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`
`Integration of
`Pharmacokinetics,
`Pharmacodynamics,
`and Toxicokinetics
`in Rational
`Drug Development
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2071
`
`1
`
`

`

`Integration of
`Pharmacokinetics,
`Pharmacodynamics,
`and Toxicokinetics
`in Rational
`Drug Development
`
`2
`
`

`

`Integration of
`Pharmacokinetics,
`Pharmacodynamics,
`and Toxicokinetics
`in Rational
`Drug Development
`
`Edited by
`
`Avraham Yacobi
`
`American Cyanamid Company
`Pearl River, New York
`
`Jerome P. Skelly
`
`Food and Drug Administration
`Washington, D.C.
`
`Vi nod P. Shah
`
`Food and Drug Administration
`Rockville, Maryland
`and
`Leslie Z. Benet
`
`University of California, San Francisco
`San Francisco, California
`
`.
`.
`Published in cooperation with the
`American Association of Pharmaceutical Sc1ent1sts
`
`Plenum Press• New York and London
`
`3
`
`

`

`Library of Congress Catalog1ng-1n-Publ1cat1on Data
`
`Integration of pharmacokinetics, pharmacodynamics, and toxicokinetics
`in rational drug development / edited by Avraham Yacobi ... let
`a 1. ].
`cm.
`p.
`"Sponsored by the American Association of Pharmaceutical
`Scientists, the U.S. Food and Drug Administration, and the American
`Society for Cl lnical Pharmacology and Therapeutlcs"--T.p. verso.
`"Published In cooperation with the American Association of
`Pharmaceutical Scientists."
`Includes bibliographical references and Indexes.
`ISBN 0-306-44356-2
`1. Drugs--Research--Methodology--Congresses. 2. Pharmacoklnetlcs(cid:173)
`-Congresses. 3. Drugs--Physiologica I effect--Congresses. 4. Drugs-
`-Toxicology--Congresses.
`I. Yacobi, Avraham.
`II. American
`Association of Pharmaceutical Scientists.
`III. United States. Food
`and Drug Administration.
`IV. American Society for Clinical
`Pharmacology and Therapeutics.
`[DNLM: 1. Drug Evaluation--congresses. 2. Drug Screening(cid:173)
`-congresses. 3. Drugs, Investigatlonal--congresses.
`av 771 I602l
`4. Pharmacoklnetics--congresses.
`RM301.25.I58 1993
`615' .1 '072--dc20
`DNLM/DLC
`for Library of Congress
`
`92-48285
`CIP
`
`Invited papers presented at a conference entitled "The Integration of Pharmacokinetic,
`Pharmacodynamic, and Toxicokinetic Principles in Rational Drug Development," held
`April 24-26, 1991, in Arlington, Virginia, sponsored by the American Association of
`Pharmaceutical Scientists, the U.S. Food and Drug Administration, and the American
`Society for Clinical Pharmacology and Therapeutics
`
`ISBN 0-306-44356-2
`
`© 1993 Plenum Press, New York
`A Division of Plenum Publishing Corporation
`233 Spring Street, New York, N.Y. 10013
`
`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, microfilming,
`recording, or otherwise, without written permission from the Publisher
`
`Printed in the United States of America
`
`4
`
`

`

`CONTENTS
`
`INTRODUCTION
`
`SECTION
`I
`
`INTRODUCTION
`
`1. Rationale for the Effective Use of Pharmacokinetics and Pharmacodynamics in
`Early Drug Development
`Carl C. Peck
`
`12. The Case for Preclinical Pharmacodynamics
`
`Gerhard Levy
`
`xv
`
`l
`
`7
`
`3. Utility of Kinetic, Dynamic, and Metabolic Data in Nonclinical
`Pharmacology{foxicology Studies
`
`Judi Weissinger
`
`15
`
`SECTION
`II
`
`PRECLINICAL PHARMACOKINETIC & PHARMACODYNAMIC
`STUDIES
`· 4. Pharmacokinetics and Drug Metabolism in Animal Studies (ADME, Protein
`Glenna G. Fitzgerald
`Binding, Mass Balance, Animal Models)
`! 5. Nonclinical Considerations: Disposition of Drugs
`
`Martin David Green
`
`"6. Use of Acute Toxicity Data in the Design and Interpretation of Subchronic and
`Chronic Toxicity Studies
`Karl K. Rozman
`
`I
`
`17. Use of Pharmacokinetics and Pharmacodynamics in Preclinical Studies to Guide
`Dosage Escalation Schemes in Phase I Studies of Anticancer Drugs
`Jerry M. Collins
`
`J 8. Use of Toxicokinetic Principles in Drug Development: Bridging Preclinical and
`Mauricio Leal, Avraham Yacobi and Vijay K. Batra
`Clinical Studies
`
`23
`
`33
`
`39
`
`49
`
`55
`
`xi
`
`5
`
`

