`of
`Bas·c
`Pharmacoki etics
`
`
`
`
`
`
`
`. . . including Clinical Applications
`
`by W. A. Ritschel
`
`Ph.D., M.D., Mro Pharm., F.A.S.A., F.C.P.
`
`Professor of Pharmacokinetics
`and Biopharmaceutics
`College of Pharrnacy
`Professor of Pharmacology
`and Cell Biophysics
`College of Medicine
`University of Cincinnati
`Cincinnati 45267
`
`FOURTH EDITION, 1992
`DRUG INTELLIGENCE PUBLICATIONS, INC.
`HAMILTON, IL 62341
`
`AQUESTIVE EXHIBIT 1023 page 0001
`
`
`
`Copyright © 1992 by
`DRUG INTELLIGENCE PUBLICATIONS, IN-C.
`
`1241 Broadway, Hamilton, IL 62341 U.S.A.
`
`All rights, including that of translation, reserved. This book is protected
`
`
`
`
`
`by copyright. No part of this book may be reproduced in any form or by
`
`
`
`any means, including photocopying, or utilized by any information
`
`
`storage and retrieval system without prior written permission from the
`
`copyright owner.
`
`Library of Congress Cataloging-in-Publication Data
`
`
`
`
`
`Ritschel, W. A. (Wolfgang A.)
`Handbook of basic pharmacokinetics-including
`
`
`
`
`clinical applications/by W. A. Ritschel - 4th ed.
`
`Includes bibliographical references and index.
`
`588 p. 10.8 X 18.2 em.
`
`
`
`ISBN 0-914768-50-6 (soft)
`
`1. Pharmacokinetics-Handbooks, manuals, etc. I. Title.
`[DNLM: 1. Biopharmaceutics. 2. Chemistry, Pharmaceutical.
`
`3. Drug Interactions. 4. Kinetics. 5. Pharmacology.
`QV 38 R612h]
`RM301.5.R57 1992
`615'.7-dc20
`DNLM/DLC
`for Library of Congress
`
`91-38402
`CIP
`
`NOTICE
`
`The information in this book has been derived from a wide variety of
`
`
`
`published drug information as well as appropriate unpublished data.
`
`While diligent care has been taken to assure the accuracy of the book's
`
`content when it went to press, neither the author nor the publisher can
`
`
`be responsible for the continued accuracy and completeness of informa
`tion or any consequences therefrom. Ongoing research and new
`
`
`developments in the field should be consulted.
`
`Printed in the United States of America by Hamilton Press, Inc.
`
`Hamilton, Illinois 62341
`
`
`
`Fourth Edition 1992
`
`AQUESTIVE EXHIBIT 1023 page 0002
`
`
`
`36
`
`Bioavai ab ·1ity a d
`ioequivalence
`
`Definitions
`
`i s defined by the United States
`Bioavailability
`Food and Drug Administration ( FDA) as the rate
`
`and extent to which tl1e active drug ingredient or
`therapeutic moiety is absorbed from a drug product
`and becomes available at the site of drug action.
`
`It is unfortunate that this official definition is not
`precise enough.
`First, consider the statement with respect to the
`
`site of drug action. Althougl1, in general, we assume
`that the drug concentration in blood, plasma or
`serum correlates with the pharmacologic response,
`
`it is not applicable to all drugs . Furthermore, the
`
`
`actual bioavailability testing as outlined in the regu
`lation does not attempt to determine the drug con
`centration at the site of drug action but in systemic
`circulation. Exception to it is given when it is not
`
`possible to measure blood levels; then the bioavail
`
`ability test is substituted by a pharmacologic or
`clinical test.
`
`493
`AQUESTIVE EXHIBIT 1023 page 0003
`
`
`
`494
`Secondly, this definition does not explicitly in
`
`
`growing group of prodrugs. As a
`clude the steadily
`
`working hypothesis, we will therefore define bio
`availability as follows: bioavailability is both the
`amount of therapeutic
`moiety in form of a
`relative
`
`parent drug, active metabolite or active moiety
`of a prodrug from an administered dosage form
`wl1ich enters systemic circulation and the rate the
`drug appears in it.
`Contrary to the belief of m any, bioavailability is
`
`
`not a criterion of clinical effectiveness per se.
`Clinical effectiveness is so complex (disease states,
`nutritional status) and the factors influencing ab
`sorption so numerous (food intake/fasting, type
`and amount of food, circadian rhythm, age, etc.)
