a·dboo
`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
`
`
`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.
`
`588 p. 10.8 X 18.2 em.
`
`
`Includes bibliographical references and index.
`
`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`published drug information as well as appropriate unpublished data.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
`
`is 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 many, 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 forms, 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 bioequivalence
`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 drug 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 have 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 have 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.
`Regarding 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] • Ds.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 bioavailability is actuall
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