`

`SECTION
`III
`
`METHODOLOGY FOR PRECLINICAL PHARMACODYNAMIC STUDIES
`
`9. Preclinical Phannacodynamics of Central Nervous System Active Agents
`Meindert Danlzof, Jaap W. Mandema and Arendien Hoogerkamp
`
`10. Preclinical Pharmacodynamics of Antihypertensives
`Robert A. Branch and Edwin K. Jackson
`
`11. Preclinical Pharmacodynamics of Anxiolytics: Effects of Chronic
`Benzodiazepine Administration
`Lawrence G. Miller
`
`69
`
`81
`
`91
`97
`
`12. Guidelines for Development of a New Diuretic Agent
`13. Preclinical Pharmacodynamics of Anti-Inflammatory Drugs
`Asoke Mukherjee, Conrad Chen, Lucy Jean and Claude B. Coutinho 105
`
`D. Craig Brater
`
`SECTION
`IV
`
`PRECLINICAL & CLINICAL PIIARMACOKINETICS
`
`J 14. The Role of Pharmacokinetics in the Drug Development Process
`Leslie z. Benet 115
`15. Implementation of an Effective Pharmacokinetics Research Program in Industry
`Avraham Yacobi, Vijay K. Batra, Robert Desjardins, Robert D. Faulkner,
`Gabriela Nicolau, William R. Pool, Anita Shah and Alfred R Tonelli 125
`
`16. Pharmacoepidemiology, Population Pharmacokinetics and New
`Thaddeus fl. Grasela and Edward J. Antal 137
`Drug Development
`
`17. Assessment of Pharmacokinetic Drug Interactions in Clinical Drug Development
`Jerome J. Schentag 149
`
`SECTION
`V
`
`CLINICAL PHARMACODYNAMICS
`
`18. Pharmacokinetic/Pharmacodynamic Models and Methods
`Davide Verotta and Lewis B. Sheiner 159
`
`19. Pharmacokinetic and Pharmacodynamic Modeling Applied to Anesthetic Drugs
`Donald R Stanski 179
`
`20. Pharmacodynamic/Pharmacokinetic Relationships for Rapidly Acting Drugs
`(NSAIDS) in Rheumatoid Arthritis: Problems and Preliminary Solutions
`Daniel E. Furst 193
`
`xii
`
`This material was c,opied
`
`6
`
`

`

`21. The Value of Plasma-Warfarin Measurement
`
`22. Clinical Phannacodynamics of Cardiovascular Agents:
`Focus on Sudden Cardiac Death
`
`23. The Benzodiazepines: Kinetic-Dynamic Relationships
`
`RobertA.O'Reilly 201
`
`Dan M. Roden 207
`
`David J. Greenblatt 217
`
`SECTION
`VI
`
`APPLICATION OF PIIARMACODYNAMICS & PHARMACOKINETICS IN
`THE DRUG DEVELOPMENT PROCESS
`
`24. The Integration of Phannacodynamics and Pharmacokinetics in Rational Drug
`Development
`Sally Usdin Yasuda, Sorell L. Schwartz, Allton Wellstein and
`Raymond L. Woosley
`
`25. Concentration-Controlled Trials: Basic Concepts, Design, and Implementation
`
`225
`
`lilly Sanathanan and Carl C. Peck 239
`
`SECTION
`VII
`
`SUMMARY REPORT
`
`26. Opportunities for Integration of Pharma co kinetics, Pharmacodynamics and
`Toxicokinetics in Rational Drug Development
`
`A~m~~
`
`Subject Index
`
`249
`
`~
`
`267
`
`This material was<:opied
`at th,e NLMand may he
`
`xiii
`
`7
`
`

