Michael E. Winter, Pharm.D.
`Professor of Clinical Pharmacy
`School of Pharmacy
`University of California, San Francisco
`and
`Director
`Clinical Pharmacokinetics Consultation Service
`
`Applied Therapeutics, Inc.
`Vancouver, WA
`
`IPRZO17-00011 SHIRE EX2053, p. 1
`
`Basic Clinical
`
`Pharmacokinetics
`
`University of California Hospitais and Clinics
`San Francisco, Caiifornia
`
`Edited b y:
`Mary Anne Koda-Kimble, Pharm.D.
`Profeaior of Ciinicai Pharmacy
`Chairwoman, Division of Clinical Pharmacy
`School of Pharmacy
`,
`University of Cafifornia
`San Francisco, California
`
`IPR2017-00011 SHIRE EX2053, p. 1
`
`
`Professor of Clinical Pharmacy
`School of Pharmacy
`University of California, San Francisco
`and
`Director
`Clinical Pharmacokinetics Consultation Service
`
`Applied Therapeutics, Inc.
`Vancouver, WA
`
`IPRZO17-00011 SHIRE EX2053, p. 1
`
`Basic Clinical
`
`Pharmacokinetics
`
`University of California Hospitais and Clinics
`San Francisco, Caiifornia
`
`Edited b y:
`Mary Anne Koda-Kimble, Pharm.D.
`Profeaior of Ciinicai Pharmacy
`Chairwoman, Division of Clinical Pharmacy
`School of Pharmacy
`,
`University of Cafifornia
`San Francisco, California
`
`IPR2017-00011 SHIRE EX2053, p. 1
`
`
`
`Applied Therapeutics, Inc.
`Post Office Box 5077
`
`Vancouver, Washington 98668-5077
`(206) 253-7123
`
`© Copyright 1994 by Applied Therapeutics, Inc.
`Printed in the United States of America
`
`All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or
`transmitted, in any form or by any means, electronic, mechanical, photocopying, recording,
`or otherwise now known or by any future method without prior written permission from the
`
`
`
`
`
`
`pubfisher.
` Library of Congress Catalog Card Number 94-70212
`
`
`
`ISBN 0—915486-22-9
`
` First Printing, July 1994
`Second Printing, August 1994
`
` IPRZO17-00011 SHIRE EX2053, p. 2
`
`
`
`IPR2017-00011 SHIRE EX2053, p. 2
`
`
`
` iiioovoilobiliiy (F)
`
`
`
`Definition
`
`Bioavailability is the percentage or fraction of the administered dose
`which reaches the systemic circulation of the patient. Examples of factors
`which can alter bioavailability include: the inherent dissolution and ab-
`sorption characteristics of the administered chemical form (e.g., salt, es-
`ter), the dosage form (e.g., tablet, capsule), the route of administration,
`the stability of the active ingredient in the gastrointestinal tract, and, the
`extent of dlug metabolism before reaching the systemic circulation. Drugs
`can be metabolized by gastrointestinal bacteria, by the gastrointestinal
`mucosa, and by the liver before reaching the systemic circulation.
`
`To calculate the amount of drug absorbed, the administered dose
`should be multiplied by a bioavailability factor, which is usually repre-
`sented by the letter "F." For example, the bioavailability of digoxin (Lan-
`oxin) is estimated to be 0.7 for orally administered tablets.” This means
`that if 250 ug (0.25 mg) of digoxin is given orally, the effective or absorbed
`dose can be calculated by multiplying the administered dose by F:
`
`
`
`= (0.7)(250 pg)
`
`= 175 pg
`
`
`
`It should be emphasized that this factor does not take into consider-
`ation the rate of drug absorption; it only estimates the extent of absorption.
`Although the rate of absorption can be important when rapid onset of
`pharmacological effects is required, it is not usually important when a
`drug is administered chronically. The rate of absorption is important only
`when it is so slow that it limits the absolute bioavailability of the drug, or
`when it is so rapid that too much drug is absorbed. The former occasion-
`ally occurs with some sustained—release preparations.“
`J
`
`Dosage Form
`
`As noted earlier, bioavailability can vary among different formula-
`tions and dosage forms of a drug. For example, digoxin elixir has a bio-
`
`
`IPRZO17-00011 SHIRE EX2053, p. 3
`
`_ 2
`
`
`
`IPR2017-00011 SHIRE EX2053, p. 3
`
`
`
`
`
`
`
`Biaavailability
`
`availability of approximately 77% (F = 0.77) While the soft gelatin cap—
`sules have a bioavailability of 100% (F = 1.0). This is in contrast to the
`tablets which have a bioavailability of 70% (F 2 0.7).2'5'5 When drugs are
`administered parenterally, the bioavailability is usually considered to be
`100% (F = 1.0). By rearranging Equation 1, this principle can be used to
`calculate equivalent doses of a drug when a patient is to receive a different
`
`dosage form of the same drug.