`that a test in a small sample size of the population
`
`can only be regarded as a biologic quality control
`test under specified conditions .
`A drug product is defined as a finished dosage
`form ; this means a tablet, capsule, solution, sup
`pository, etc. that contains the active dru g in
`
`gredient generally, but not necessarily in associa
`tion witl1 inactive ingredients. One has to imply
`
`that under active drug ingredient also prodrugs are
`meant, although not explicitly stated.
`are defined as drug
`
`
`Pharmaceutical equivalents
`products that contain identical amounts of the
`
`
`identical active drug ingredient, i.e., the same salt
`or ester of the same therapeutic moiety in identical
`dosage form s, but not necessarily containing the
`
`same inactive ingredients, and that meet the identi
`cal compendia! or other applicable standard of iden
`
`tity, strength, quality, and purity, including potency
`and, where applicable, content uniformity, disin
`tegration times and/ or dissolution rates.
`
`AQUESTIVE EXHIBIT 1023 page 0004
`
`
`
`BIOAVAILABILITY 495
`are drug products
`
`Pharmaceutical alternatives
`
`that contain the identical therapeutic moiety or its
`precursor, but not necessarily in the same amount
`or dosage form or as the same salt or ester. Each
`
`drug product individually meets either the identi
`cal or its own respective compendia! or other
`
`applicable standard of identity, strengtl1, quality
`
`and purity, including potency and, where applica
`
`ble, content uniformity, disintegration ti1nes and/ or
`dissolution rates.
`is to demonstrate the
`Whereas bioavailability
`
`amount and rate of drug or active moiety appear
`ing in s ystemic circulation, and has to be deter-·
`mined for any new drug or new drug product,
`bioequivalence is to demonstrate that other drug
`products are comparable with respect to bio
`
`logic performance to an already approved drug
`product.
`A b ioequivalence
`problem may arise when two
`or pharmaor more pharmaceutical equivalents
`
`
`
`ceutical alternatives , which meet all applicable in
`vitro standards when administered at the same
`molar dose of the active therapeutic moiety to the
`
`
`same individuals with tl1e same dosage regimen,
`
`ty. In this result in inequivalent bioavailabili
`
`case,
`
`it could either be that the current in vitro standards
`for the drug products are not adequate to test and
`assure bioequivalence or that the products are not
`
`appropriately labelled according to their different
`
`
`pharmacokinetic bel1avior of the dosage form.
`
`It is in the public interest that all products con
`taining the same active ingredient be interchangea
`able which would require that they are bioequiva
`
`lent or that for special and desired purposes a dif
`
`ferent labelling, easily recognizable, is required to
`tic
`indicate a different phannacokine
`immediately
`
`�
`
`r
`�
`
`r
`::t
`�
`t
`l
`�
`
`,
`
`AQUESTIVE EXHIBIT 1023 page 0005
`
`
`
`496
`profile.
`drug products are defined as
`Bioequivalent
`pharmaceutical equivalents or pharmaceutical
`alternatives whose rate and extent of absorption
`do not show a significant difference when ad
`ministered at the same molar dose of the
`therapeutic moiety, under similar experimental
`conditions, either single dose or multiple dose.
`
`Some pl1armaceutical equivalents or pharmaceu
`tical alternatives may be equivalent in the extent
`of tl1eir absorption but not in their rates and, yet,
`may be considered bioequivalent because such dif
`ferences in the rate of absorption are intentional
`
`and are reflected in the labelling, are not essential
`of effective body dru g concen
`to the attainn1ent
`trations on chronic use, or are considered medically
`insignificant for the particular drug product.
`In order to demonstrate hioequivalence, the Food
`and Drug AdministratioL has imposed bioequiva
`lence requirements
`for in vitro and/or in vivo test
`ing of specified drug products which must be
`satisfied as a condition of marketing.
`
`1
`(
`]
`f
`(
`
`(
`
`1
`1
`j
`
`(
`i
`
`Factors Modifying Bioavailability
`
`In all cases, except when a drug is administered
`intravenously in form of a true solution, the drug
`has to be released from the dosage form and then
`by passing
`be absorbed into systemic circulation
`through various membranes.
`A drug given in different dosage forms or by
`different routes of administration will yield varying
`amounts of drug absorbed and, l1ence, differences
`in onset, intensity, and duration of tl1e pharmaco
`
`logic or clinical effect.
