Bioavilability and Bioequivalence study designs

Bioavilability and Bioequivalence study designs

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  Bioavailability & Bioequivalence Studies RAJENDRAD. MAHAJAN M.PHARM – 2ND YEAR PHARMACEUTICS
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  Essential to ensureuniformity in standards of quality, efficacy & safety of Pharmaceutical products. Release of an active substance should be known & reproducible. Both Bioavailability & Bioequivalence focus on release of drug substance from its dosage form & subsequent absorption in circulation.
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  Bioavailability  Measurement ofthe relative amount & rate at which, the drug from administered dosage form, reaches the systemic circulation & becomes available at the site of action  Bioavailable fraction (F), refers to the fraction of administered dose that enters the systemic circulation  F = Bioavailable dose Administered dose
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  Therapeutic Relevance
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  Absolute Bioavailability  Comparesthe bioavailability of the active drug in systemic circulation following non-intravenous administration with the same drug following intravenous administration  For drugs administered intravenously, bioavailability is 100%  Determination of the best administration route Fab = (AUC)drug (AUC)IV
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  Relative Bioavailability  Comparesthe bioavailability of a formulation (A) of a certain drug when compared with another formulation (B) of the same drug, usually an established standard. F rel = (AUC) drug (AUC) standard
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  Concept of Equivalents Pharmaceutical equivalents  equal amounts of the identical active drug ingredient, (i.e. the same salt or ester of the therapeutic moiety)  identical dosage forms  not necessarily containing the same inactive ingredients  Pharmaceutical alternatives  identical therapeutic moiety, or its precursor  not necessarily the same: • salt or ester of the therapeutic moiety • amount • dosage form
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   Bioequivalence  Pharmaceuticalequivalent / alternative of the test product,  when administered at the same molar dose,  has the rate and extent of absorption  not statistically significantly different from that of the reference product.  Therapeutic equivalence  Same active substance or therapeutic moiety  Clinically show the same efficacy & safety profile
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  Pharmacokinetic Studies
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  Study Design  Goodexperimental design, enhances the power of the study  Depends on: question to be answered, nature of reference drug/ dosage form, benefit-risk ratio  As far as possible, the study should be of crossover design & suitably randomized  Ideal design: Randomized two-period, two-sequence,Crossover design with adequate washout period  If the half-life is long: Parallel design  For highly variable drugs: Replicate design
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  Fasting study  Bioequivalencestudies are usually evaluated by a single- dose, two-period, two-treatment, two-sequence, open-label, randomized crossover design comparing equal doses of the test and reference products in fasted, adult, healthy subjects.  This study is required for all immediate-release and modified-release oral dosage forms.  Both male and female subjects may be used in the study.  Blood sampling is performed just before (zero time) the dose and at appropriate intervals after the dose to obtain an adequate description of the plasma drug concentration–time profile.
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   The subjectsshould be in the fasting state (overnight fast of at least 10 hours) before drug administration and should continue to fast for up to 4 hours after dosing.  No other medication is normally given to the subject for at least 1 week prior to the study.  In some cases, a parallel design may be more appropriate for certain drug products, containing a drug with a very long elimination half-life.  A replicate design may be used for a drug product containing a drug that has high intrasubject variability.
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  Crossover Designs  Subjectswho meet the inclusion and exclusion study criteria and have given informed consent are selected at random.  A complete crossover design is usually employed, in which each subject receives the test drug product and the reference product.  Examples of Latin-square crossover designs for a bioequivalence study in human volunteers, comparing three different drug formulations (A, B, C) or four different drug formulations (A, B, C, D), are described in and .
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   The Latin-squaredesign plans the clinical trial so that each subject receives each drug product only once, with adequate time between medications for the elimination of the drug from the body ().  In this design, each subject is his own control, and subject-to-subject variation is reduced. Moreover, variation due to sequence, period, and treatment (formulation) are reduced, so that all patients do not receive the same drug product on the same day and in the same order.  Possible carryover effects from any particular drug product are minimized by changing the sequence or order in which the drug products are given to the subject.
