10
`
`
`
`BIOAVAILABILITY AND
`BIOEQUIVALENCE
`
`
`
`Many drugs are marketed by more than one pharmaceutical manufacturer. The
`study of biopharmaceutics gives substantial evidence that the method of manufac-
`ture and the final formulation of the drug can markedly affect the bioavailability
`of the drug. Because of the plethora of drug products containing the same amount
`of active drug, physicians, pharmacists, and others whoprescribe, dispense, or pur-
`chase drugs must select generic products that produce an equivalent therapeutic
`effect to the brand product. To facilitate such decisions, guidelines have been de-
`veloped by the United States Food and Drug Administration (FDA). The guide-
`lines are available on the Internet (http://www.fda.gov). Some of the guidelines
`also appear in the United States Pharmacopeia/National Formulary (USP-NF).
`These guidelines and methods for determining drug availability are discussed in
`this chapter.
`
`|
`
`DEFINITIONS
`
`* Bioavailability. Indicates a measurementof the rate and extent (amount) of ther-
`apeutically active drug that reaches the systemic circulation and is available at
`the site of action.
`Bioequivalence requirement. A requirement imposed by the Food and Drug Admin-
`istration (FDA)for in vitroand/orin vivo testing of specified drug products which
`mustbe satisfied as a condition for marketing.
`Bioequivatent drugproducts. Bioequivalent drug products are pharmaceuticalequiv-
`alents that have similar bioavailability (ie, are not significantly different with re-
`spect to rate and extent of absorption) when given in the same molar dose and
`studied undersimilar experimental conditions. Some drugs maybe considered
`bioequivalent that are equal in the extent of absorption but no/ in therate of ab-
`sorption; this is possible if the difference in the rate of absorptionis considered
`clinically insignificant, is not essential for the attainmentof effective body drug
`concentrations on chronic use, andis reflected in the proposed labeling. For ex-
`ample, aspirin and acetaminophenare well-absorbed drugs, and small differences
`in the rate of absorption are of very little clinical consequence. Bioequivalence
`
`247
`
`99
`
`Hopewell EX1076 (Part 2 of 2)
`Hopewell v. Merck
`IPR2023-00480
`
`Hopewell EX1076 (Part 2 of 2)
`Hopewell v. Merck
`IPR2023-00480
`
`99
`
`

`

`248
`
`CHAPTER 10. BIOAVAILABILITY AND BIOEQUIVALENCE
`
`may sometimes be demonstrated using an in vitro bioequivalence standard, es-
`pecially when such anin vitro test has been correlated with humanin vivo bioavail-
`ability data. For some products, other invivo tests may be appropriate, including
`comparative clinical trials or pharmacodynamicstudies.
`© Brand name. Trade nameof the drug. This nameis privately owned by the man-
`ufactureror distributor andis used to distinguish the specific drug product from
`competitors’ products (eg, Tylenol, McNeil Laboratories).
`© Chemical name. Nameused by the organic chemistto indicate the chemicalstruc-
`ture of the drug (eg, N-acetyl-paminophenol).
`¢ Drug product. The finished dosage form (eg, tablet, capsule or solution) that con-
`tains the active drug ingredient, generally, but not necessarily, in association with
`inactive ingredients.
`° Drug product selection. The process of choosing orselecting the drug product in
`a specified dosage form.
`© Drug substance. A drug substance is the active pharmaceutical ingredient (API)
`or componentin the drug productthat furnishes the pharmacodynamicactivity.
`© Equivalence. Relationship in termsof bioavailability, therapeutic response,ora set
`of established standards of one drug product to another.
`© Generic name. The established, nonproprietary, or common nameof the active
`drug in a drug product (eg, acetaminophen).
`© Generic substitution. The process of dispensing a different brand or unbranded
`drug productin place of the prescribed drug product. The substituted drug prod-
`uct contains the sameactive ingredient or therapeutic moiety as the samesalt or
`ester in the same dosage form but is made by a different manufacturer. For ex-
`ample, a prescription for Motrin brand of ibuprofen might be dispensed by the
`pharmacist as Advil brand of ibuprofen or as a nonbranded generic ibuprofen
`if generic substitution is permitted and desired by the physician.
`¢ Pharmaceutical alternatives. Drug products that contain the same therapeutic moi-
`ety but as different salts, esters, or complexes. For example, tetracycline phos-
`phate or tetracycline hydrochloride equivalent to 250 mg tetracycline base are
`considered pharmaceutical alternatives. Different dosage forms and strengths
`within a product line by a single manufacturer are pharmaceutical alternatives
`(eg, an extended-release dosage form and a standard immediate-release dosage
`form of the sameactive ingredient).
`© Pharmaceutical equivalents. Drug products that contain the same active drug in-
`gredient (samesalt, ester, or chemical form) andare identical in strength or con-
`centration, dosage form, and route of administration (eg, diazepam, 5 mgoral
`tablets). Chemical equivalents are pharmaceutical equivalents. Pharmaceutical
`equivalent drug products must meetthe identical standards (strength, quality,
`purity, and identity), but may differ in such characteristics as color, flavor, shape,
`scoring configuration, packaging, excipients, preservatives, expiration time, and
`(within certain limits) labeling.
`© Pharmaceutical substitution. The process of dispensing a pharmaceutical alterna-
`tive for the prescribed drug product. For example, ampicillin suspension is dis-
`pensedin place of ampicillin capsules, or tetracycline hydrochloride is dispensed
`in place of tetracycline phosphate. Pharmaceutical substitution generally requires
`the physician’s approval.
`© Therapeutic alternatives. Drug products containing different active ingredients that
`are indicated for the same therapeutic or clinical objectives. Active ingredients
`in therapeutic alternatives are from the same pharmacologic class and are ex-
`
`
`
`100
`
`100
`
`