`

`THE CASE FOR PRECLINICAL PHARMACODYNAMICS
`
`Gerhard Levy
`Department of Pharmaceutics, School of Pharmacy
`State University of New York at Buffalo, Amherst, N.Y. 14260
`
`ABSTRACT
`
`Pharmacodynamics concerns the relationship between drug concentration and intensity
`of pharmacologic effect. It includes the exploration and assessment of relevant variables such
`as pharmacologically active metabolites, pharmacodynamic drug interactions and effects of
`genetics and underlying diseases. Available (though limited) infonnation indicates that drug
`concentrations required to produce a defined intensity of pharmacologic action are quite
`similar in man and animals. For such interspecies comparisons, consideration must be given
`to possible differences in drug-protein binding, active metabolites, kinetics of equilibration
`of drug between plasma and biophase, and definition of the pharmacologic endpoint. It is now
`evident that many unanticipated, phannacodynamically relevant clinical risk factors, includ(cid:173)
`ing some that have caused a substantial number of deaths, could have been recognized in
`preclinical pharmacodynamic studies. Examples based on studies in the author's laboratory
`include potentiation of barbiturates in renal failure, increased response to benzodiazepines in
`severe liver disease, increased neurotoxicity of theophylline in renal failure, increased potency
`of general anesthetics in hemorrhagic hypovolemia, and the steep responder syndrome in
`warfarin therapy. Preclinical pharmacodynamics provides a means for identifying, in advance
`of clinical use, potential risk factors and conditions under which drugs may be subject to
`profound changes in their concentration-effect relationships.
`
`INTRODUCTION
`
`If the process of drug development is to be productive and efficient, the various phases
`of this process must be designed to elicit information which is useful for the subsequent phases
`of development. There must be a logical continuum wherein previous infonnation is used as
`a basis for the design of the next studies. This is particularly important in the planning of
`
`!111egra1io11 of Pharmacokinelics, Pharmacodynamics, and Toxicoki11etics in Ralional
`Drug Developme11/, Edited by A. Yacobi el al., Plenum Press, New York, 1993
`
`7
`
`8
`
`

`

`clinical investigations and the development of clinical protocols because inadequate clinical
`studies can contribute substantially to the cost of a drug development and to the time required
`to bring a new drug on the market.
`
`PRECLINICAL PHARMACOKINETICS AND PHARMACODYNAMICS
`
`The place of preclinical (animal) phannacokinetics in drug development is well estab(cid:173)
`lished. Assessment of drug absorption and elimination kinetics is done as part of the selection
`of the most promising in a series of pharmacologically active compounds. Studies in animals
`are performed also to determine if the candidate compounds are enzyme inducers or inhibitors,
`or if they are subject to other time-dependent effects such as product inhibition or cosubstrate
`depletion. If such is the case, then future clinical studies must be designed to assess the
`magnitude and time course of these alterations in the therapeutically relevant drug concentra(cid:173)
`tion range. Determination of the pharmacokinetics of the drug candidate in several animal
`species is the logical precursor of well-designed animal toxicology studies and provides the
`opportunity to explore interspecies correlations with the ultimate aim of predicting, by
`appropriate extrapolation, the pharmacokinetic characteristics of the compound in man.
`Unlike pharmacokinetics, the role of pharmacodynamics in the preclinical phase of drug
`development is barely in its beginning. This is unfortunate because pharmacodynamics, i.e.
`the relationship between drug concentration in plasma or certain tissue fluids and the intensity
`of drug action, is essential to the optimum interpretation and utilization of phannacokinetic
`information. At present, only one relatively minor aspect of preclinical pharmacodynamics
`appears to be an established part of the drug development process. That aspect is the
`assessment of the pharmacologic activity of the metabolites of a drug or drug candidate. The
`relevance of this assessment to the drug discovery process is obvious. There are, however,
`other aspects of preclinical pharmacodynamics that are important and yet frequently ne(cid:173)
`glected. These include in the first instance the characterization of the relationship between
`drug concentration and intensity of drug action(s), preferably in sufficient detail to permit
`modelling and to recognize time-dependent phenomena such as the development of functional
`tolerance. Several other aspects of preclinical pharmacodynamics can contribute substantially
`to the drug development process. One of these is the use of animal data to predict therapeutic
`and toxic drug concentrations in humans.
`
`EFFECTIVE DRUG CONCENTRATIONS IN ANIMALS AND HUMANS
`
`The plasma concentration of a drug required to elicit a certain (intensity of) action is
`often similar in experimental animals and humans. In a report on the Workshop on the
`Qualitative and Quantitative Comparability of Human and Animal Developmental Neuro(cid:173)
`toxicity, Francis, Kimmel, and Rees (1990) stated that "Comparisons of administered doses
`(resulting in similar effect levels) revealed a wide range of differences across species (up to
`a 10,000-fold difference). On the other hand, comparisons across species using internal
`
`8
`
`9
`
`