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   Thus, drugproduct B may be followed by drug product A, D, or C ().  After each subject receives a drug product, blood samples are collected at appropriate time intervals so that a valid blood drug level–time curve is obtained.  The time intervals should be spaced so that the peak blood concentration, the total area under the curve, and the absorption and elimination phases of the curve may be well described.
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  I.Two-Period Crossover Design 2 formulations, even number of subjects, randomly divided into 2 equal groups.  First period , each member of one group receive a single dose of the test formulation; each member of the other group receive the standard formulation  After a wash period (5 half lives), in second period , each member of the respective groups will receive an alternative formulation & experiment will be repeated.
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  Subjects Period 1Period 2 1-8 T S 9-16 S T
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  II.Latin Square Design More than two formulations.  A group of volunteers will receive formulations in the sequence shown.  a design for three different drug treatment groups given in a three-period study with six different sequences.
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   A designfor four different drug treatment groups given in a four-period study with sixteen different sequences.
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  III.Balance Incomplete BlockDesign (BIBD)  More than 3 formulations, Latin square design will not be ethically advisable.  Because each volunteer may require drawing of too many blood samples.  If each volunteer expected to receive at least two formulation, then such a study can be carried out using BIBD.
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  IV.Parallel-Group Design  Evennumber of subjects in two groups.  Each receive a different formulation.  No washout necessary.  For drugs with long half life.
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  T TREATMENT A TRAETMENTB 1 2 3 4 5 6 7 8 9 10 11 12
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  Parallel Crossover • Groupsassigned different treatments • Each patient receives both treatments Shorter duration Longer duration Larger sample size Smaller sample size No carryover effect Carryover effect •Doesn’t require stable disease & similar baseline •Requires stable disease & similar baseline
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  V.Replicate Crossover-study design For highly variable drugs  Allows comparisons of within-subject variances  Reduce the number of subjects needed  Four-period, two-sequence, two-formulation design (recommended) OR  Three-sequence, three-period, single-dose, partially replicated
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  Replicated Crossover Design Replicated crossover designs are used for the determination of individual bioequivalence, to estimate within-subject variance for both the Test and Reference drug products, and to provide an estimate of the subject-by-formulation interaction variance. Generally, a four-period, two-sequence, two-formulation design is recommended by the FDA. where R = reference and T = treatment.  The same reference and the same test are each given twice to the same subject. Other sequences are possible. In this design, Reference-to-Reference and Test-to-Test comparisons may also be made. PERIOD 1 2 3 4 Group 1 T R T R Group 2 R T R T
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  Multiple-Dose (Steady-State) Study In a few cases, a multiple-dose, steady-state, randomized, two-treatment, two-way crossover study comparing equal doses of the test and reference products may be performed in adult, healthy subjects.  For these studies, three consecutive trough concentrations (C min) on three consecutive days should be determined to ascertain that the subjects are at steady state.  The last morning dose is given to the subject after an overnight fast, with continual fasting for at least 2 hours following dose administration.  Blood sampling is performed similarly to the single-dose study.
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   Statistical Evaluation Primary concern of bioequivalence is to limit Consumer’s & Manufacturer’s risk • Cmax & AUC analysed using ANOVA • Tmax analysed by non-parametric methods  Use natural log transformation of Cmax and AUC • Calculate Geometric means of Cmax of Test [Cmax’t] • Calculate Geometric means of Cmax of Reference [Cmax’r] • Calculate Geometric Mean Ratio= [Cmax’t] / [Cmax’r]
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   Calculate 90%confidence interval for this GMR for Cmax  Similarly calculate GMR for AUC  To establish BE:  The calculated 90% CI for Cmax & AUC, should fall within range: 80-125% (Range of Bioequivalence)  Non-parametric data 90% CI for Tmax should lie within clinical acceptable range
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  References  Leon Shargel,Susanna wu-pong, Andrew Yu. Applied biopharmaceutics and pharmacokinetics. 6th edition, pg no- 417-421.  D. M. Brahmankar, S.B. Jaiswal; “Biopharmaceutics & Pharmacokinetics”; first edition, 12th reprint; Vallabh Prakashan; 339 – 343.  www.wikipedia.com 30