Basic Clinical
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`Pharmacokinetics
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`Michael E. Winter, Pharm.D.
`Professor of Clinical Pharmacy
`School of Pharmacy
`University of California, San Francisco
`and
`Director
`Clinical Pharmacokinefics Consultation Service
`University of California Hospitals and Clinics
`San Francisco, California
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`Edifed b y:
`Mary Anne Koda-Kimble, PharmD.
`Professor of Cfiinical Pharmacy
`Chairwoman, Division of Clinical Pharmacy
`School of Pharmacy
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`University of California
`San Francisco, California
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`Applied Therapeutics, Inc.
`Vancouver, WA
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`Page 1
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`SHIRE EX. 2029
`KVK v. SHIRE
`IPR2018-00293
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`Pharmacokinetics
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`Michael E. Winter, Pharm.D.
`Professor of Clinical Pharmacy
`School of Pharmacy
`University of California, San Francisco
`and
`Director
`Clinical Pharmacokinefics Consultation Service
`University of California Hospitals and Clinics
`San Francisco, California
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`Edifed b y:
`Mary Anne Koda-Kimble, PharmD.
`Professor of Cfiinical Pharmacy
`Chairwoman, Division of Clinical Pharmacy
`School of Pharmacy
`,
`University of California
`San Francisco, California
`
`Applied Therapeutics, Inc.
`Vancouver, WA
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`Page 1
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`SHIRE EX. 2029
`KVK v. SHIRE
`IPR2018-00293
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`Applied Therapeutics, Inc.
`Post Office Box 5077
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`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 irom the
`publisher.
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`Library of Congress Catalog Card Number 94-70212
`ISBN 0-915486-22—9
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`First Printing, July 1994
`Second Printing, August 1994
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`:3
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`3,
`§
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`Page 2
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`i229t 3 :
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`mxmswmwm
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` aioovoilobility (F)
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`Definition
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`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 drug 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.
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`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}!2 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:
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`= (0.7)(250 ug)
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`= 175 pg
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`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 bioavailabiiity of the drug, or
`when it is so rapid that too much drug is absorbed. The former occasion-
`ally occurs with some sustained—release preparationss'd‘
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`Dosage Form
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`As noted earlier, bioavailability can vary among different formula-
`tions and dosage forms of a drug. For example, digoxin elixir has a bio—
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`Page 3
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`Biaavailabilitym
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`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 : 0.7).2'5'6 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.
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`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,
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`an equivalent dose of the elixir would be calculated as follows:
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` Dose of Elixir = #35753
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`m 227 pg
` If the soft gelatin capsules of digoxin Were to be administered, the
`bioavaflability or F of the new dosage form would have been 1.0 and the
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`equivalent dose would have been 175 ug.
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`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 <1.0. For example, parenteral chloramphenicol is given as the
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`succinate ester, and this chloramphenicol ester must be hydrolyzed to the
`active compound. The bioavailability of the parenterally—administered
`Cldoramphenicol succinate ranges from 55% to 95%, because from 5% to
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`45% of the chloramphenicol ester is eliminated renally before it can be
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`converted to the active compound.7
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`Page 4
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`Bioavaflabifity
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` Chemical Form (8)
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`The chemical form of a drug must aiso be considered when evaluating
`bioavailabiiity. For example, when a salt or ester of a drug is administered,
`the bioavail'ability factor (F) should be multipiied by the fraction of the _
`total molecular weight which the active drug represents. If “S” represents
`the fraction of the administered dose which is the active drug, 'then the
`amount of drug absorbed from a salt or ester form can be calculated as
`foHOWs:
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`The "S" factor should be included in all bioavailability equations as
`a constant reminder of its importance in assessing bioavailability of the
`active drug form. When a drug is administered inits parent or active form,
`the “S" for that drug is 1.0.
`Equation 2 can now be expanded to consider the salt factor as well as
`the bioavailability when calculating the dose of a new dosage form:
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`3
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`Aminophyllme is an excellent example of this principle. (See Figure
`1.) Aminophyiline is the ethylenediamine salt of the pharmacologically-
`active moiety, theophylline. Eighty to eighty—five percent (by weight) of
`this salt is theophylljne, so that the “S” for arrfinophylline is approxi—
`mately 0.8. Uncoated aminophylline tablets are considered to be com-
`pletely (100%) bioavailable; the bioavailability factor (F) for this dosage
`1.0. It is important to consider the salt form in deter—
`form is, therefore,
`absorbed from an aminophylline tab—
`mining the amount of theophylline
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`——4
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`Page 5
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`Bioavailability
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`let. When Equation 3 is applied to this situation, it can be demonstrated
`that 160 mg of theophylline is absorbed from a 200 mg aminophylline
`tablet:
`”
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`_
`Amount of Drug. Absorbed or
`Reaching the Systemic Circulation m (SXFXDOSE)
`= (0.8)(1.0)(200 mg Aminophylline)
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`= 160 mg Theophylline
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`First-Pass Effect
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`Since drugs are absorbed from the gastromtestinal 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.)
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`Lidocaine is an example of a drug with a first—pass effect that is so
`great that oral administration is not practical.3 In the case of propranolol
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`*i
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`20%
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`EEii
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`mewrwwmwwwmw-
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` 200 mg Aminophyiline
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`(Ethylenecliamlne Salt
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`F
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`of Theophyillne)
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`Ethylenediamlne
`(40 mg)
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`30% Whoyiline
`A
`-ime9) 9 i" '
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`Figure l. The Efleci of the Chemical~Drug Form an Bioavailahiiity.
`The example above emphasizes the Importance of considering the
`chemical farm 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 bioavailabillty of the dosage
`form itself must also be considered when drugs are administered by the
`oral route.
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`Page 6
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`Bioa vailabilr‘ty 3
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`40 mg
`OraEiy
`Administered
`Dru
`Q g
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`POWG'
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`Circulation
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` 2mg
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` intravenous
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`Administration
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`Figure 2. First-Pass Effect. When drugs with a high “first-pass effect"
`are administered orally. or large amount of the absorbed drug is metab—
`olized before it reaches the systemic circulation. If the drug is adminis—
`tered intravenously, the liver 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 pharmacologlc effects.
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`(Inderal), a significant portion of the orally administered dose is metab~
`oljzed through a first—pass effect; therefore, a much larger oral dose is
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`required to achieve the same pharmacologic response as that obtained
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`from a dose administered intravenously. However, the propranolol issue
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`is further complicated by the fact that one of the metabolites, 4-hydroxy—
`propranolol, is pharmacologicaliy active.9
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`"—6
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`Page 7
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`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 (1:).
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`When drugs are administered as a continuous infusion, the dosing
`interval can be expressed in any convenient time unit. For example, the
`theophylline administration rate resulting from aminophylline infused at
`a rate of 75 mg/hr is calculated from Equation 5 as follows:
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`RA
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`E (S)(F)(Dose)
`T
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`(0.8)(l.0)(75 mg)
`1 hr
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`_ '
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`60 mg/hr
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`0"
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`(0.8)(1.0)(75 mg)
`60 min
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`1 mg/min
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`Page 8
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`Rate of Administration
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`When drugs are administered at fixed dosing intervals, the calculateda
`administration rate is an average value. For example, the average admin-
`istration rate of the‘ophylline in mg/hr resulting from an oral dose of 300
`mg aminophylline given every six hours would be calculated using Equa-
`tion 5 as fofloWs:
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`RA
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`= (S)<F)<Dose)
`T
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`_ (0.8)(1.0)(300 mg)
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`6 hr
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`= 40 mg/hr
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`E
`§
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`4
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`Page 9
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