different; (3) clinical trial formulations and to-be- marketed drug product; and (4) any other appropriate comparisons

POSSIBLE OUTCOMES CASE(1) CASE(2) Note: *

CA SE(3) Note: *

REGULATORYCONCERN Case (1): Test product generates plasma levels that are substantially above those of the reference product Concern: Not therapeutic failure, but the adequacy of the safety database from the test product

REGUATORYCONCERN Case (2): The test product has levels that are substantially below those of the reference product Concern: Therapeutic Efficacy Case (3): Variability of the test product Concern: Ensuring safety & Efficacy Contd..

For Case (3) the FDA needs : Individual dose response Curves Population dose response Curves Concentration dose response curves Burden is on the sponsor to demonstrate the adequacy of the clinical trial dose-response or concentration-response data to provide evidence of therapeutic equivalence.

ANDA Purpose: To demonstrate BE between a pharmaceutically equivalent generic drug product and the corresponding reference listed drug (21 CFR 314.94(a)(7)). BE + Pharmaceutical equivalence Therapeutic equivalence

POST APPROVAL CHANGES Immediate release dosage forms Modified release dosage forms Requirements of in vitro dissolution & in vivo BE studies depend on the type (level 1,2,3) Ref: corresponding detailed guidance from FDA

METHODS TO DOCUMENT BA &BE 320.24 - Invitro & in vivo methods used to measure product quality and establish BE 1) Pharmaco-kinetic study 2)Pharmacodynamic Study 3)Comparative clinical studies 4)In-vitro studies

Comparison of BA measures in BE studies FDA sApproach: (1) a criterion to allow the comparison, (2) a confidence interval for the criterion, and (3) a BE limit

DOCUMENTATION OF BA &BE An in vivo study is generally recommended for all solid oral dosage forms approved after 1962 and for bioproblem drug products approved before 1962.

BIOWAIVER 320.22(d)(2): 1) the drug product is in the same dosage form, but in a differentstrength; this different strength is proportionally similar in its active and inactive ingredients to the strength of the product for which the same manufacturer has conducted an appropriate in vivo study;and 3) the new strength meets an appropriate in vitro dissolutiontest. 2)

PROPORTIONALLYSIMILAR 1) All active and inactive ingredients are inexactly the same proportion between different strengths if not, 2) ratios of inactive ingredients to total weight of the dosage form are within the limits defined by the SUPAC-IR and SUPAC-MR guidance up to and including LevelII 3) For high potency drug substances, where the amount of the active drug substance in thedosage form is relatively low, the total weight of the dosage form remains nearly the same for all strengths ( 10 % of the total weight of the strength on which a biostudy wasperformed)

DOSAGEFORMS Solutions: For oral solutions, elixirs, syrups, tinctures, or other solubilized forms, in vivo BA and/or BE can be waived (21 CFR320.22(b)(3)(i)). Generally, in vivo BE studies are waived for solutions on release of the drug substance from the drug product is self-evident and that the solutions do not contain any excipient that significantly affects drug absorption (exceptions - Sorbitol,Mannitol) Contd....

Suspensions: BA BE for immediate release solid orals Both Invivo & invitro studies are recommended. Capsules & Tablets (Immediate release): Single dose fasting study Focus on release of DS into Systemic circulation) & Invitro dissolution profiles on all strengths of each product. ANDAs: BE Test vs RL product (strength-Orange book)

DIFFERENCEFACTOR The difference factor (f 1) calculates the percent (%) difference between the two curves at each time point and is a mea- surement of the relative error between the two curves:

SIMILARITY FACTOR(f2) n = number of time points R(t) = mean % API dissolved of reference product at time point x T(t) = mean % API dissolved of test product at time point x Range : 0-100

PRE-APPROVALBIOWAIVERS In vivo BE demonstration of one or more lower strengths can be waived based on dissolution tests and an in vivo study on the highest strength when drug product is in the same dosage form, but in a different strength, and is proportionally similar in its active and inactive ingredients to the strength on which BA or BE testing has beenconducted Contd...

Biowaiver for Higher strength for NDAis based on: (1)clinical safety and/or efficacy studies including data on the dose and the desirability of the higher strength, (2)linear elimination kinetics over the therapeutic dose range, (3)the higher strength being proportionally similar to the lower strength, & (4)the same dissolution procedures being used for both strengths and similar dissolution results obtained Contd....

