t
`
`Tenth Edition,
`
`McGraw-Hill
`MEDICAL PUBLISHING DivisioN
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`

`McGraw-Hill
`A Division of The McGrawHiU Companies
`
`Goodman and GilmÆn’s THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 10/e
`
`1975, 1970, 1965, 1955, 1941 by The McGraw-Hill
`Copyright ' 2001, 1996, 1990, 1985, 1980,
`Companies, Inc. All rights reserved. Printed in the United States of America. Except as
`permitted under the United States Copyright Act of 1976, no part of this publication may be
`reproduced or distributed in any form or by any means, or stored in a data base or retrieval
`system, without the prior written permission of the publisher.
`
`1234567890 DOWDOW 0987654321
`
`ISBN 0-07-135469-7
`
`This book was set in Times Roman by York Graphic Services, Inc. The editors were Martin J.
`Wonsiewicz and John M. Morriss; the production supervisor was Philip Galea; and the cover
`designer was Marsha Cohen/Parallelogram. The index was prepared by Irving CondØ Tullar and
`Coughlin Indexing Services, Inc.
`R.R. Donnelley and Sons Company was printer and binder.
`
`This book is printed on acid-free paper.
`
`Library of Congress Cataloging-in-Publication Data
`
`Goodman and Gilinan’s the pharmacological basis of therapeutics.(cid:151)lOth ed. / [edited by]
`Joel G. Hardman, Lee E. Limbird, Alfred Goodman Gilman.
`p. cm.
`Includes bibliographical references and index.
`ISBN 0-07-135469-7
`I. Title: Pharmacological basis of therapeutics.
`2. Chemotherapy. (cid:9)
`1. Pharmacology. (cid:9)
`II. Goodman, Louis Sanford III. Gilman, Alfred IV. Hardman, Joel G.
`V. Limbird, Lee E. VI. Gilman, Alfred 3oodman
`[DNLM: 1. Pharmacology. 2. Drug Therapy. QV 4 06532 20021
`RM300 G644 2001
`615’.7(cid:151)dc2l
`
`2001030728
`
`INTERNATIONAL EDITION ISBN 0-07-112432-2
`for manufacture and export.
`Copyright ' 2001. Exclusive rights by The McGraw-Hill Companies, Inc.,
`This book cannot be re-exported from the country to which it is consigned by McGraw-Hill. The
`International Edition is not available in North America.
`
`(cid:9)
`

`

`Table A(cid:151)Il--i
`PHARMACOKINETIC DATA
`
`AVAILABILITY (ORAL) URINARY EXCRETION (cid:9)
`(%) (cid:9)
`(%) (cid:9)
`
`BOUND IN PLASMA
`(%) (cid:9)
`
`I (cid:9)
`
`CLEARANCE (cid:9)
`(MI .min 1 ’kg 1 ) (cid:9)
`
`VOL. DIST. (cid:9)
`(1iters/k_j (cid:9)
`
`HALF-LIFE (cid:9)
`(hours) (cid:9)
`
`I (cid:9)
`PEAK TIME (cid:9)
`PEAK
`(hours) ___L CENTRAT
`IONS
`
`83 (63-110) (cid:9)
`
`11(0-4) (cid:9)
`
`I- (cid:9)
`
`112.8 (9.3-17.5)
`
`0.84 (0.69-1.03) (cid:9)
`
`1.0
`
`501: 0.5 (05...06)b (cid:9)
`
`I(cid:228)L:2.(cid:244)(2.3-2.9)
`/Lg/ml5
`So!: 2.9 (2.5-3.4)
`jzg/m1 5
`
`’Data from male subjects with HIV infection. Values are geometric means and 95% CI. Metabolized
`byADH, UGT, and other enzymes.
`bCnu, and T,,,,, (geometric mean and 95% CI) following a 300-mg oral tablet (Tab) or solution (Sol).
`
`References: Barry, M, Mulcahy, F., Merry, C., Gibbons, S., and Back, D. Pharmacokinetica and
`potential interactions amongst antiretroviral agents used to treat patients with NW infection.
`din.
`Pharmacoki,sef., 1999, 36:289-304.
`Chittick, G.E., Gillotin, C., McDowell, l.A., Lou, Y., Edwards, K.D., Prince, W.T., and Stein,
`D.S. Abacavir: absolute bioavai!ability, bioequivalence of three oral formulations, and effect of food.
`Pharmacotherapy, 1999, 19:932-942.
`
`88 – 15
`+(cid:151)* Child
`
`3 + 1
`Neo, Child
`
`<20
`
`5.0 – 14b
`.t. Hepc
`’s(cid:151)s Aged, Child
`t Obes, 11Th. Preg
`
`095 – 012b
`i(cid:151)* Aged, Hep’
`LTh, 11Th, Child
`
`2.0 – 0.4
`’s(cid:151)i’ RD, Obs, Child
`t Neo, Hep
`.
`.HTh, Preg
`
`0,33-1,4"
`
`20 ,LglmJe
`
`’ (cid:9)
`
`Valuesreported are for i linear kinetic model for doses less than 2 g drug exhibits concentration (cid:9)
`dependent kinetics above this dose. (cid:9)
`b,455.4g a 70-kg body weight; reported range, 65 to 72 kg.
`’Acetaminophen-induced hepatic damage or acute viral hepatitis.
`5 Absorpsion rate, but not extent, depends on gastric emptying; hence, slowed after food as well as
`in some disease states and entreatment With drugs that cause gaslroparesia.
`’Mean concentration following a 20-mg/kg oral dose. Hepatic toxicity associated with levels >300
`jag/mt at 4 hours after an overdose.