`
`For example, if a patient who has been receiving digoxin 250 ug
`(0.25 mg) in the tablet dosage form, needs to receive digoxin elixir instead,
`an equivalent dose of the elixir would be calculated as follows:
`
`
`
`we;‘»:¥.~§r..<«zn2m.2‘a<.$'_>¢-“.-'>-“-"4‘-‘="-‘4.-'.
`
`175
`Dose of Elixir = —-——0-7:3
`
`z 227 pg
`
`If the soft gelatin capsules of digoxin were to be administered, the
`bioavailability or F of the new dosage form would have been 1.0 and the
`equivalent dose would have been 175 pig.
`
`The bioavailabiiity of parenterally—administered drugs usually is con-
`sidered to be 1.0. Drugs which are administered as inactive precursors
`that must then be converted to an active product are an exception to this
`rule. If some of the inactive precursor is excreted or eliminated from the
`
`body before it can be converted to the active compound, the bioavailability
`will be <1.D. For example, parenteral chlorarnphenicol is given as the
`succinate ester, and this chlorarnphenicol ester must be hydrolyzed to the
`
`active compound. The bioavailability of the parenterally—administered
`chloramphenicol succinate ranges from 55% to 95%, because from 5% to
`45% of the chloramphenicol ester is eliminated renally before it can be
`converted to the active compound.7
`IPR2017-00011 SHIRE EX2053,3p. 4
`
`
`
`
`
`IPR2017-00011 SHIRE EX2053, p. 4
`
`
`
`
`
`
`
`Bioavaiiability
`
`Chemical Form (8)
`The chemical form of a drug must also be considered when evaluating
`bioavailability. For example, when a salt or ester of a drug is administered,
`the bioavailability factor (F) should be multiplied by the fraction of the
`total molecular weight which the active drug represents. If ”S" represents
`the fraction of the administered dose w ‘ch is the active drug, then the
`amount of drug absorbed from a salt or ester form can be calculated as
`follows:
`
`
`
`
`
`an excellent example of this principle. (See Figure
`Arninophylline is
`lenediarnine salt of the pharrnacologically—
`1.) Aminophylline is the ethy
`o eighty—five percent (by weight) of
`active moiety, theophylline. Eighty t
`this salt is theophylline, so that the "S" for aminophylline is approxi-
`mately 0.8. Uncoated aminophylline tablets are considered to be com-
`pletely (100%) bioavailable; the bioavailability factor (F) for this dosage
`form is, therefore, 1.0. It is important to consider the salt form in deter-
`mining the amount of theophylline absorbed from an ainjnophylline tab-
`
`4
`
`IPRZO17-00011 SHIRE EX2053, p. 5
`
`The "S” factor should be included in all bioavailability equations as
`a constant reminder of its importance in assessing bioavailabiiity of the
`active drug form. When a drug is administered in its parent or active form,
`the ”S" for that drug is 1.0.
`Equation 2 can now be expanded to consider the salt factor as weli as
`the bioavailability when calculating the dose of a new dosage form:
`
`
`
`IPR2017-00011 SHIRE EX2053, p. 5
`
`
`
`Bioavailability
`
`
`
`
`
`
`let. When Equation 3 islapplied to this situation, it can be demonstrated
`that 160 mg of theophylline is absorbed from a 200 mg aminophylline
`tablet:
`
`_
`Amount of Drug; Absorbed or
`Reaching the Systemic Circulation " (S_)(F)(D0Se)
`= (0.8)(1.0)(200 mg Aminophyiljne)
`
`= 160 mg Theophyiiine
`
`
`
`First-Pass Effect
`
`
`
`
`
`
`
`Since drugs are absorbed from the gastrointestinal tract into the portal
`circulation, some drugs may be extensively metabolized in the liver before
`reaching the systemic circulation. This “first—pass effect” can substantially
`decrease the amount of active drug reaching the systemic circulation and
`thus, its bioavailability. (See Figure 2.)