`These variations are primarily due to differences
`
`AQUESTIVE EXHIBIT 1023 page 0006
`
`
`
`BIOAVAILABILITY 497
`
`in the efficiency and rate of absorption which may
`
`originate either with the patient or the dosage form.
`In the first case, we call it a physiologically
`modi.,
`and i11 the second case, a
`fled bioavailability
`dosage form modified bioavailability.
`
`In testing of bioavailability and bioequivalence
`one has to carefully design the study protocol in
`order to exclude physiologically based modifica ..
`These include age, sex,
`tions of bioavailability.
`
`physical state of the patient, time of administration,
`stomach emptying rate, type and amount of food,
`pH and enzyme variations
`in the gastro-intestinal
`
`tract, motility of the gastro-intestinal tract, blood
`
`flow, liver function, kidney function, body weight,
`psychological factors such as stress, etc. It is im
`
`perative that any design must be able to either ex
`
`clude such factors or to allow their proper evalua
`tion. The logical consequence is a true cross-over
`design.
`The bioavailability or bioequivalence problems as
`specified in the new regulation are, therefore, those
`which depend on the physico-chemical characteris
`tics of the drug or the dosage form. These factors
`
`are particle size, polymorphic form, presence of a
`
`solvate or a hydrate, chemical presentation in salt,
`ester, ether, complex, pH of dosage forms, environ
`ment, solubility characteristics, type and amount
`
`of vel1icle substances present, the manufacturing
`method employed for preparing the dosage forms
`sucl1 as type of granulation, change in manufactur
`ing practices , change in blending and mixing prac
`tices, improper drying conditions, high-speed tab
`
`leting, variation in compression force, and insta
`bility.
`
`AQUESTIVE EXHIBIT 1023 page 0007
`
`
`
`498
`Bioavailability of New Drugs
`
`pharmacologists and toxi
`In the past, clinical
`
`
`have paid too little attention to biopl1ar
`cologists
`of new drug products to be
`
`maceutical evaluation
`tested in man during Phase I studies.
`It is well known that the LADMER-system (lib
`eration, absorption, distribution, metabolism,
`elimination, response) applies also to the first ad
`ministration of a new drug to man with all its im
`plications of physicochemical parameters of the
`drug and the product. It is very likely that if one
`would reanalyze under our present understanding
`of biopharmaceutics and pharmacokinetics all
`those drugs which h ave been abandoned during
`the past decades as being ineffective in the first
`clinical trial, one would find quite a number of
`useful drugs .
`The regulation on bioavailability requires that
`any new drug application submitted in the United
`States to the FDA m ust h ave a complete biophar
`
`maceutical and pharmacokinetic evaluation, in
`
`cluding the determination of bioavailability.
`
`Bioequivalence Requirements
`
`According to the regulation, the FDA on its own
`or in the response to a petition by an interested
`person, m ay identify specific pharmaceutical
`equivalents or pharmaceutical alternatives that
`are not or may not be bioequivalent drug products
`and determine whether to propose or promulgate
`regulation to establish a bioequivalent require
`ment for these products.
`
`The criteria and the evidence when bioequiva
`
`l1ave to be established are listed
`lence requirements
`
`AQUESTIVE EXHIBIT 1023 page 0008
`
`
`
`BIOAVAILABILITY 499
`Table 36-1. Criteria and Evidence to Establish a Bioequivalent
`Requirement
`
`1. Difference in therapeutic effects.
`
`
`2. Bioinequivalence
`demonstrated.
`3. LD5o/ED5o<2 or Cmin toxJMEC<2.
`4. If bioinequivalence
`would be of serious consequence.
`<0.5 °/o, or if <50 °/o dissolved
`in 30 min, or �f particle size is
`
`5. If solubility
`
`
`
`critical, or if drug forms polymorphs, solvates, hydrates, complexes of
`
`
`decreased dissolution, or if drug/excipients <1/5, or if ingredients
`
`might interfere with absorption.
`6. If absorption
`site, Q!_ f 1 <0.5, or FPE2, or {33 or km 4 is ex
`from localized
`
`
`
`tremely fast, or if buffers, enteric-or film-coatings are required, or if
`
`
`dose dependent kinetics are in or near therapeutic range.
`
`1fraction of drug absorbed
`
`
`2first-pass effect
`
`3terminal elimination rate constant
`4rate constant of metabolism
`
`in Table 36-1 .