`
`47–5
`
`6
`
`80
`
`.93+0.58
`
`(LAAM) (Clthpter 23)
`
`(cid:176)Data from healthy adult male subjects. LAAM (L) is metabolized by cytochrome P450 (primarily
`CYP3A) to active metabolites, nor-LAAM (NL) and dinor-LAAM (DL).
`i’Following a single 40-mg oral dose.
`
`Reference Forrest i A Clements J A and Prescott L F Clinical pharmacokinettcsofdxacetasnol
`COn. Phamsacokinet., 1982, 7:93-107.
`
`7.0
`
`L: 2.6+0.2b
`L: 63–8 ng/mlb
`L:18.3–4.9
`NL: 3.9 + 0,7b
`NL: 23.9 – 3.2
`NL: 44 + 4 ng/mlb
`DL: 31 + 9.6
`DL: 65.8 – 10.1
`DL: 19 + 1 ng/mib
`References: Kalko, R.F., Chstterjie, N., and Inturrisi, C.E. Simultaneous determination of acetyl-
`methadol and its active biotransformation products in human biofluids. J. Chmmatogr., 1975, 109:
`247-258.
`Walsh, S.L., Johnson, RE., Cone, El., and Bigelow, G.E. Intravenous and oral l-a-acetylmethadol:
`pharmacodynamics and pharrnacokinetics in humans. J. Phar,nacol. Exp. Thee., 1998, 285:71-82.
`
`68 – 3 (cid:9)
`’s(cid:151)s Aged, Cirr
`
`1.4 :E 1.2 (cid:9)
`
`49 (cid:9)
`.. RD (cid:9)
`
`9.3 – 11
`’s(cid:151)s Aged, Cirr
`
`0.15 1 0.03 (cid:9)
`
`0.25 – 0.03 (cid:9)
`’s(cid:151)s Rep
`
`0.39 – 021b (cid:9)
`
`24 – 4 cg/m1 1
`
`’Values given are for unchanged parent drag Acetylsalicylic acid is converted to salicylic acid
`during and after absorption
`(CL. and 11/2 of salle late are dose-dependent; half-life varies between
`24 hours after a 300-mg dose to 19 hours when there is intoxication).
`5Po11owiug a single 1.2-g oral dose given to adults.
`
`Reference: Roberts, M.S., Rumble, REt., Wanwirnoiruk, S., Thomas, D:, and Brooks, P.M. Phanuia-
`cokinetics of aspirin and salicylate in elderly subjcors and in patients with alcoholic liver disease. Ear
`J. Clin. Phcrnoacol.. .1983, 25:253-261.
`
`(cid:9)
`(cid:9)
`

`

`15_30a (cid:9)
`
`75 – 10
`
`15 – 4
`
`-Decreases with increasing dose.
`tRange of steady-slate concentrations following
`state.
`
`ALBIJTEROL(cid:176) (Chapters 10,(28)
`
`CL = 3.37CL (cid:9) + 0.41
`4. Neo
`=cu
`
`a 400-mg oral dose, given every 4 hours to steady
`
`R:46–8 (cid:9)
`S: 55 Iz 11
`
`RIS:7+1
`
`PO, R:30–7 (cid:9)
`P0, S: 71 + 9 (cid:9)
`IH, R: 25
`IH,S:47
`eData from healthy subjects for R and S enantiomers. No major gender differences. No kinetic (cid:9)
`differences in asthmatics. fi-Adrenergic activity resides primarily with R-enantiomer. P0, oral; IH, (cid:9)
`inhalation. Oral dose undergoes extensive first-pass sulfation at the intestinal mucosa.
`bCIJF reduced, moderate renal impairment, (cid:9)
`’Median (range) following a single 4-mg oral dose of raceunic (R/S)-albuterol.
`
`R:10.3–3.O
`S: 6.5 + 2.0
`RDb
`4.
`
`ALENDRONATE5 (Chapter 62) (cid:9)
`
`.’
`
`In
`
`44.9 + 9.3 (cid:9)
`
`78 (cid:9)
`
`<07b (cid:9)
`4. Food (cid:9)
`Data from healthy postmenopausal female subjects. (cid:9)
`bBased on urinary recovery and reduced when taken <1 hour before and up to 2 hours after a (cid:9)
`meal. (cid:9)
`. (cid:9)
`’CL and V, values represent mean and 900k CI. (cid:9)
`dThe 11/2 for release from bone is ’-"11.9 years. (cid:9)
`’Mild to moderate renal impairment-
`’Following a single 10-mg IV infusion over 2 hours, and a 10-mg oral dose daily for >3 years.
`
`ii 1(1.00-1.22) (cid:9)
`’s* RD (cid:9)
`
`0.69 + 0.19
`2.4 – 0.7
`4. Neo
`1’ RD, Neo
`+-* RD
`’t-* Child
`Reference: Laskin, O.L. Clinical pliarmacolcinetics of acyclovir. (cid:9) Clin. (cid:9) Phannacokiner., (cid:9) 1983, 8:
`187-201.
`
`3 .5_5,4 .eMt
`
`1 (cid:149) 5_2b (cid:9)
`
`R:2.00+0.70
`S: 1.77 – 0.69
`4. RDb
`
`R:2.00–Q.49
`S: 2.85 – 0.85
`
`R: 1.5’ (cid:9)
`S: 2.0 (cid:9)
`
`R: 3.6(l.95.9) nmlc
`lS (cid:9) 11.4(7.1-16.2)
`I (cid:9)
`ng/rnl5
`
`References: Boulton, D.W., and Faw4tt,".P. Enantioselective disposition of albuterol in humans.
`Cue. Rev. Allergy Itnntunol., 1996, 14:115-138.