`

`
`
`BIOAVAILABILITY AND BIOEQUIVALENCE CHAPTER 10. 249
`
`pected to have the same therapeutic effect when administered to patients for
`such condition of use. For example, ibuprofen is given instead of aspirin; ci-
`metidine may be given instead of ranitidine.
`© Therapeutic equivalents. Therapeutic equivalents are drug products that contain
`the same therapeuticallyactive drug that should give the same therapeutic effect
`andhave equal potential for adverse effects under conditionsset forth in the la-
`bels of these drug products. Therapeutic drug products maydiffer in certain
`characteristics, such as color, scoring, flavor, configuration, packaging, preserva-
`tives, and expiration date. Therapeutic equivalent drug products must be (1) safe
`andeffective, (2) pharmaceutical equivalents, (3) bioequivalent, (4) adequately
`labeled, and (5) manufactured in compliance with current good manufacturing
`practices.
`¢ Therapeutic substitution. The process of dispensing a therapeutic alternative in
`place of the prescribed drug product. For example, amoxicillin is dispensed for
`ampicillin or acetaminophenis dispensed foraspirin.
`
`PURPOSE OF BIOAVAILABILITY STUDIES
`
`Bioavailability studies are performed for both approved active drug ingredients or
`therapeutic moieties not yet approved for marketing by the FDA. Newformulations
`of active drug ingredients or therapeutic moieties must be approvedprior to mar-
`keting by the FDA.In approving a drug product for marketing, the FDA must en-
`sure that the drug productis safe and effective for its labeled indications foruse.
`Moreover, the drug product must meetall applicable standards ofidentity, strength,
`quality, and purity. To ensure that these standards are met,
`the FDA requires
`bioavailability/ pharmacokinetic studies and where necessary bioequivalence stud-
`ies for all drug products.
`For unmarketed drugs which do not have full new drug application (NDA) ap-
`proval by the FDA,in vitroand/orin vivo bioequivalence studies must be performed
`on the drug formulation proposed for marketing as a generic drug product.
`Furthermore, the essential pharmacokinetics ofthe active drug ingredient orther-
`apeutic moiety must be characterized. Essential pharmacokinetic parameters in-
`cluding the rate and extent of systemic absorption, elimination half-life, and rates
`of excretion and metabolism should be establishedafter single- and multiple-dose
`administration. Data from these in vivo bioavailability studies are important to es-
`tablish recommendeddosage regimens and to support drug labeling.
`In vivo bioavailability studies are performed also for new formulations ofactive
`drug ingredients or therapeutic moieties that have full NDA approval andare ap-
`proved for marketing. The purpose ofthese studies is to determine the bioavail-
`ability and to characterize the pharmacokinetics of the new formulation, new
`dosage form, or newsalt or ester relative to a reference formulation.
`After the bioavailability and essential pharmacokinetic parameters of the active
`ingredient or therapeutic moietyare established, dosage regimens may be recom-
`mended in support of drug labeling.
`In summary, clinical studies are useful in determining the safety and efficacy of
`the drug product. Bioavailability studies are used to define the effect of changes
`in the physicochemical properties of the drug substance and the effect of the drug
`product (dosage form) on the pharmacokinetics of the drug. Bioequivalence stud-
`ies are used to compare the bioavailability of the same drug (same salt or ester)
`
`101
`
`101
`
`