`Inspecting Table 36-1, it is quite obvious that for
`many drugs such a bioequivalent requirement
`exists a priori due to low solubility of the active in
`gredient or the fact that they appear in form of
`polymorphs, in hydrous and anhydrous form, as
`complexes, solvates, etc.
`A bioequivalent requiren1ent may be one or more
`of the following as specified by the FDA, namely,
`an in vivo test in humans, an in vivo test in animals
`other than humans that has been correlated with
`human in vivo data, or in an animal model without
`witl1 human in vivo data, or an in vitro
`correlation
`
`test which either has been correlated with human
`or for which no correlation
`in vivo bioavailability
`has been established. In vivo bioequivalence re
`quirement in man is mandatory, if there is docu
`mented evidence tl1at pl1armaceutical equivalents
`
`or pharmaceutical alternatives do not give compar
`are not bioequivalent, or
`
`able therapeutic effects or
`
`AQUESTIVE EXHIBIT 1023 page 0009
`-1"""!
`
`
`
`500
`Table 36-2. Criteria for Waiver of in vivo Bioavailability
`1. I. V.
`
`
`
`solution, solution, topical product for local effect, drugs not in
`
`
`
`tended for P.O. absorption, inhalation product similar to approved one.
`
`
`2. P.O. (except enteric coated or controlled release) dosage form similar
`to approved one except tor some drugs of the following
`groups:
`
`
`
`
`antiarrhythmics,anticoagulants, anticonvulsants, antihypertensives,
`
`
`antimalarials, antineoplastics, antithyroids, antituberculars, bron
`
`chial dilators, carbonic acid inhibitors, cardiac glycosides,
`
`
`
`
`corticoids, estrogens, hypoglycemics, thyroid supplements, tran
`vitamin K.
`quilizers,
`
`3. Or otherwise waiver is granted.
`
`is less than 2, or the
`wl1ere the ratio of LD50/ED50
`ratio of the minimal toxic concentratio11 to tl1e mini
`is less tl1an 2.
`mal effective concentration
`The new regulation also specifies criteria for
`
`
`waiver of evidence of in vivo bioavailability under
`which are listed in Table 36-2.
`certain conditions
`
`General Guidelines for the Determination
`
`of in vivo Bioavailability
`
`The in vivo bioavailability of a drug product is
`
`
`demonstrated by both the rate and extent of ab
`
`
`sorption of the active ingredient or therapeutic
`
`moiety. In principle there are four possible ap
`
`proaches to measure the bioavailability, namely:
`1. Blood Level Data.
`2. Urinary Excretion Data.
`3. Pharmacologic Data.
`4. Clinical Data.
`Whenever possible blood level studies should be
`
`carried out and are preferable to all other studies.
`If such studies are not feasib le, they can be substi
`
`tuted by urinary excretion studies. Only if neither
`one can be done, particularly if the drug cannot be
`assayed accurately in biological fluid but the phar
`macologic response can be measured, a pharmaco-
`
`AQUESTIVE EXHIBIT 1023 page 0010
`
`
`
`BIOAVAILABILITY 501
`logic method can be used to substitute for blood
`level or urinary excretion studies. In the case where
`it is difficult or impossible to quantify a given phar
`n1acologic response, clinical studies in patients are
`permissible
`to substitute
`for a blood level or urinary
`excretion
`study.
`The latter approach can also be used for dosage
`forms intended to deliver the therapeutic moiety
`locally sucl1 as, for topical preparations for tl1e skin,
`
`ear, eye, mucous membrane, oral dosage forn1s not
`
`intended to be absorbed, and also for broncllodi
`
`
`lators ad1ninistered by inhalation. Although clearly
`specified in tl1e law, this specific reference seems
`
`of bioavailto be in contradiction to the definition
`
`ability. However, it means that controlled clinical
`studies may be submitted if low systemic absorp
`tion is expected and the bioavailability is substi
`
`tuted by a local availability test where the drug ap
`parently does not enter systemic circulation.
`
`
`
`Selection of a Standard for Bioavailability Testing
`
`
`
`
`
`The previous practice that the inventor's product
`
`
`
`is considered as the standard has been abandoned.
`it might
`
`Tl1e change is legitimate because otherwise
`
`hinder progress. In general, an aqueous true solu
`tion of the drug, an aqueous solubilized system of
`the drug, or an aqueous suspension of the micro
`
`nized drug will, for most instances, be considered
`
`as the standard. However, no strict regulation can
`be applied since there are drugs which are absorbed
`
`solely from the duodenum. In that case, the transi
`
`tion time through the duodenum migl1t be too short
`for the drug to be quantitatively absorbed.