`Mohamed, M.H., Lima, JJ., Eberle, LV., Self, T.H.. and Johnson, J.A. Effects of gender and race
`on albaterot pharmacokinetics. Pharinacotherapy, 1999, 19:157-161.
`
`044 (034-0.55) (cid:9)
`
`10d (cid:9)
`
`IV: 21 (cid:9)
`
`IV: ’--275 nglm11
`Oral: 5-8.4 ngfmI t
`
`References: Cocquyt, V., Kline, W.F., Gertz, BJ., Van Belle, S.J., Holland, S.D., DeSmet, M.,
`Quan, H., Vyas, KR, Zhang, KB., Dc Greve, J., and Porras, A.G. Pharmacokinetics of intravenous
`alendronate. J. Clin. Pharmacol., 8999, 39:385-393.
`Porras, A.G., Holland, S.D., and Gertz, B.J. Pharitsacokjnetics of alendronate. Clin. Pharmacokinet.,
`1999, 36:315-328.
`
`-
`
`<1
`
`92–2u
`4. Cirr
`
`6.7–2.4b
`4. Aged, Cite
`CPBS
`
`’Blood-to-plasma concentration ratio = 0.63 – 0.02.
`5Metabolically cleared by CYP3A.
`’Provides adequate anesthesia for superficial surgery.
`tiprovides adequate anesthesia for abdominal surgery,
`
`1.6–0.2
`IC Aged, Cirr, CPBS
`
`0.8–0.3
`-* Aged
`CPBS
`4. Cirr
`Reference: Bodenham, A., and Park, G.R. Atfentanil infusions in patients requiring intensive care.
`Clin. Pharmacokinet., 1988, 15:216-226.
`
`100200nmF
`310-340 ng/ml’
`
`Key: Unless otherwise indicated by a specific footnote, the data are presented for the study population as a mean value – I standard deviation, a mean and range (lowest-highest in parenthesis) of values, a range
`of She lowest-highest values, or a single mean value.
`ADH = alcohol dehydrogenase; Aged = aged; AIDS = acquired immunodeficiency syndrome; Alb = hypoalbuminemia; Ant Fib = atrial fibrillation; AVH = acute viral hepatitis; Burn = bum patients; Cu =
`peak concentration; CAD ,= coronary artery disease; Celiac = celiac disease; CF = cystic fibrosis; CHF = congestive heart failure; Child = children; Cirr = hepatic cirrhosis; COPD
`chronic obstructive
`pulmonary disease; CP = cur pulmonale, CPBS = cardiopulmonary bypass surgery; CR1 = chronic respiratory insufficiency; Crohu = Crohns disease: Cush Cuoluing’s syndrome; CYP cytoctsrome P450;
`Fern = female; Hep = hepatitis; HIV = human immunodeficiency virus; DL = hyperlipoproteinernia; 11Th = hyperthyroid: IM = intramuscular; Infiaia = inflammation; IV = intravenous; LD = liver disease;
`LTh = hypothyroid; MAO = monoamine oxidaae; Ml = myocardial infarction; NAT = N-acetyltransferase; Neo = neonate; NIDDM = non-insulin-dependent diabetes mellitus; NS = nephrotic syndrome; Obes =
`obese; Pneu = pneumonia; Preg = pregnant; Prem = premature; BA = rheumatoid arthritis; RD = renal disease (including uremia); SC = subcutaneous; Sark = smoking; ST = sulfotransferase;
`T,ac = peak
`time: Tach = ventricular tachycardia; UGT = UDP-glucuronosyl transferase; Ulcer = ulcer patients. Other abbreviations are defined in the text section of this appendix.
`
`(cid:9)
`(cid:9)
`

`

`Table A-Il-i
`PHARMACOKINETIC DATA (Continued)
`
`AVAILABILITY (ORAL) URINARY EXCRETION (cid:9)
`(%) (cid:9)
`(%) (cid:9)
`
`BOUND IN PLASMA
`(%) (cid:9)
`
`I (cid:9)
`
`CLEARANCE (cid:9)
`(m1’min 1 kg 1 ) (cid:9)
`
`I (cid:9)
`
`VOL. tEST. (cid:9)
`(liters/kg) (cid:9)
`
`HALF-LIRE (cid:9)
`(hours) (cid:9)
`
`PEAK TIME (cid:9)
`(hours) (cid:9)
`
`PEAK
`CONCENTRA TIONS
`
`53 + 13 (cid:9)
`
`12
`
`- (cid:9)
`
`9.9 + 24b (cid:9)
`RD, Agedb (cid:9)
`
`0.87 – 0.13 (cid:9)
`
`A: 1.2 4:0.3
`0: 24 – 4.5
`
`A: 1.7 4 l.O (cid:9)
`0: 4.1 – 1.4’ (cid:9)
`
`A: 1.4 – 0.5 ,igimF
`egInaIC
`0: 6.4 – 0.8
`
`’Data from healthy male and female subjects. Allopurinol (A) is rapidly metabolized to the (cid:9)
`pharmacologically active oxypurinol (0). (cid:9)
`tIncrease d oxypurinol AUC during renal impairment and in the aged. (cid:9)
`’Following a single 300-mg oral dose, (cid:9)
`
`References: Physicians Desk Reference,
`p. 1976.
`and pharinacodynamics of allopurinol
`l’umheim, K., Krivanek, P., and Oberbauer, R. Pharmacokinetics
`in elderly and young subjects. Be J. Clin. PharmacoL, 1999, 4&501-509.
`
`54th ed. Medical Economics Co. Montvale, NJ, 2000,
`
`’ALPRAZOLAM (chapter, (cid:9)
`
`.9 ? (cid:9) ’l;,"6 (cid:9)
`. (cid:9)
`,, (cid:9) (cid:149)’ (cid:9)
`
`, (cid:9)
`
`. (cid:9)
`
`3’%u
`
`.