`

`——————————————————
`
`250
`
`CHAPTER 10. BIOAVAILABILITY AND BIOEQUIVALENCE
`
`from various drug products. If the drug products are bioequivalent and therapeu-
`tically equivalent (as defined above), then the clinical efficacy and the safety pro-
`file of these drug products are assumed to be similar and may be substituted for
`each other.
`
`RELATIVE AND ABSOLUTE AVAILABILITY
`
`The area underthe drug concentration-time curve (AUC) is used as a measure of
`the total amount ofunaltered drug that reaches the systemic circulation. The AUC
`is dependent on the total quantity of available drug, MD, divided bythe elimina-
`tion rate constant, k, and the apparent volumeofdistribution, Vp. Fis the fraction
`of the dose absorbed. After IV administration, Fis equal to unity, because the en-
`tire dose is placed into the systemic circulation. Therefore, the drug is considered
`to be completelyavailable after IV administration. After oral administration of the
`drug, F mayvary from a value of 0 (no drug absorption) to 1 (complete drug ab-
`sorption).
`
`Relative Availability
`Relative (apparent) availability is the availability of the drug from a drug product
`as comparedto a recognized standard. The fraction of dose systemicallyavailable
`from anoral drug productis difficult to ascertain. The availability of drug in the
`formulation is compared to the availability of drug in a standard dosage formula-
`tion, usually a solution of the pure drug evaluated in a crossover study. The rela-
`tive availability of two drug products given at the same dosage level and by the same
`route of administration can be obtained with the following equation:
`
`: enitie,—AUCIa
`
`Relative availability = ————
`(10.1)
`[AUC],
`
`where drug product B is the recognized reference standard. This fraction may be
`multiplied by 100 to give percent relative availability.
`Whendifferent doses are administered, a correction for the size of the dose is
`made, as in the following equation:
`AUC]
`,/dose A
`Relative availability =TASLafseea
`
`[AUC] p/dose B
`
`Urinary drug excretion data may also be used to measurerelative availability, as
`long as the total amount ofintact drug excreted in the urine is collected. The per-
`cent relative availability using urinary excretion data can be determinedasfollows:
`x
`[Duala
`Percentrelative availability = 1D.Js x 100
`ul B
`where [D,]* is the total amount of drug excreted in the urine.
`
`(10.2)
`
`Absolute Availability
`The absolute availability of drug is the systemic availability of a drug after ex-
`travascular administration (eg, oral, rectal, transdermal, subcutaneous). The ab-
`solute availability of a drug is generallymeasured by comparingthe respectiveAUCs
`
`
`
`102
`
`102
`
`