`The selection of the standard for the various
`
`categories of bioavailability testing depends on the
`
`AQUESTIVE EXHIBIT 1023 page 0011
`
`
`
`.,...
`
`502
`
`Table 36-3. Selection of Standard
`
`CATEGORY
`
`PARAMETERS
`TOBE
`DETERMINED
`
`STANDARD
`
`ROUTE OF
`ADMINISTRATION
`FOR STANDARD
`
`New drug in any Extent and rate
`Solution or suspen-Same as drug
`drug product
`of absorption: sion of drug in
`product unless
`
`elimination half-life,
`single dose study drug is poorly
`rate of metabolism
`absorbed. In the
`and/or excretion;
`latter case addi-
`dose proportionality
`tional I.V. route
`after single and
`multiple dosing
`
`New formulation Extent and rate of Current batch of ap- Same as drug
`
`absorption; pharma-proved drug product product
`of marketed
`product
`on the market in
`cokinetic param-
`eters of new formu- single dose study
`
`I at ion
`
`Extent and rate of Solution or suspen-Same as drug
`Controlled
`phar-sion of drug and/or product
`release formula-bioavailability:
`tion
`macokinetic perfor-currently marketed
`mance of dosage non-controlled re-
`lease and/or con-
`form
`
`trolled release prod-
`uct in single and
`multiple dosing
`study
`
`Combination drug Rate and extent of Two or more single-Same as drug
`product
`absorption of one, ingredient drug
`product
`more or all active products in single
`drugs
`dose study
`
`Any drug product Pharmacologic ef- Placebo in single or Same as drug
`when drug con- feet or clinical multiple dose study product
`centration is not response
`determined in
`biological fluid
`
`type of drug product and the questions to be an-·
`swered. It can be broken down into the following
`, namely: bioavailability testing for a new
`categories
`drug in any new drug product, for any new formu
`
`lation of a known and marketed product, for a con
`
`trolled release formulation, for a combination ·drug,
`product containing two or more drugs, and for any
`drug product when the drug concentration cannot
`
`be determined in biological fluid. The parameters
`to be determined in each of these categories, the
`
`AQUESTIVE EXHIBIT 1023 page 0012
`
`
`
`BIOAVAILABILITY 503
`Table 36-4. Possible Methods
`to Assess Bioavailability
`
`SEQUENCE OF
`EVENTS UPON
`ADMINISTRATION OF
`
`A DRUG PRODUCT
`
`METHOD OF EVALUATION
`
`EXAMPLE
`
`
`Drug liberation
`
`and dissolution at
`
`administration or
`
`absorption site
`
`Dissolution rate
`
`In vitro:
`water, buffer,
`
`artificial gastric
`fluid, artificial
`
`intestinal fluid,
`artificial saliva,
`
`artificial rectal
`fluid
`
`(1) Blood level-time
`
`Free drug in
`In vivo:
`profile
`systemic
`whole blood,
`
`(2) Peak blood level
`circulation
`plasma, serum
`(3) Time to reach peak
`
`(4) Area under blood level
`time curve
`
`Pharmacologic
`effect
`(2) Duration of effect
`
`
`(3) Intensity of effect
`
`(1) Onset of effect
`
`In vivo:
`discriminate
`
`measurement of
`
`pharmacologic ef
`fect (blood
`
`pressure, blood
`sugar, blood
`
`coagulation time)
`
`Clinical
`
`response (1) Controlled
`
`clinical blind In vivo:
`
`or double blind study evaluation of
`
`reponses (2) Observed clinical success clinical
`
`
`or failure
`
`Elimination
`
`(1) Cumulative
`
`In vivo:
`amount of
`urine
`drug excreted
`
`(2) Maximum excretion rate
`(3) Peak time of excretion
`
`standards and route of administration to be used
`are listed in T able 36-3. FDA should be consulted
`prior to applying the standard to any study.
`In Vitro - In Vivo Methods for
`
`Bioavailability Testing
`Possible methods to access bioavailability include
`determination of the drug liberation and dissolution
`at the administration or absorption site, determina
`tion of the free drug in systemic circulation, mea-
`
`AQUESTIVE EXHIBIT 1023 page 0013
`
`
`
`504
`suring the pharmacologic effect or clinical response,
`
`
`
`or to determine the urinary excretion of the drug.