`
`88 – 16
`
`20
`
`71 – 3
`Cirr
`I
`s, Aged
`eObe
`’Metabolically cleared by CYP3A and other cytocl*onae P450a. (cid:9)
`’Data from male subjects only, (cid:9)
`eMean (range) from 19 studies following a single l-g oral dose given to adults.
`
`0.74 + 0.14’
`4. Obes, Cirr, Agedi
`~- RD
`
`R. (cid:9)
`21 (15-32) ngfmF
`
`2
`
`0.72 –0.12
`#- Obes, Cirr, Aged
`
`.5 (0.5_3.0)c
`
`~d"
`
`12 – 2 (cid:9)
`I t Obes, Cirr, Ag
`RD
`
`Reference: Greenblatt, Di., and Wright, C. E. Clinical pharmacokinetics of alprazolam. Therapeutic
`implications. Cl/n. Phannacokiner,, 1993, 24:453-471.
`
`SD
`Di
`
`A.LTEPLASE (tPA) (chapter 55)
`- (cid:9)
`-
`’Initial half-life is dominant; terminal half-life is 0.43 – 0.17 hours. (cid:9)
`’Following a single SO-mg IV dose of s-PA infused over 30 minuses to healthy adults. (cid:9)
`
`10–4 (cid:9)
`
`jLow (cid:9)
`
`
`
`
`
`J8 0 .04 ’ (cid:9)
`
`973 (cid:9)
`10–00
`F-
`Reference: Seifried, F., Tanswell, P., Rijken, D.C., Ban
`tt Be hoeff, MM., Su, CA, and Kluft, C.
`Pharnsacokinetics of antigen and activity of recombinant tissue-type plasminogen activator after infusion
`in healthy volunteers. Arzneinsittelforschung, 1988, 38:418-422.
`
`133 ng/m1b
`
`50-90’ (cid:9)
`
`(ChÆpthr 50),
`. ......
`........- (cid:9)
`50_90a (cid:9)
`67 (cid:9)
`
`.’; (cid:9)
`
`. (cid:9)
`
`.....,,.,;,,.,.,(cid:231)S. (cid:9)
`
`4.8 – 0.8 (cid:9)
`4. Aged, RD (cid:9)
`
`YgM
`
`6.6 – 1.5 (cid:9)
`4. Aged (cid:9)
`RD
`
`nnf.2SaeamS-M;i5arnamS ,namnaanen’scns’sansmwn’-.smwanwnavs,pnesans,srt:n
`1_.4 (cid:9)
`16 – 3.4 (cid:9)
`7 475 – 110 nglmltic
`f Aged
`t Aged, RD. (cid:9)
`
`--
`
`’Drug is not metabolized; oral bioavailability equals percent excreted unchanged.
`’Plasma C,,,, and T,,,, following a 100-mg oral dose given twice a day to steady slate in healthy
`young adults. Mean steady-state trough concentrations with
`the same dosing regimen were 302 – 80
`ngIml.
`’Efficacy is associated with a trough level of 300 ng/ml. Psychosis can occur at levels >1 pg/mI.
`
`References: Aoki, FY., and Sitar, D.S. Clinical pharmacolsinetics of amantadine hydrochloride. C/in.
`Phannacokinet., 1988, 14:35-51.
`Aoki, EY., Sitar, D.S., and Ogilvie. R .I. Amantadine kinetics in healthy young Subjects after
`long-term dosing. Clin. Pharnnacol. Thee., 1979, 26:729-736.
`
`AMIKACIN (Chapters 46 48)
`
`- (cid:9) ------ (cid:9) -- .....................’. (cid:9)
`
`_______
`
`O (cid:9)
`CL = - 0.6CL, + 0.14 (cid:9)
`. (cid:9) Obes (cid:9)
`- (cid:9)
`4. CF (cid:9)
`
`’At a serum concentration of 15 pg/rnL (cid:9)
`51’ollowing a i-hour 1V infusion of a 6.3 – 1.4-mg/kg dose, given
`state in patients without renal disease. (cid:9)
`
`three times a day to steady (cid:9)
`
`7
`+- Aged, Child, CF 4. RD
`4. Obea (cid:9)
`e- (cid:9) Obes (cid:9)
`4. Burn, Child, CF
`4. Neo (cid:9)
`Reference. Bauer, L.A., and Blouin, R.A. Influence of age on amikacin pharmacoldnetucs in patients
`without renal disease- Comparison with gentamacin and tobramycin. Ear J. C/in. Phannacol., 1983,
`24:639-642
`
`-
`
`(cid:9)
`

`

`49+10
`t Hep
`4. RD
`’Greater than or equal to percent excreted unchanged. (cid:9)
`bCIJF and V,,.,a/F reported, assuming a 70-kg body weight. Lower values for
`(6-9) reported.
`’Following a single 10-mg oral dose given to healthy adults.
`
`-
`
`1.9b
`9 .7 (cid:9)
`I 4. Aged, Hep, RD
`
`4b
`17 (cid:9)
`4. RD
`Hep, Aged
` (cid:151)~
`
`21 zl, 3b
`f Aged, Hep, RD
`
`3.1 (cid:9)
`
`1.2c
`
`. ..
`
`ng/rall
`
`- -
`
`t1d (5-5.5) and t12 (cid:9)
`
`Reference: Spahn, H., Reuter, K., Mstschler, P., Gerok, W., and Knauf, H. Pharmacokinetics of
`amiloride in renal and hepatic disease. Eue J. Clin. Pharinacol., 1987, 33:493-498.