`

`
`
`BIOAVAILABILITY AND BIOEQUIVALENCE CHAPTER 10. 251
`
`after extravascular and IV administration. This measurement may be performed as
`long as Vp and k are independentof the route of administration. Absolute avail-
`ability after oral drug administration using plasma data can be determined asfol-
`lows:
`
`AUC]po/d
`
`(10.3)
`Absolute availability = AUCIro/dosero _ F
`[AUC]1/dosery
`z
`Absolute availability using urinary drug excretion data can be determined bythe
`following:
`
`F
`
`Dulfo/d
`
`(10.4)
`Absolute availability = LDulPo/dosero
`[Duliv/dosery
`The absolute bioavailability is also equal to F, the fraction of the dose that is
`bioavailable. Absolute availability is sometimes expressed as a percent, ie,= 1, or
`100%. For drugs given intravascularly, such as by IV bolusinjection, F = 1, because
`all the drug is completely absolved.Forall extravascular routes of administration,
`F = 1. Fis usually determined by Equations 10.3 or 10.4.
`
`
`(eZ) PRACTICE PROBLEM
`
`The bioavailability of a new investigational drug was studied in 12 volunteers. Each
`volunteer received either a single oral tablet containing 200 mg of the drug, 5 mL of
`a pure aqueoussolution containing 200 mg of the drug, or a single IV bolus injec-
`tion containing 50 mgof the drug. Plasma samples were obtained periodically up to
`48 hrafter the dose andassayed for drug concentration. The average AUC values (0
`to 48 hr) are given in the table below. From these data, calculate (1) the relative
`bioavailability of the drug from the tablet comparedto the oral solution and (2) the
`absolute bioavailability of the drug from thetablet.
`Drug Product
`Dose (mg)
`AUC(pug hr/mL)
`Oraltablet
`200
`89.5
`Oral solution
`200
`86.1
`IV bolusinjection
`50
`37.8
`Solution
`Therelative bioavailability of the drug from thetablet is estimated using Equation
`10.1. No adjustmentfor dose is necessary.
`ee Saat+Oe
`Relative bioavailability = —— = 1.04
`86.1
`Therelative bioavailability of the drug from thetabletis 1.04, or 104%, compared
`to the solution. In this study, the difference in drug bioavailability between tablet and
`solution was notstatistically significant.
`The absolute drug bioavailability from the tabletis calculated using Equation 10.3
`and adjusting for the dose.
`
`Standard Deviation
`19.7
`18.1
`5.7
`
`103
`
`103
`
`

`

`
`
`PaaSs—._—_._SeeV—_umOOO_
`
`252
`
`CHAPTER 10. BIOAVAILABILITY AND BIOEQUIVALENCE
`
`0.59
`
`F= absolute bioavailability =
`
`89.5/200 _
`37.8/50
`Because F, the fraction of dose absorbed from thetablet, was less than 1, the drug
`was not completely absorbed systemically either due to poor absorption or metabo-
`lism byfirst-pass effect. Therelative bioavailability of the drug from the tablet was ap-
`proximately 100% when comparedto the oral solution. Results from bioequivalence
`studies may showthatthe relative bioavailability of the test oral productto be greater
`than, equal to, or less than 100% compared to the reference oral drug product.
`However, the results from these bioequivalence studies should not be misinterpreted
`to imply that the absolute bioavailability of the drug from the oral drug products is
`also 100% unless the oral formulation was compared to an intravenousinjection of
`the drug.
`
`METHODSFOR ASSESSING BIOAVAILABILITY
`
`Direct and indirect methods maybe used to assess drug bioavailability. The design
`of the bioavailability study dependson the objectives of the study, the ability to an-
`alyze the drug (and metabolites) in biologicalfluids, the pharmacodynamicsofthe
`drug substance, the route of drug administration andthe nature of the drug prod-
`uct. Pharmacokinetic and/or pharmacodynamic parameters as well as clinical ob-
`servations andin vitro studies may be used to determine drug bioavailability from
`a drug product (Table 10.1).
`
`Plasma Drug Concentration
`Measurement of drug concentrations in blood, plasma, or serum after drug ad-
`ministration is the most direct and objective data to determine systemic drug
`bioavailability. By appropriate blood sampling, an accurate description of the
`
`|
`
`| /
`
`TABLE 10.1 Methods for Assessing Bioavailability and Bioequivalence
`Plasma Drug Concentration
`The time for peak plasma (blood) concentration (tax)
`The peak plasma drug concentration (Cmax)
`The area under the plasma drug concentration versus time curve (AUC)
`Urinary Drug Excretion
`The cumulative amount of drug excreted in the urine (D,)
`The rate of drug excretion in the urine (dD,/dt)
`The time for maximum urinary excretion (t)
`Acute Pharmacodynamic Effect
`Maximum pharmacodynamic effect (Ewax)
`Time for maximum pharmacodynamic effect
`Area under the pharmacodynamic effect versus time curve
`Onset time for pharmacodynamic effect
`Clinical Observations
`Well-controlled clinical trials
`In Vitro Studies
`
`Drug dissolution———————
`
`b
`
`|
`
`-
`
`104
`
`104
`
`