`

`(
`t'
`measurements of dose (e.g., blood or brain levels) showed a rema k bl
`
`.
`,,
`11 r a e corre a 1011 genera y,
`1
`a 1 to 2-fold difference). In the case of the antiepileptic drug phenytoin, Ramzan (1990)
`reported that the onset of ataxia occurred in rats at serum unbound d
`t
`t'
`f 6 3
`rug concen ra ions o
`.
`± 1.7 (mean± S.D.) mg/1. The serum total phenytoin concentrations associated with ataxia in
`humans are between 30 and 40 mg/1 (Kutt and co-workers, 1964); the corresponding
`concentrations of unbound drug ar~ between 3 and 6 mg/I based 011 the typical phenytoin
`protein binding of 10 to 15 percent 111 human serum. In another study, neurotoxic manifesta(cid:173)
`tions of phenytoin in pregnant rhesus macaques occurred at plasma concentrations (total drng)
`in excess of 30 µg/ml, "consistent with data reported in mouse, rat, rabbit, dog, rhesus macaque
`and human" (Hendrie and co-workers, 1990). The plasma concentration of the antihyperten(cid:173)
`sive agent nilvadipine associated with a 20 percent reduction of diastolic blood pressure was
`about 20 mg/ml in dogs (Wu and co-workers, 1988) and the same in humans (Cheung and
`co-workers, 1988). The concentration of ethanol in brain, serum and cerebrospinal fluid of
`rats at onset of loss of righting reflex (i.e. sleep) is between 3 and 4 mg/ml or mg/g (Danhof,
`Hisaoka and Levy, 1985); the hypnotic concentrations of ethanol in man are similar.
`It is unfortunate that comparative information on the effective concentrations of new
`drugs in various species of animals and ( eventually) humans is either not obtained or not fully
`utilized in drug development. Knowledge of effective drug concentrations in animals can
`greatly facilitate dose ranging in Phase I studies. There is increasing evidence that, as Gianni
`and co-workers ( 1990) have stated, "preclinical phannacology offers reliable guidelines to
`safely accelerate the process of Phase I trials".
`One must, however, be aware of several important considerations when making inter(cid:173)
`species comparisons of effective drug concentrations. First, the phannacologic endpoint used
`for detenninations of effective concentration must be comparable in the different species.
`Next, attention must be paid to the appropriate fluid or tissue for concentration determination
`in the context of the possibility of a disequilibrium between drug in plasma and drng at the
`site of action (Danhof and Levy, 1984). Differences in plasma protein binding of a drug
`between species must be taken into consideration; concentrations of unbound drug should be
`compared in cases where drug-protein binding is extensive. Also, the possible contribution of
`active metabolites to the pharmacologic effect of a drug must be kept in mind.
`
`ASSESSMENT OF COMPLEX PHARMACODYNAMIC RELATIONSHIPS
`
`Studies in experimental animals can reveal and elucidate complex pharmacodynamic
`relationships which also occur in humans. An excellent example are the pharmacodynamics
`of the coumarin anticoagulants. These agents, of which warfarin and dicumarol are best known
`in the United States, act indirectly and their maximum clinically apparent effect (increase of
`prothrombin time) occurs in man about 2 days after maximum plasma concentrations
`produced by a single, large dose (Nagashima, O'Reilly and Levy, 1969). We have developed
`a pharmacodynamic model which permits resolution of the observed change in prothrombin
`complex activity (which is derived from the prothrombin time) into its components: the
`synthesis and elimination of prothrombin complex activity. The direct effect of the coumarin
`
`9
`
`10
`
`