`
`AMIODARONEa (Chapter 35)
`
`46 + 22
`
`0
`
`
`
`99.98.– 001b
`
`11.9 – 0.4c
`Aged, Fern, CHF,
`I (cid:9)
`RD
`
`66– (cid:9)
`
`- 25– 12 days"
`-~ Aged, Fern, RD
`
`210
`
`’Significant plasma concentrations of an active desethyl metabolite are observed (ratio of drug!
`metabolite --1); C1,2 for metabolite = 61 days.
`bBlood to plasma concentration ratio = 0.73 – 0.06.
`’Metabolized by CYP3A,
`dLonger half-life noted in patients (53 – 24 days); all reported half-lives may be underestimated
`because of insufficient length of sampling.
`’Following a 400-mg/day oral dose to steady state in adult patients.
`
`Reference: Gill, J., Heel, R.C., and Fitton, A. Amiodarone. An overview of its pharmacological
`properties, and review of its therapeutic use in cardiac arrhythmias. Drugs, 1992, 43:69-110.
`
`-3
`
`<2 (cid:9)
`
`48 + 11 (cid:9)
`+(cid:151)+ Aged (cid:9)
`
`94.8 – 086 (cid:9)
`11.5 – 3.4’ (cid:9)
`s. Aged, Smk (cid:9)
`---+ Aged (cid:9)
`’s(cid:151)
`L______________
`’Active metabolite is nortnptyline
`(See drug listing for kinetic data). (cid:9)
`5 Blood-to-plasma concentration ratio = 0.86 – 0.13. (cid:9)
`’Blood CL and V,, reported; formation of nortnptyline is Catalyzed by CYP2CI9 (polymorphic),
`CYP3A4, and other cytochroine P450s; formation of 10-hydroxy metabolites are catalyzed by CYP2D6
`(polymorphic).
`dgollowing a 100-mg/day dose to steady state in adults. The nortriptyline/amitriptyline concentration
`ratio = 1.1 – 0.6. Optimal range of nortriptyline + amitriptyline is 60 to 220 ng/ml. Toxic effects
`occur at total concentrations >1
`.egIml.
`
`15 – 3c (cid:9)
`4. Aged (cid:9)
`
`21 – 5
`4. Aged
`
`3.6 – 1.411 (cid:9)
`
`64 – 35 ng/ml"
`
`
`
`Reference: Schulz, P., Dick, P., Blaschke, T.F., and Hollister, L. Discrepancies between pharmacoki-
`netic studies of amitriptylinc. Clin. Pharinacokinet., 1985, 10:257-268.
`
`Key: Unless otherwise indicated by a specific footnote, the data are presented for the study population as a mean value – 1 standard deviation, a mean and range (lowest-highest in parenthesis) of values, a range
`of the lowest-highest values, or a single mean value.
`ADH = alcohol dehydrogenaae; Aged = aged; AIDS = acquired immunodeficiency syndrome; Alb = hypoatbuminemia; Ati Fib = atrial fibrillation; AVH = acute viral hepatitis; Bum (cid:9)
`barn patients; C,,.,,, =
`peak concentration; CAD = coronary artery disease; Celiac = celiac disease; CF = cystic fibrosis; CBF = congestive heart failure; Child = children; Cite = hepatic cirrhosis; COPD (cid:9)
`chronic obstructive
`pulmonary disease; CP = cor pulmonale; CPBS = cardiopulmonary bypass surgery; CR1 = chronic respiratory insufficiency; Crohn = Crohn’s disease; Cush = Cushing’s syndrome; CYP = cytochrome P450;
`Fern = female; Hep = hepatitis; lIly = human immunodeficiency virus; HL = hyperlipoproteiaemia; HTh = hyperthyroid; ilvI = intramuscular; Infiam = inflammation; IV = intravenous; LD = liver disease;
`LTh = hypothyroid; MAO = monoamine oxidase; MI = myocardial infarction; NAT - N-acetyltransferase; Neo = neonate; NIDDM = non-insulin-dependent diabetes mellitus; NS = nephrotic syndrome; Obes =
`obese; Pneu = pneumonia; Preg = pregnant; Prem = premature; RA rheumatoid arthritis; RD = renal disease (including uremia); SC = subcutaneous; Sunk = smoking; ST = sulfotransferase; T,,,,, = peak
`time; Tach = ventricular tachycardia; UGT = UDP-glucuronosyl transferase; Ulcer = ulcer patients. Other abbreviations are defined in the text section of this appendix.
`
`

`

`Table A(cid:151)Il--i
`PHARMACOKINETIC DATA (Continued)
`
`AVAILABILITY (ORAL) URINARY EXCREtION (cid:9)
`
`BOUND IN PLASMA (cid:9)
`(%) (cid:9)
`
`CLEARANCE (cid:9)
`(ml min- 14g (cid:151) I (cid:9)
`
`VOL 01ST. (cid:9)
`(liters/kg) (cid:9)
`
`H (cid:9)
`(hours) (cid:9)
`
`PEAK TIME (cid:9)
`(hours) (cid:9)
`
`PEAK
`CONCENTRATIONS
`
`t4
`7
`
`10
`
`5.9 – 1.5
`+(cid:151)s RD
`J, Aged, Hep
`’Racemic mixture; in young, healthy subjects, there are no apparent differences between the kinetics (cid:9)
`of the more active R-enantiomer and S-esantiomer. (cid:9)
`’Following a 10-mg oral dose given once daily for 14 days to healthy male adults.