`

`
`
`BIOAVAILABILITY AND BIOEQUIVALENCE CHAPTER 10.
`
`253
`
`plasma drug concentration versus time profile of the therapeutically active drug
`substance(s) can be obtained usinga validated drug assay (see Appendix).
`
`Thetime of peak plasma concentration, fax, Corresponds to the time required to
`reach maximum drug concentration after drug administration. At fax, peak drug
`absorption occurs and the rate of drug absorption exactly equals the rate of drug
`elimination (Fig. 10-5). Drug absorptionstill continuesafter fax is reached, butat
`a slower rate. When comparing drug products, 4nax can be used as an approximate
`indication of drug absorption rate. The value for fyax will become smaller (indi-
`cating less time required to reach peak plasma concentration) as the absorption
`rate for the drug becomes more rapid. Units for fyax are units of time (eg, hours,
`minutes).
`
`The peak plasmadrug concentration, Gnax, represents the maximum plasma drug
`concentration obtained after oral administration of drug (Fig. 10-5). For many
`drugs, a relationship is found between the pharmacodynamic drug effect and the
`plasma drug concentration. Cyax provides indications that the drugis sufficiently
`systemically absorbedto provide a therapeutic response. In addition, Gnax provides
`warning of possibly toxic levels of drug. The units of Gnax are concentration units
`(eg, ug/mL, ng/mL).
`
`tmax
`
`AUC
`
`The area underthe plasmalevel-time curve, AUC,is a measurementof the extent
`ofdrugbioavailability. The AUCreflects the total amountofactive drug that reaches
`the systemic circulation. The AUCis the area under the drug plasmalevel-time
`curve from ‘= 0 to ¢= %, and is equal to the amount of unchanged drug reach-
`ing the generalcirculation divided by the clearance.
`[AUC] = i. Codi
`siege = 2D
`clearance
`kVp
`
`(10.5)
`
`(10.6)
`
`where F'= fraction of dose absorbed; Dy = dose; k = elimination rate constant; and
`Vp = volumeof distribution. The AUCis independentof the route of administra-
`tion and processes of drug elimination as long as the elimination processes do not
`change. The AUC can be determined by a numerical integration procedure, such
`as the trapezoidal rule method. The units for AUC are concentration time (eg,
`beg hr/mL).
`For many drugs, the AUCis directly proportional to dose. For example,if a sin-
`gle dose of a drug is increased from 250 to 1000 mg, the AUCwill also show a four-
`fold increase (Figs. 10-1 and 10-2).
`In somecases, the AUCis not directly proportional to the administered dose
`for all dosage levels. For example, as the dosage of drug is increased, oneof the
`pathwaysfor drug elimination may becomesaturated (Fig. 10-3). Drug elimination
`includes the processes of metabolism and excretion. Drug metabolism is an en-
`
`
`
`105
`
`105
`
`