`

`anticoagulants is the inhibition of the synthesis of prothrombin complex activity (which
`reflects the inhibition of the synthesis of vitamin K dependent clotting factors) and this
`inhibitory effect is related linearly to the logarithm of the drug concentration in plasma without
`any delay (Nagashima, O'Reilly and Levy, 1969). The pharmacodynamic model includes the
`assumption that prothrombin complex activity declines exponentially with time after admini(cid:173)
`stration of a synthesis-blocking dose of the coumarin anticoagulant. Despite the complexity
`of the pharmacodynamic model, it was found to apply equally to humans and rats (Yacobi,
`Wingard and Levy, 1974). This exemplifies the possibility of exploring pharmacodynamic
`modelling approaches in preclinical studies for the purpose of optimizing subsequent clinical
`protocols.
`Another of our studies of warfarin phannacodynamics in rats provided additional,
`valuable information relevant to the therapeutic use of the drug in humans. Warfarin pharma(cid:173)
`codynamics, like the pharmacodynamics of other drugs (Levy, 1985), exhibit pronounced
`inter-individual but relatively little intraindividual variability in humans. We observed such
`inter-individual variability also in rats and found a strong correlation between the slope of the
`anticoagulant effect-log concentration relationship of warfarin and the free fraction value of
`the drug in the serum (Yacobi and Levy, 1977). Based on that observation, Routledge and
`co-workers (1979) recognized a similar relationship in man. Since the serum or plasma free
`fraction value of warfarin can be determined by the in vitro addition of the drug to a drug-free
`serum or plasma sample, one is able to characterize "steep" and "shallow" warfarin responders
`before initiation of therapy.
`
`EFFECT OF DISEASE STATES ON THE KINETICS OF DRUG ACTION
`
`There are many reasons for the large interindividual variability in the pharmacody(cid:173)
`namics of drugs (Levy, 1985). One such reason is the presence of underlying disease. Our
`group has intensively explored this aspect of pharmacodynamics in recent years. One of our
`first efforts in this area was stimulated by a report in 1954 by Dundee and Richards of
`significantly lower loading and maintenance dose requirements for thiopental-mediated
`general anesthesia in uremic patients as compared to patients with normal renal function.
`These investigators also reported that such increased sensitivity to the drug could be produced
`in patients with normal renal function by administration of urea before thiopental. We were
`able to demonstrate the same dose-sparing effect of urea on thiopental in normal rats and we
`established that its mechanism was pharrnacokinetic rather than pharmacodynamic (Danhof
`and Levy, 1985). In further explorations on rats with either surgically or chemically-induced
`renal failure, we found that the concentrations of barbiturates required to produce sleep (loss
`of righting reflex) in rats were substantially decreased by renal failure (Danhof, Hisaoka and
`Levy, 1984). This pharmacodynamic alteration is mediated by an endogenous, dialyzable
`material which accumulates in renal failure (Hisaoka and Levy, 1985). Clearly, the ability to
`discover such effects of disease on drug action in preclinical studies is of enonnous value.
`Another example of the potential utility of preclinical pharrnacodynamic investigations
`derives from a tragic occurrence following the Japanese attack on Pearl Harbor during World
`
`10
`
`11
`
`

`

`War II. Surgery had to be performed on many casualties whose blood volume w
`as severely
`depleted by hemorrhage. The general anesthetic agent used in these procedures w
`as usua ly
`1
`thiopental. As reported by Halford in 1943, "death ensued in enough cases to cau
`, se us to
`abandon it (thiopental) as too dangerous". We found in studies on rats that heinor h
`.
`r ag1c
`.
`.
`.
`.
`hypovolemta caused a pronounced mcrease m central nervous system sensitivity to the
`depressant effect of a barbiturate, an observation which, had it been made before the use of
`thiopental at Pea~l H~rbor,_might have saved h~ndreds oflives (Klockowski and Levy, 1988).
`Theophyllme 1s a widely used bronchod1lator. Its usual therapeutic plasma concentra(cid:173)
`tion range is quite narrow and is frequently exceeded due to pronounced inter- and intraindi(cid:173)
`vidual variations in the total clearance of this drug. High concentrations of theophylline can
`cause neurotoxicity of which the most serious manifestation is generalized seizures that are
`often fatal or the cause of permanent brain damage. Noting that some patients had seizures at
`relatively low (but super therapeutic) plasma theophylline concentrations whereas others did
`not experience seizures even at ten-fold higher concentrations, we explored various potential
`risk factors for theophylline neurotoxicity in rats. We found one such risk factor to be renal
`failure; rats with bilaterally ligated ureters had convulsions at drug concentrations in cerebro(cid:173)
`spinal fluid that were about one-half those in normal controls (Ramzan and Levy, 1987).
`Significantly, Aitken and Martin (1985) concluded from a retrospective review of hospital
`records of patients with theophylline toxicity that "patients with renal dysfunction may be at
`higher risk for life-threatening complications of theophylline intoxication". This important
`observation could have been predicted (and lives could have been saved!) by appropriate
`preclinical studies.
`As a final example of the value of preclinical pharmacodynamics for predicting effects
`of underlying diseases in humans, I cite our experience with the benzodiazepines. Recent
`clinical reports have described pronounced increases in the central nervous system depressant
`effect of a benzodiazepine in hepatic cirrhosis compared to the effect on individuals without
`liver disease at comparable plasma concentrations of unbound drug (Fisch and co-workers
`'
`1986; Bakti and co-workers, 1987). We studied the pharmacokinetics and pharmacodynamics
`of desmethyldiazepam in rats with carbon tetrachloride induced liver dysfunction (Klock(cid:173)
`owski and Levy, to be published). Using rota rod performance as an index of CNS functionality,
`we observed that a serum concentration of about 0.04 mg/1 of unbound desmethyldiazepam
`produced an impairment of about 20 percent in normal rats and of 100 percent in rats with
`liver disease. Again, the preclinical observations could have predicted the clinical effects and
`prevented many cases of unanticipated adverse effects due to benzodiazepines in patients with
`liver disease.
`In conclusion, knowledge derived from preclinical pharmacodynamic studies on suit(cid:173)
`able animal models can be extraordinarily useful for the design and efficient perfonnance of
`subsequent clinical studies, for the development of phannacodynamic models and for antici(cid:173)
`pating and exploring the effects of variables such as underlying diseases on drug concentration
`vs. pharmacologic activity relationships. Drug development will be facilitated and human
`pharmacotherapy will become safer and more effective if properly conducted preclinical
`phannacodynamic studies become an integral part of the drug development process.
`
`11
`
`12
`
`