DISSOULTION NOT DEPENDENT ON STRENGTH Dissolution profile from one medium are enough to support waivers or profiles from three media (PH 1.2, 4.5 & 6.8) are needed F2 test is used to compare profilesdifferent strengths of the product F2 50 no further in vivo studies are needed. Not suitable for rapidly dissolving drug prod- ucts (e.g., > 85% dissolved in 15 minutes or less). Contd.....

Invivo studies are NOT required for high- est strength for an ANDA if : 1) Linear elimination kinetics has been shownover the therapeutic doserange 2) The higher strengths of the test andreference products are proportionally similar to their corresponding lowerstrength. 3) Comparative dissolution testing on the higher strength of the test and reference products is submitted and found to beappropriate

POST APPROVAL: NDAs & ANDAs SUPAC IR provides specific guidance. Eg: Looking at level 2change BCS class II(LS/HP): In vitro dissolution (pH 1-7.4) Multiple profiles f2 50 BCS class IV(LS/LP): In vivo AUC & Cmax: 80-125% (90% CI )

MODIFIED RELASE PRODUCTS Delayed release products Extended (controlled) release products

NDAs : BA BE 320.25(f)- BArequirements Purpose: The drug product meets thecontrolled- release claims made forit. The BA profile established for thedrug product rules out the occurrence of any dosedumping. The product s steady-state performance is equivalent to a currently marketed noncontrolled release or controlled-release drug product that contains thesame active drug ingredient or therapeutic moiety of approvedNDA Thedrug product s formulation providesconsistent pharmacokinetic performance between individual dosageunits

TYPE OFSTUDIES A single-dose, fasting study on all strengthsof tablets and capsules and highest strength of beaded capsules A single-dose, food-effect study on the highest strength A steady-state study on the higheststrength BE studies : substantial changes in the components or composition and/or method of manufacture for an extended-release drug product occur between the to be-marketed NDA dosage form and the clinical trialmaterial

ANDAs: BE Studies (1)a single-dose, nonreplicate, fasting study comparing the highest strength of the test and reference listed drug product and (2)a food-effect, non replicate study comparing the highest strength of the test and reference product

Tablets: When Proportionality applies: In Vivo study for the highest strength Waiver for lower strengths with comparison of dissolution with higher strengths Similar dissolution profiles ( f2 50 ) inthree dissolution media (pH 1.2, 4.8 & 6.8) Post Approval Changes : SUPAC-MR guidance applies Invitro Prechange vs Post change product

BIO WAIVERS (BE) : NDAs& ANDAs Beaded Capsules: Strength no. of beads BE study for Highest Strength is sufficient. Bio Waiver for lower strengths based on dissolutionprofiles F2 50

MISC. DOSAGEFORMS 1)Rapidly dissolving drug products buccal & sublingual usage: 2) Both in vivo BA & /BE and in vitro dissolution: WHY?

SPECIAL TOPICS FOOD - EFFECTstudies: 1)Influence of Co-administation of food with oral dosage forms 2)BA studies focus on effect of food drug release 3)BE demostration comparable BA (test vs ref.) when coadministered with food 4)Single dose, two period, two sequence corssover study.

MOIETIES MEASURED Parent drug vs metabolities BA Studies- Concentration & Activity BE studies Parent drug preferred. WHY? Except : =>Low Parent drug levels Analysis problems Contd...

Enantiomers vsRacemates: BA studies: Individual enantiomers BE Studies: Measurement of racemate Individual enantiomers are preferred when : Enantiomers exhibit different PK /PD characteristics, Primary efficacy and safety activity re- sides with the minor enantiomer, & Nonlinear absorption is present for at least one of the enantiomers Contd.....

COMPLEX MIXTURES AS ACTIVE Some or all of the APIs can t becharacterized with regard to chemical structure /activity Case by Case basis BA and BE studies be based on a small number of markers of rate and extent of absorption Possibility of pharmacodynamic or clinical approach

LONG HALF LIFEDRUGS Adequate characterization of half life Non-replicate single dose cross over Parallel study when cross over is not feasible Sample collection time gastro-intestinal transit (2-3 days ) Truncated Curve: AUC 0-72 hr Intra subject variabilityissue.

FIRST POINTCmax First point of concentration time curve reflects Cmax Early sampling times ? insufficient sampling? Better sampling approach : Initial 5-15 min after administration Additional 2-3 samples in the first hour

NTIDRUGS Note :*

BE STUDIES

BE LIMITS FOR GENERIC NTIDRUGS

REFERENCES 1) www.FDA.gov 2) * - Taken from the work of LAWRENCE YU, Acting Director Office of Pharmaceutical science FDA.