`
`93 nil 1
`(cid:151)* Aged
`
`16 – 4 (cid:9)
`Aged (cid:9)
`
`I (cid:9)
`
`
`
`8
`
`~(cid:151)*
`
`Hep
`
`s .4_8.Ob (cid:9)
`
`I (cid:9)
`
`18.1 – 7.1 nglmib
`C Aged
`
`
`
`Reference: Meredith, PA., and Elliott, H .L. Clinical pharmacokinetics of amlodipine. din. Phanna-
`cokinet., 1992, 22:22-31.
`
`’Dose-dependent; value shown is for a 375-mg dose; decreases to about 50% at 3000 mg. (cid:9)
`’No change if renal function is not decreased, (cid:9)
`’Following a single 500-mg IV bolus dose to healthy elderly adults or a single 500-mg oral dose (cid:9)
`to adults. (cid:9)
`
`References: I-loftIer, D. (The pharmacokinetics of amoxicillin.1 Adv. C/in. Phannacol., 1974, 7:28-30.
`Sjovall, J., Alvan, G., and Huitfeldt, B. Intra- and inter individual variation in pharmacokisetics of
`intravenously infused amoxicillin and arepicilhin to elderly vole errs
`nc J. Ci n Pharnacol., 1986,
`2/:171-181.
`
`Qr
`
`’Data for arnpltotericin B shown. Also formulated by liposomal encapsulation (ABELCET and AMBI-
`SOME); the distribution and clearance properties of these products are different from the nonencapsulated
`form; a terminal half-life of 173 – 78 and 110 to
`153 hours, respectively; however, an effective
`steady-state concentration can be achieved within 4 days.
`5 Dal, for eight children (age 8 months to 14 years) yield a linear regression with CL decreasing
`with age: CL = -0.046- age (years) + 0.86. Newborns show highly variable CL values.
`’Volume of central compartment. V. increases with dose from 3.4 1/kg for single 0.25-mg/kg doses
`to 8.9 11kg for 1.5-mg/kg doses.
`tHalf life for multiple dosing. In single-dose studies, a prolonged dose-dependent half-life is seen.
`’Following 0.5 -mg/kg IV dose of amphotericin B given as a I-hour infusion, once daily for 3 days.
`Whole blood concentrations (free and lipososne encapsulated) of 1.7 – 0.8 jsgfml and 83535 izg/ml
`. day IV dose (presumed 60- to 120-min infusion) of ABELCET
`were reported following a 5-mg. kg
`and AMSISOME, respectively.
`
`-
`
`References: Gallis, U.A., Drew, RH., and Pickard, W.W. Ampholericis B: 30 years of clinical
`experience. Rev. Infect. Dis., 8990, 12:308-329.
`Physicians’ Desk Reference, 54th ed Medical Economics Co., Montvale, Ni, 2000, pp. 1090-1091,
`1654.
`
`’Data from healthy pre- and postmenopausal female subjects. Metabolized by cylochrtsme P450 and
`UGT. (cid:9)
`’CLJF reduced, stable alcoholic cirrhosis. (cid:9)
`’C,,,, and 5,,,, following a single 3-mg oral dose. Accumulates three- to
`multiple daily dosi,,g. (cid:9)
`
`fourfold from single to (cid:9)
`
`References: Lonmng, PE., Geisler, 1., and Dowselt, M. Pharmacological and clinical profile of
`anastrozole. Breast Cancer Res. Treat., 1998, 49(suppl 1):S53-S57; discussion S73-S77.
`Physicians’ Desk Reference 54th ed. Medical Economics Co., Montvale, NJ, 2000, p. 537.
`Plourde, PV., Oyeoff, M., Dowsete, M., Demers, L., Yates, R., and Webster, A. AISIMIDEX: a new
`oral, once-a-day aromatase inhibitor, J. Steroid Bioelrem. Mo!. BioL, 1995, 53:175 -179-
`
`,
`
`(cid:9)
`

`

`’Data from healthy adult male and female subjects. No clinically significant gender differences. (cid:9)
`Atorvastatin undergoes extensive CYP3A-dependent first-pass metabolism in the gut wall and liver.
`Metabolites are active and exhibit a longer half-life (20 to 30 hours) than parent drug. (cid:9)
`bMean CL/F parameter calculated from reported AUC data at steady state after a once a day 20-mg (cid:9)
`oral dose, assuming a 70-kg body weight, (cid:9)
`0AUC following oral administration increased, mild to moderate hepatic impairment. (cid:9)
`dFollnwing a 20-mg oral dose, once daily, for 14 days.
`
`References: Gibson, D.M., Bron, N.J., Richens, A., Hounslow, N.J., Sedman, A.J., and Whitfield,
`L.R. Effect of age and gender on pharmacokinetics of atoevastatin in humans. J. Clin. Phas-inacol.,
`1996, 36:242-246.
`Lea, AR, and McTavish, D. Atorvastatin. A review of its pharmacology and therapeutic potential
`in the management of hyperlipidaemias, Drugs, 1997, 53:828-847.
`Physicians’ Desk Reference, 54th ed. Medical Economics Co., Montvale, NJ, 2000, p. 2254.
`
`23 – 11 (cid:9)
`t Food" (cid:9)
`
`<1 (cid:9)
`
`99.9 (cid:9)
`
`0.15 + 0.09 (cid:9)
`4. Child’ (cid:9)
`0Data from patients with DIV infection. Atovaquone is thought to undergo enterohepatic recycling,
`with eventual elimination as unchanged drug in feces.
`bMarkedly increased absorption with high-fat meal.
`(cid:176) CUF reduced, children <2 years of age.
`dFollowing 1000-mg suspension daily for 14 days.