`

`————_,
`
`254—CHAPTER10. BIOAVAILABILITY AND BIOEQUIVALENCE
`
`
`
`
`
`Plasmalevel(11g/ml)
`
`mg, and (C) 1000 mg of drug.
`
`Figure 10-1. Plasma level-time curve following ad-
`ministration of single doses of (A) 250 mg, (B) 500
`
`zyme-dependentprocess. For drugs such as salicylate and phenytoin, continued in-
`crease of the dose causes saturation of one of the enzyme pathways for drug me-
`tabolism and consequentprolongation ofthe elimination half-life. The AUC thus
`increases disproportionally to the increase in dose, because a smaller amount of
`drugis being eliminated (ie, more drugis retained). When the AUCis notdirectly
`proportionalto the dose, bioavailability of the drug is difficult to evaluate because
`drug kinetics may be dose dependent.
`
`Urinary Drug Excretion Data
`Urinary drug excretion data is an indirect method for estimating bioavailability.
`The drug mustbe excretedin significant quantities as unchanged drug in the urine,
`timely urine samples mustbe collected and the total amountof urinary drug ex-
`cretion must be obtained (see Chapter3).
`
`The cumulative amountof drug excreted in the urine, Dj is directly related to the
`total amount of drug absorbed. Experimentally, urine samples are collected peri-
`odically after administration of the drug product. Each urine specimenis analyzed
`for free drug with a specific assay. A graph is constructed relating the cumulative
`drug excreted to thecollection time interval (Figure 10-4B).
`
`Du
`
`Q
`
`:
`3
`5
`‘
`
`0
`
`250
`
`500 750 1000
`Dose (mg)
`Figure 10-2. Linear relationship be-
`tween AUC and dose (data from Fig.
`10-1).
`
`=
`
`z
`5
`Vv3
`:
`
`Dose (mg)
`10-3. Relationship between
`Figure
`AUC and dose when metabolism is sat-
`urable.
`
`L
`
`|
`
`106
`
`106
`
`

`

`BIOAVAILABILITY AND BIOEQUIVALENCE CHAPTER 10.
`
`255
`
`Therelationship between the cumulative amount of drug excreted in the urine
`and the plasmalevel-time curve is shown in Figure 10-4. When the drug is almost
`completely eliminated (point C), the plasma concentration approaches zero and
`the maximum amount of drug excreted in the urine, Dy, is obtained.
`
`dD,,/dt
`
`Because most drugs are eliminatedbya first-order rate process, the rate of drug ex-
`cretion is dependentonthefirst-order elimination rate constant k and the concen-
`tration of drug in the plasmaG,. In Figure 10-4, the maximumrate of drug excretion
`would beat point B, whereas the minimumrate of drug excretion wouldbe at points
`A and C. Thus, a graph comparingthe rate of drug excretion with respect to time
`should besimilar in shape as the plasmalevel-time curve for that drug (Fig. 10-5).
`
`Thetotal time for the drug to be excretedis ¢*. In Figures 10-4 and 10-5,the slope of
`the curve segment A-Bis related to the rate of drug absorption, whereas pointCis
`related to the total time required after drug administration for the drug to be absorbed
`and completely excreted (¢ = ). The ¢® is a useful parameter in bio-equivalence stud-
`ies that compareseveral drug products,as will be describedlater in this chapter.
`
`Acute Pharmacodynamic Effect
`In somecases, the quantitative measurement of a drugis notavailable, orit lacks
`sufficient accuracy and/or reproducibility. An acute pharmacodynamic effect—
`such as an effect on pupil diameter, heart rate, or blood pressure—can be used as
`an index ofdrug bioavailability. In this case, an acute pharmacodynamiceffect-time
`curve is constructed. Measurementsof the pharmacodynamiceffect should be made
`with sufficient frequency to permit a reasonable estimate of the total area under
`
`j
`
`A
`
`=
`.
`=
`
`A
`
`3 |
`3 |
`o
`2
`z=
`
`AB
`
`Time
`
`AB
`
`Cc
`
`Time
`
`B
`=
`ge
`He
`3?
`3-O
`5S
`3
`
`B
`
`=
`oN I
`$8
`25
`o
`“sg
`3
`
`AB
`
`Cc
`
`Time
`
`Figure 10-4. Corresponding plots re-
`lating the plasma level-time curve and
`the cumulative urinary drug excretion.
`
`AB
`
`Time
`
`Figure 10-5. Corresponding plots re-
`lating the plasma level-time curve and
`the rate of urinary drug excretion.
`
`107
`
`107
`
`€
`€
`