`The methods of evaluation and examples are
`listed in Table 36-4.
`Regardin g the question whether or not
`bioavailability may be measured by some in vitro
`methods, a personal remark should be voiced. In a
`true meaning and sense of bioavailability, no in
`vitro method can be substituted for a biologic test.
`An in vitro bioavailability is a contradiction per se.
`However, in vitro methods are necessary to
`simulate and understand physicochemical pro
`cesses of absorption, in dosage form development,
`and as in vitro quality control tests to guarantee
`batch-to-batch consistency.
`determined Since bioavailability is most precisely
`
`
`from either blood level or urinary excretion data,
`we will discuss the scientific aspects of bioavaila
`bility testing based on blood sampling or urine
`sampling studies only.
`
`Types of Bioavailability
`From a scientific point of vie\1;, we distinguish
`
`between four different types of bioavailability,
`depending on the purpose of the study and the
`scientific question to be solved. If new drugs are
`to be studied probably all four types should be ap
`
`plied, whereas for existing approved drugs only the
`third or fourth type will be necessary, if a test for
`
`bioequivalence is required.
`
`Absolute Bioavailability or Fraction of Drug Absorbed f
`
`
`
`
`The principle of determining the absolute
`bioavailability is shown in Figure 36-1.
`The fraction of drug absorbed fallows determina-
`
`AQUESTIVE EXHIBIT 1023 page 0014
`
`
`
`BIOAVAILABILITY 505
`
`ABSOLUTE BIOAVABILITY
`
`� ../'
`r ,.
`e
`
`t
`
`z 0 -1-<t a: t-z w {) z 0 {)
`
`TIME
`
`Figure 36-1. Schematic diagram to determine absolute bioavailability
`the areas under the curve upon I. V. and E. V. administration
`
`from
`
`of identical dose
`
`sizes.
`
`tion of the absolute amount of drug absorbed from
`an extravascularly administered drug product. It
`is, therefore, essential that the drug be also ad
`ministered intravenously. However, it is not re
`quired to give the same dose I.V. as is administered
`extravascularly. For a valid study, both the intra
`venously and extravascularly administered drug
`must be given to the same subjects in a cross-over
`design. The fraction of drug absorbed f is the ratio
`
`of the total area under the blood level-time curv e
`upon extravascular route of administration to the
`total area under the blood level-time curve upon
`intravenous admii1istration, corrected for the dif
`tl1e dose size as given in Equation 36.1:
`ference in
`
`AQUESTIVE EXHIBIT 1023 page 0015
`
`
`
`>
`
`506
`
`f
`
`f =
`
`• h] • DI.V. [mg]
`AUCeox�a�ascular [(mg/ml)
`A UC�� 00 [ ( mg/ml) • h] • Dextra vascular [mg]
`Eq. 36.1
`Since the elimination rate constants m ay vary
`inter-and intra-individually for the same drug and
`upon different routes of administration, correction
`for the observed terminal elimination rate con
`stant data and also for the individual body weight
`should be made as shown in Equation 36.2:
`·
`Dr.v. [ mg]
`o� oo
`AUCextravascular [(mg/ml) • h] • _B_W_I.V-.-(-kg_]_•_{3_I.V-.-[h---1J
`f= -----------------------------------------
`[ mg]
`AUC��tlO[ (mg/ml )•h]· Dextra vase.
`_,
`BWextravasc
`. [kg] • f3extravasc.
`[h J
`Eq. 36.2
`
`If instead of blood level, urinary excretion data
`are used, the fraction of drug absorbed f is deter·
`
`mined from the ratio of the total amount of un
`changed drug excreted into urine upon extravascu
`lar administration to that upon intravenous ad
`ministration, corrected for the dose size as shown
`
`in Equation 36. 3:
`
`f = Ae�travascular [mg] • DI.V. [mg]
`Ae�. [mg] • Dextravasc
`ular [mg]
`
`Eq. 36.3
`
`
`
`Bioavailability in Presence of First-Pass Effect
`
`
`
`may result in
`Drugs showing a first-pass effect
`considerable lower blood level versus time curves
`
`AQUESTIVE EXHIBIT 1023 page 0016
`
`
`
`BIOAVAILABILITY 507
`even though all of the parent drug was absorbed
`from the site of administration, yet did not reacl1
`systemic circulation
`in unchanged form. A drug
`given I.V., I . M., S.C. or orally will eventually pass
`through the liver, too. However, it is first distrib
`uted in systemic circulation and probably, at least
`in part, throughout the volume .of distribution
`be
`liver. At any ·given time
`fore being exposed to the
`about 80 percent of the blood volume is metaboli
`cally inactive.