`
`0.6 – 0.17 (cid:9)
`
`62.5 + 35.3 (cid:9)
`
`1.5-2.5 (cid:9)
`
`24.2 – 12.1
`f Food
`References: Dixon, R., Pozniak, AL., Watt, H.M., Rolan, P., and Posner, J. Single-dose and steady-
`state pharenacokinetics of a novel microfluidized suspension of atovaquone in human immunodeficiency
`virus-seropositive patients. Antimicrob. Agents Chetnother, 1996, 40:556-560.
`Physicians’ Desk Reference, 54th ed. Medical Economics Co., Montvale, NJ, 2000, p. 1233.
`Rolan, RE., Mercer, Al., Tate, E., Benjamin, I., and Posner, J. Disposition of atovaquonc in humans.
`Antimicrob. Agents Chemother., 1997, 41:1319-1321,
`
`eg/m1d
`
`’Racemic mixture of active l-hyoscyamine and inactive d-layoscyamine. (cid:9)
`bintramutcular injection. (cid:9)
`clHyoscyamine clearance after an intramuscular dose is 3-fold greater than that for d-hyoscyamine.
`’Mean for 1-hyoscyamine after a single 0.02-mg/kg intramuscular dose given to healthy adults.
`
`Reference: Kentala, E., Kaila, T., lisalo, E., and Kanto, J. Intramuscular atropine in healthy volunteers:
`a phartnacokinetic and pharmacodynsm.ic study.
`If. J. COn. Phannacok Thee Toricof, 1990, 28:
`399-404.
`
`Key: Unless otherwise indicated by a specific footnote, the data are presented for the study population as a mean value – 1 standard deviation, a mean and range (lowest-highest in parenthesis) of values, a range
`of the lowest-highest values, or a single mean value.
`
`C,,,0,, =
`ADD = alcohol dehydrogenase; Aged = aged; AIDS = acquired immunodeficiency syndrome; Alb = hypoalbuminemia; Ate Fib = atrial fibrillation; AVH = acute viral hepatitis; Bum = bum patients;
`peak concentration; CAD = coronary artery disease; Celiac = celiac disease; CF = cystic fibrosis; CHF = congestive heart failure; Child
`children; Cirr = hepatic cirrhosis; COPD = chronic obstructive
`pulmonary disease; CE’ = cor pulmonale; Cl’BS = cardiopulmonary bypass surgery; CR8 = chronic respiratory insufficiency; Crohn = Crohn’s disease; Cush = Cushing’s syndrome; CYP (cid:9)
`cytochrome P450;
`Fern = female; [tap = hepatitis; HIV = human immunodeficiency virus; [IL = hyperlipoproteinemia; HTh = hyperthyroid; Dvi = intramuscular; Inflam = inflammation; tY = intravenous; LI) = liver disease;
`LTh = hypothyroid; MAO = monoamine oxidase; MI = myocardial infarction; NAT = N-acetyltransferase; Neo = neonate; NIDDM = non-insulin-dependent diabetes mellitus; NS = nephrotic syndrome; Ohm
`obese; Pneu = pneumonia; Preg = pregnant; Prem = premature; RA = rheumatoid arthritis; RD = renal disease (including uremia); SC = subcutaneous; Smk
`smoking; ST = sulfotransferase; T,,se = peak
`time; Tach = ventricular tachycardia; .UGT = UDP-glucuronosyl transferase; Ulcer = ulcer patients. Other abbreviations are defined in the text section of this appendix.
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`Table A-Il-i
`PHARMACOKINETIC DATA (Continued)
`
`AVAILABILITY (ORAL) URINARY EXCRETION (cid:9)
`(%) (cid:9)
`(%) (cid:9)
`
`BOUND IN PLASMA (cid:9)
`(%) (cid:9)
`
`CLEARANCE (cid:9)
`(ml. mm" 1 kg 5) (cid:9)
`
`VOL. 1)1ST. (cid:9)
`(liters/kg) (cid:9)
`
`HALF-LIFE (cid:9)
`(hours) (cid:9)
`
`PEAK TIME (cid:9)
`(hours) (cid:9)
`
`PEAK
`CONCENTRATIONS
`
`aKinelic values are for intravenous azathioprine. Azathioprine is metabolized to mercaptopurine (Ml’). (cid:9)
`See mercaptopurine for listing of its kinetic parameters. (cid:9)
`bDetem.,ined as the bloavailability of mercaptopurine; intact azathioprine is undetectable after oral
`administration because of extensive first-pass metabolism.
`eData from kidney transplant patients.
`dRange of steady-elate peak mercaptopurine concentration following a 135 – 34-mg oral dose of
`azathioprine, given daily to kidney transplant patients.
`
`5t,Ea5c4’c,,v-rc-tfl-r.ctrGV ,
`34 – 19
`12
`. Food (capsules)
`-f Food (suspension)
`aDose depefldent plasma binding. The bound fraction is 50% at 50 nglml and 12% at 500 ng/ml. (cid:9)
`bA longer terminal plasma half-life of 68 – 8 hours, reflecting release from tissue stores, overestimates (cid:9)
`the multiple-dosing half-life.
`Following a 250-mg/day oral dose to adult patients with an infection.
`
`7.50a
`
`9
`
`Reference: Lie, SN., Jessup, K., Floyd, M., Wang, T.P., van Buren, C.T., Caprioli, R.M., and
`Kahan, B.D. Quantitation of plasma azathioprine and 6-mercaptopus’tne levels in renal transplant
`patients. Transplantation, 1980, 29:290-294.
`
`.
`,,.,.,.--.,,,.(cid:149),,,,,.
`401 (cid:9)
`. (cid:9)
`CUT
`
`ON
`
`2_3c (cid:9)
`
`31.
`
`0.4 jag/rode
`
`
`Reference: Lalak, N.J., and Morris, D.L. Azithromycin clinical pharmacokinetics, Clin. Pharina-
`cokiiset., 1993, 25:370-374.