`

`SSS
`
`256
`
`CHAPTER 10. BIOAVAILABILITY AND BIOEQUIVALENCE
`
`the curve for a time period at least three timesthe half-life of the drug (Gardner,
`1977).
`The use of an acute pharmacodynamiceffect to determine bioavailability gen-
`erally requires demonstration of a dose-related response. Bioavailability is determined
`by characterization of the dose-response curve. Pharmacodynamic parameters that
`are obtained include the total area underthe acute pharmacodynamiceffect-time
`curve, peak pharmacodynamiceffect, and time for peak pharmacodynamiceffect.
`Onset time and duration of the pharmacokinetic effect may also be included in
`the analysis of the data.
`
`Clinical Observations
`
`Well-controlled clinical trials in humansthatestablish the safety and effectiveness
`of the drug product. Theclinical trials approach is the least accurate, least sensi-
`tive and least reproducible of the general approaches for determining in vivo
`bioavailability. The FDA only considers this approach whenanalytical methods are
`notavailable to permit use of one of the approachesdescribed above. An example
`of this approachis for the determination of the bioequivalence of two topical an-
`tifungal products by different manufacturers containing the same active antifungal
`agent (eg, ketoconazole)
`
`In Vitro Studies
`
`Drug dissolution studies may undercertain conditionsgive an indication of drug
`bioavailability. Ideally, the in vitro drug dissolution rate should correlate with in vivo
`drug bioavailability. Dissolution studies are often performed onseveral test for-
`mulations of the same drug. Thetest formulation that demonstrates the most rapid
`rate of drug dissolution in vitro will generally have the most rapid rate of drug
`bioavailability 7vivo.
`
`BIOEQUIVALENCE STUDIES
`
`For many years, medicalpractitioners have observed either lack of response (ther-
`apeutic failure), good therapeutic response,or toxicity in patients receiving simi-
`lar drug products.
`Differences in the predicted clinical response may be dueto differences in both
`the pharmacokinetic and/or pharmacodynamic behavior of the drug amongindi-
`viduals. Bioequivalent drug products that have the same systemic drug bioavail-
`ability will have the same predictable drug response. However, variable clinical
`responses amongindividuals that are unrelated to bioavailability may be due to dif
`ferences in the pharmacodynamicsof the drug. Differences in pharmacodynamics,
`ie, the relationship between the drug and the receptor site, may be due to differ-
`encesin receptorsensitivity to the drug. Variousfactors affecting pharmacodynamic
`drug behavior mayinclude age, drug tolerance, drug interactions, and unknown
`pathophysiologic factors.
`The bioavailability of a drug may be reproducible amongfasted individuals in
`controlled studies who take the drug on an empty stomach. Whenthe drugis used
`on a daily basis, however, the nature of an individual’s diet may affect the plasma
`drug level due to variable absorption in the presence of food or even a change in
`the metabolic clearance of the drug. Feldman andassociates (1982) reported that
`
`ia
`
`108
`
`108
`
`