`
`The fraction of a peroral (P.O.), or in part rectal,
`dose reacl1ing systemic circulation fFPE, under the
`
`
`assumption of otherwise linear kinetics, can be de
`scribed by Equation 36.4:
`.
`fFPE = DI.v. [mgl • AUc�:-;;oo [(mg/ml) • h]
`36.4
`E
`DP.o. [mg] • A Cr.v. [ ( mg/ml) • h]
`U 0�00
`Q
`Under the assumption that only first-pass effect
`
`is involved and the drug is completely absorbed
`to specifically describe the fraction of a peroral or
`fFPE, Equa
`
`rectal dose reaching systemic circulation
`
`tion 36.5 can be used where fm is the fraction of
`drug metabolized in the liver. LBF is the liver
`blood flow rate, and A is the ratio of the concentra
`tion of the drug in whole blood to that in plasma.
`D I. v. • fm
`E 36
`q. ·
`-
`5
`1
`FPE ==
`f
`LBF • AUCo;oo • 60 • A
`I.' .
`If the numeric value of fFPE according to Equa-
`tion 36.4 is less than that obtained with Equation
`36.5 then either absorption is incomplete or FPE
`can be assumed. If the numeric value of fFPE ob
`tained with Equation 36.4 is greater than that ob
`tained with Equation 36.5 it can be assumed that
`the drug concentration in the portal vein upon
`P. 0. dosing is high enough to saturate the drug
`
`AQUESTIVE EXHIBIT 1023 page 0017
`
`
`
`p
`
`508
`metabolizing enzyme systems.
`It is possible to predict the fraction of drug reach
`ing systemic circulation upon P.O. dosing from I.V.
`
`data. In this case one determines the total area
`under tl1e curve upon the I.V. administration and
`calculates the fFPE according to Equation 36.6,
`knowing the dose administered I.V. and assuming
`a liver blood flow of 1.53 ( I· min-1 ):
`D
`LV.
`1
`f
`FPE ==
`-
`LBF • AUC0� 00 • 60
`I.V.
`
`For differentiation between incomplete absorp
`Chapter 13.
`
`tion and first-pass effect see
`
`
`Relative Bioavailability EBA and RBA,
`and Bioequivalence
`The principle for determination of relative
`is shown in Figure 36-2.
`bioavailability
`RELATIVE BIOAVAILABILITY
`OR BIOEQUIVALENCE
`
`Eq. 36.6
`
`�dard
`
`z 0 -.... � a: ....
`z UJ u z 0 u
`
`Cma
`1 C"ft:Jaz. Test
`I /\ �
`[ I " ,r\
`I I
`r...\
`I I
`I
`'�)'\
`I I
`' "
`I
`,,
`'-'t--.. ""�
`I
`I
`�
`I� 1. 1.�
`�
`
`tmax
`i i
`TIME
`Figure 36-2. Schematic diagram to determine relative bioavailability from
`
`
`
`
`
`
`the areas under the curve from two different drug products given E. V. by the
`
`
`same route of administration in identical dose sizes.
`
`AQUESTIVE EXHIBIT 1023 page 0018
`
`
`
`BIOAVAILABILITY 509
`The relative bioavailability is the extent EBA
`and rate RBA of the bioavailability of a drug from
`two or more different dosage forms given by the
`sam e route of administration. According to the
`new FDA regulation the standard used in this pro
`cedure is either an approved marketed drug pro
`duct, or a solution of the drug, or suspension
`of the
`micronized drug.
`n of EBA and RBA either blood
`
`For determinatio
`data upon single or multi
`level or urinary excretion
`ple dosing can be used. For valid studies a cross
`over design has to be used, w hereby differences
`in clearance and/ or tern1inal
`disposition rate con
`
`stants should cancel out. For a single dose blood
`level study EBA is calculated according to Equa
`tion 36.7 where the indices tdp and sdp mean "test
`drug product" and "standard drug product," re
`spectively.