`
`Data from healthy adult male subjects. (cid:9)
`bBioavallability estimate based on urine recovery of unchanged drug after oral dose.
`"CL/F, Varea/F reported for intestinal infusion of drug. (cid:9)
`dLimited data suggest CL/F reduced with renal impairment. (cid:9)
`(mean and range) and C,,,., following s single to-mg oral dose, (cid:9)
`(cid:176)T,,,,,,
`
`References: Kochsk, G.M., Rakhit, A., Wagner, W.E., Hone, F., Waldes, L., and Kershaw, R.A.
`The pharmacokinetics of baclofeu derived from intestinal infusion. Clin. Pharmacol. Thee, 1985,
`38:251-257.
`Wuis, E.W., Dirks, M.J., Termond, ER, Vree, T.B., and Van der Kleijn, C. Plasma and urinary
`excretion kinetics of oral baclofen in healthy subjects. Eui: J. COn. Pharmacol., 1989, 37:181-184.
`
`BenazepriI (B) is a prodrug for the active metabolite, benazeprilat (BT). Minimum bioavailability
`of BT based on urinary recovery data. (cid:9)
`. (cid:9)
`r1,2 ’.22 hours. (cid:9)
`’Data for active metabolite; terminal
`’Following an oral dose of benazepril. BT is cleared by renal and biliary excretion.
`5 CL/F and Va,’ea/F reported.
`"Following a single 10-mg oral dose given to healthy adults. C,,,.,, calculated from original data
`assuming a plasma density of I g/int.
`
`. (cid:9)
`
`Reference: Balfour, l.A., and Goa, K.L. Benazepril. A review of its pharmacodynanaic and phar-
`macokinetic properties, and therapeutic efficacy in hypertension and congestive heart failure.
`Drugs,
`1991, 42:511539.
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`’Racemic mixture; S-(-)-rnantiomer is more active than the R-(+)-enantiomer.
`5Following a single 20-mg oral dose given to healthy adults, (cid:9)
`
`BICALUTAMmE (Chapters 52 59)
`
`-1O.3
`
`96
`
`R: 0.3 – 0013b
`S; 7.3 – 40b
`-->LD, RD, Aged
`
`Data from healthy male subjects. Exhibits utereoselective metabolism(cid:151)S-enantiomer, primarily
`glucuronidation; R-enantiomer, primarily oxidation,
`bCL/p reported for oral dose.
`dlncreased t112 of R-enantiomer, severe liver disease.
`’wean Tm , x and C,, m following a single (SD) 50-mg oral dose (tablet) and 50-mg once-a-day oral
`dose (MD) to steady state.
`
`BLEOMYCIN (Chapt&r 52) (cid:9)
`
`’ (cid:9)
`
`, (cid:9)
`
`. ’ (cid:9)
`
`, (cid:9) (cid:149). (cid:9)
`
`.’ . ’ .(cid:149) :’
`
`. (cid:9)
`2 ’ (cid:9)
`
`44.8 – 11.3 ml -min- 9.7 – 2.8 (cid:9)
`(m
`RD (cid:9)
`Childb (cid:9)
`
`.i-,Child5 (cid:9)
`
`References: Fnshman, W.H., Tepper, D., Lazar, E.J., and Behrman, D. Betaxolol; a new long-acting
`beta 1-selective adrenergic blocker. J. C/in. Pharrnacol., 1990, 30:686-692.
`Warrington, S.J., Turner, P., Kilborn, J.R., Bianchetti, 0., and Moraclli, P.L. Blood concentrations
`and pharmacodynamic effects of betaxolol (SL 75212) a new beta-adrenoceptor antagonist after oral
`and intravenous administration. Br. J. C/in. Pharmacol., 1980, 10:449-452.
`
`
`
`-
`
`R;139 – 32.
`S: 29 – 8.6
`t Me
`
`R : 23.4d (cid:9)
`S: 20.7’ (cid:9)
`
`SD, R: 734 ng/mld
`SD, S: 84 ng/mld
`MD, R/S: 8.9 –
`cg/m1
`References: Cockshots, ED., Oliver, S.D., Young, J.J, Cooper, K.J., and Jones, D.C. The effect of
`food on the pharenscokinetics of the bicalutarnide ("Casodex") enantiomers. Biopharm. Drug Dispos.,
`1997, 18:499-507.
`McKillop, D., Boyle, G.W., Cockshott, ID., Jones, D.C., Phillips, P.3., and Yates, R.A. Metabolism
`and enantioselective pharrnacokinetics of Casodex in man. Xenobiotica, 1993, 23:1241-1253.
`Physicians’ Desk Reference, 54th ed. Medical Economics Co., Montvale, NJ, 2000, p. 538.
`
`., ,-’. (cid:9)
`
`- (cid:9) (cid:149), ,
`
`V (cid:9)
`
`’
`
`3.1 – 1.7 (cid:9)
`
`tRD
`Child’
`
`- (cid:9)
`
`g/ml5 .
`
`Data from eight patients 9 to 17 years of age.
`Data from three children <3 years of age.
`’Range of steady-state concentration following a 30-mg/rn 2 per day IV infusion given to children
`with cancer.
`
`References: Crom, W.R., Glynn-Barnhart, AM., Rodman, J.H., Teresi, M.E., Kavanagh, R.E.,
`Christiansen, M.L., Relling, MV., and Evans, W.E. Pharmacokinetics of anticancer drugs in chil-
`dren. C/in. Pharmacokiner., 1987, 12:168-213,
`Yee, G.C., Crom, W.R., Lee, F.H., Smyth, RD., a