`
`Lidocaine is an example of a drug with a first—pass effect that is so
`great that oral administration is not practical}; In the case of propranolol
`
`
`
`
`
`
`7
`T
`Eihyienediamlne
`
`
`
`
`
`
`
`
`
`200 mg Aminophylline
`
`(Ethylenediarnine Salt
`
`of Theophylline)
`
`30°/o Theophyliine
`
`
`
`
`
`
`Figure 1. The Effect of the Chernicai—Drug Farm on Bioavcrilabillty.
`The example above emphasizes the importance of considering the
`
`chemlcai form administered when calculating the amount of active
`
`drug actually administered. The amount of active drug administered
`
`may represent only a fraction of the salt, ester. or other chemical form
`of the drug contained in formulation. The bioavaiiabllity of the dosage
`form itself must also be considered when drugs are administered by the
`oral route.
`
`
`
`IPRZO17-00011 SHIRE EX2053, p. 6
`
`5 _
`
`IPR2017-00011 SHIRE EX2053, p. 6
`
`
`
`
`
`Bioavailabiiity
`
`.
`
`40 mg
`
`Oratiy
`Administered
`
`Drug
`
`
`
`
`
`intravenous
`Administration
`
`‘
`
`E
`
`;
`1
`
`'
`
`-
`
`
`Figure 2. First-Pass Effect. When drugs with a high “first-pass effect"
`are administered orally. a large amount of the absorbed drug is metab-
`olized before it reaches the systemic circuiation. if the drug is adminis-
`tered intravenously, the iiver is bypassed and the fraction of the admin-
`istered dose that reaches the circulation is increased. Parenteral doses
`of drugs with a “high first-pass” are much smaller than oral doses which
`produce equivalent pharmacoiogic effects.
`
`
`
`»
`'
`
`
`
`
`
`(inderal), a significant portion of the orally administered dose is metab-
`olized through a first-pass effect; therefore, a much larger oral dose is
`required to achieve the same pharmacologic response as that obtained
`from a dose administered intravenously. However, the propranolol issue
`is further complicated by the fact that one of the metabolites, 4—hydroxy-
`propranoloi, is pharmacologically active.9
`
`
`
` —6
`IPRZO17-00011 SHIRE EX2053, p. 7
`
`IPR2017-00011 SHIRE EX2053, p. 7
`
`
`
` dmirnistroltion Rate (RA)
`
`
`The administration rate is the average rate at which absorbed drug
`reaches the systemic circulation. This is usually calculated by dividing the
`amount of drug absorbed (see Equation 3) by the time over which the '
`drug was administered (dosing interval). The dosing interval is usually
`represented by the symbol, tau (T).
`
`
`
`
`
`
`
`
`
`
`
`
`
`When drugs are administered as a continuous infusion, the dosing
`interval can be expressed in any convenient time unit. For example, the
`theophylline adntinisi-ration rate resulting from amjnophyfline infused at
`a rate of '75 mg/hr is calculated from Equation 5 as follows:
`
`RA
`
`2 <s)(F)<Dose)
`T
`
`_ (o.3)(1.o)(75 mg)
`" '
`1 hr
`
`60 mg/hr
`
`(o.s)(1.0)(75 mg)
`60 min
`
`[1
`
`1 mg/min
`
`IPRZO17-00011 SHIRE EX2053, p. 8
`7 j
`
`
`
`IPR2017-00011 SHIRE EX2053, p. 8
`
`
`
`
`
`
`
`
`
`Rate of Administration
`
`When drugs are administered at fixed dosing intervals, the calculatedfl
`admiriistrafion rate is an average value. For example, the average admin-
`istration rate of theophylline in mg/hr resulting from an oral dose of 300
`mg aminophylline given every six hours would be calculated using Equa-
`tion 5 as follows:
`
`RA
`
`= (S)(F)(D0se)
`T
`
`_ (o.s)(1.o)(3oo mg)
`’
`6 hr
`
`= 40 mg/hr
`
`
`
`
`
`
`
`IPRZO17-00011 SHIRE EX2053, p. 9
`
`
`
`IPR2017-00011 SHIRE EX2053, p. 9
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