`AUC�_:p� [(mg/ml) • h] • Ds.d.p. [mg] • lOO
`EBA = -----------------------------
`AUC�_:.: [(mg/ml) • h] • Dt.ct.p. [mg] Eq. 36.7
`
`In case of multiple dosing EBA can be deter
`mined from the blood level-time curve w ithin a
`complete dosing interval T at steady state using
`Equation 36.8:
`
`Tn�T n+l
`EBA =AUC�.,1n l(mg/ml)•hl•D.ctp_[rng]
`•lOO
`Tn� 7 n+l
`AUCs.d.p. [ ( mg/ml )•h]•Dt.d.p.
`[mg]
`Eq. 36.8
`In tl1e case of urinary excretion data, the total
`amount of unchanged drug excreted into urine upon
`single dose administration is used applying Equa
`tion 36.9 to determine EBA:
`
`AQUESTIVE EXHIBIT 1023 page 0019
`
`
`
`510
`Aeoo t.d.p. [ mg] • D s.d.p. [mg]
`EBA = -----------
`· 100 Eq. 36.9
`Ae00 s.d.p. [ mg] • Dt.d.p. [mg]
`In the case a urinary excretion is carried out up011
`multiple dosing Equation 36.10 is applicable:
`
`EBA =
`
`.dn.�p.T n+l [mg] • Ds.d.p. [mg]
`AetT
`• 100 Eq. 36.10
`Tn�T n+l
`Ae s.ct.p. [ mg] • Dt.ct.p. [mg]
`
`Bioequivalence is given if there is no significant
`
`
`difference in extent and rate of relative bioavail
`ability of a test product when compared to the ap
`proved standard.
`
`EBA ret opt.
`Relative Optimal Bioavailability
`The term relative optimal bioavailability
`
`has been
`suggested in 1970 for optimizing extent and rate of
`
`bioavailability for a drug product during the de
`velopment phase. For determination of EBA ret opt.
`the active drug is administered in aqueous solution
`without addition of any further excipient by the
`same route which is intended for the drug product
`under development. In the case the drug is not
`water soluble an aqueous-organic solvent, such as,
`
`
`glycerol, propylene glycol, alcohol, or polyetl1ylene
`glycol-water mixture is used. Tl1e total AUC and the
`absorption rate constant ka are determined from
`blood level-time data.
`The EBAopt. r<>L is termed optimal because the first
`step in the sequence of events responsible for bio
`
`availability, tl1e drug liberation, is omitted since
`the drug is already in aqueous solution, hence, in
`
`absorbable optimal form. However, it is relative,
`
`AQUESTIVE EXHIBIT 1023 page 0020
`
`
`
`BIOAVAILABILITY 511
`
`because the bioavailability might be further in
`creased by the addition of buffers to either prevent
`decomposition or inactivation, or to increase the
`
`nonionized moiety, or by addition of sorption pro
`
`moting agents. It is further relatively optimal, be
`cause the assumption that a drug in aqueous solu
`
`tion is always "better'' absorbed may not be valid
`in all cases. It is well known that if a drug is ab
`sorbed exclusively from the duodenum the transit
`time of the drug in solution might be too short to
`permit complete absorption.
`
`The absorption rate constant obtained with the
`
`solution is termed "true" rate constant for this par
`
`ticular route of administration, whereas the rate
`
`constant for absorption obtained with the drug
`product will only be an apparent one which is
`overlapped by the process of drug liberation and
`
`dissolution. If one determines the blood level-time
`profiles and absorption rate constants upon ad
`
`ministration of the drug in solution, drug in powder
`
`form filled into gelatin capsules, then of the drug
`in powder form with the addition of the anticipated
`excipients filled into gelatin capsules, followed by
`administration of the granules filled into gelatin
`capsules, and finally of the tablet, or any other
`dosage form, it is possible to pinpoint whether a
`ty problem may be associated with the
`bioavailabili
`drug, the excipients, or the manufacturing method.
`The EBAreLopt.
`is detern1ined according to Equa
`tion 36.11:
`uco�co
`A (drug; + vehicle; granules; tablet)
`
`
`
`• 100
`- - - -
`EBArel.opt. = --- -o-�-00- --
`--
`AUC (solution)
`Eq. 36.11
`
`The method of optimal relative bioavailability
`
`will definitely be determined in animal models and
`
`AQUESTIVE EXHIBIT 1023 page 0021
`
`
`
`512
`not in man. It constitutes a useful tool in drug prod ...
`uct developn1ent.
`For determination of area under the concentra
`tion-time curve see Chapter 20.
`
`
`Determination of Rate of Bioavailability RBA
`The rate of bioa