`

`BIOAVAILABILITY AND BIOEQUIVALENCE CHAPTER 10.
`
`257
`
`patients on a high-carbohydrate diet have a much longerelimination half-life of
`theophylline, due to the reduced metabolic clearance of the drug (t,/9, 18.1 hr),
`compared to patients on normaldiets (t; 2, 6.76 hr). Previous studies demonstrated
`that the theophylline drug product was completely bioavailable. The higher plasma
`drug concentration resulting from a carbohydrate diet may subject the patient to
`a higher risk of drug intoxication with theophylline. The effect of food on the avail-
`ability of theophylline has been reported by the FDA concerningtherisk of higher
`theophylline plasma concentrations from a 24-hoursustained release drug prod-
`uct taken with food. Although most bioavailability drug studies use fasted volun-
`teers, the diet of patients actually using the drug product mayincrease or decrease
`the bioavailability of the drug (Hendles etal, 1984).
`
`Bases for Determining Bioequivalence
`Bioequivalence is established if the in vivo bioavailability of a test drug product
`(usually the generic product) does notdiffer significantly (ie, statistically insignif-
`icant) in the product's rate and extent of drug absorption, as determined by com-
`parison of measured parameters (eg, concentration of the active drug ingredient
`in the blood, urinary excretion rates, or pharmacodynamic effects), from that of
`the reference material (usually the brand nameproduct). In addition, statistical
`techniques used should beofsufficient sensitivity to detect differences in the rate
`and extent of absorption thatare not attributable to subject variability.
`A drug productthat differs from the reference materialin its rate of absorption,
`butnotin its extent of absorption, may be considered bioavailable if the difference
`in the rate of absorptionis intentional and appropriately reflected in the labeling
`and/orthe rate of absorption is not detrimental to the safety and effectiveness of
`the drug product.
`
`Criteria for Establishing a Bioequivalence Requirement
`Bioequivalence requirements may be imposed by the FDA onthebasis ofthe fol-
`lowing:
`
`1. Evidence from well-controlled clinical trials or controlled observations in pa-
`tients that various drug products do not give comparable therapeutic effects.
`2. Evidence from well-controlled bioequivalence studies that such products are not
`bioequivalent drug products.
`3. Evidence that the drug products exhibit a narrow therapeutic ratio and mini-
`mum effective concentrations in the blood andthatsafe and effective use of the
`drug products requires careful dosage titration and patient monitoring.
`4. Competent medical determination that a lack of bioequivalence would have a
`serious adverse effect on the treatment or prevention of a serious disease or con-
`dition.
`5. Physicochemical evidence of the following:
`a. The active drug ingredient has a low solubility in water (eg,
`5 mg/mL).
`b. The dissolution rate of one or more such products is slow (eg, less than 50%
`in 30 min whentested with a general method specified by the FDA).
`c. The particle size and/or surface area of the active drug ingredientis critical
`in determiningits bioavailability.
`d. Certain structural formsofthe active drug ingredient (eg, polymorphic forms,
`conforms,solvates, complexes, and crystal modifications) dissolve poorly, thus
`affecting absorption.
`
`less than
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`aaaOo,
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`CHAPTER 10. BIOAVAILABILITY AND BIOEQUIVALENCE
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`258
`
`e. Such drug products have a high ratio of excipients to active ingredients (eg,
`greater than 5 to 1).
`f. Specific inactive ingredients (eg, hydrophilic or hydrophobic excipients and
`lubricants) either may be required for absorption ofthe active drug ingredi-
`ent or of therapeutic moiety or may interfere with such absorption,
`6. Pharmacokinetic evidence of the following:
`a. Theactive drug ingredient, therapeutic moiety, or its precursor is absorbed
`in large part in a particular segmentof the GI tract or is absorbed fromalo-
`calizedsite.
`b. The degree of absorptionofthe active drug ingredient, therapeutic moiety,
`orits precursoris poor (eg, less than 50%, ordinarily in comparison to anin-
`travenous dose) even whenit is administered in pure form (eg, in solution),
`c. There is rapid metabolism of the therapeutic moiety in the intestinal wall or
`liver during the absorptionprocess(first-order metabolism), so that the rate
`of absorption is unusually important in the therapeutic effect and/or toxic-
`ity of the drug product.
`The therapeutic moietyis rapidly metabolized or excreted so that rapid dis-
`solution and absorption are required for effectiveness.
`e. The active drug ingredient or therapeutic moiety is unstable in specific por-
`tions of the GI tract and requires special coatings or formulations (eg, buffers,
`enteric coatings, andfilm coatings) to ensure adequate absorption.
`f. The drug product is subject to dose-dependentkinetics in or near the ther-
`apeutic range, and the rate and extent of absorption are important to bio-
`equivalence.
`
`&
`
`Criteria for Waiver of Evidence of
`In Vivo Bioavailability
`For certain drug products, the in vivo bioavailability of the drug product maybe
`self-evident or unimportantto the achievementofthe product's intended purposes.
`The FDA will waive the requirement for submission ofin vivo evidence demon-
`strating the bioavailability of the drug productif the product meets one ofthe fol-
`lowing criteria:
`1. The drug product (a) is a solution intendedsolely for intravenous administra-
`tion and(b) containsan active drug ingredient or therapeutic moiety combined
`with the samesolvent andin the same concentrationas in an intravenous solu-
`tion that is the subject of an approved, full, new drug application.
`The drug productis a topically applied preparation (eg, a cream, ointment, or
`gel intendedfor local therapeutic effect). The FDA has released guidances for
`the performance of bioequivalence studies on topical corticosteroids and anti-
`fungal agents. The FDAis also considering performing dermatopharmacokinetic
`(DPK) studies on othertopical drug products. In addition, in vitro d