`

`REFERENCES
`
`Aitken, M. L., and T. R. Martin ( 1985). Life-threatening complications of theophylline
`toxicity are not predicted by serum theophylline levels. Amer. Rev. Resp. Dis., ill,
`A68.
`Bakti, G., H. U. Fisch, G. Karlaganis, C. Minder, and J. Bircher (1987). Mechanism of the
`excessive sedative response of cirrhotics to benzodiazepines: model experiments with
`triazolam. Hepatology, 1, 629-638.
`Cheung, W. K., L. L. Sia, D. L. Woodward, J. F. Graveline, R. E. Desjardins, A. Yacobi, and
`B. M. Silber (1988). Importance of oral dosing rate on the hemodynamic and pharma(cid:173)
`cokinetic profile on nilvadipine. J. Clin. Pharmaco)., 2.8., 1000-1007.
`Danhof, H., M. Hisaoka, and G. Levy (1984). Kinetics of drug action in disease states. II.
`Effect of experimental renal dysfunction on phenobarbital concentrations in rats at onset
`of loss of righting reflex. J. Pharmacol. Exp. Ther., 230, 627-631.
`Danh of, M., and G. Levy ( 1984). Kinetics of drug action in disease states. I. Effect of infusion
`rate on phenobarbital concentrations in serum, brain and CSP of normal rats at onset of
`loss of righting reflex. J. Pharmacol. Exp. Tuer., 229, 44-50.
`Danhof, M., and G. Levy (1985). Kinetics of drug action in disease states. V. Acute effect of
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`Danhof, M., M. Hisaoka, and G. Levy (1985). Kinetics of drug action in disease states XII:
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`Dundee, J. W., and R. K. Richards ( 1954). Effect of azotemia upon the action of intravenous
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`Fisch, H. U., G. Baktir, G. Karlaganis, and J. Bircher (1986). Excessive effects of ben(cid:173)
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`mary and implications. NeurotoxicoI. Terato)., 12, 285- 292.
`Gianni, L., L. Vigano, A. Surbone, D. Ballinari, P. Casali, C. Tarella, and J.M. Collins (1990).
`Pharmacology and clinical toxicity of 4'-iodo-4'- deoxydoxorubicin: An example of
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`Halford, F. J. (1943). A critique of intravenous anesthesia in war surgery. Anesthesiologx, 4,
`67-69.
`Hendrie, T. A., J. R. Rowland, P. E. Binkerd, and A.G. Hendrickx (1990). Developmental
`toxicity and pharmacokinetics of phenytoin in the rhesus macaque: An interspecies
`comparison. Reproductive Toxicol., 1:, 257-266.
`Hisaoka, M., and G. Levy (1985). Kinetics of drug action in disease states. XIII. Effect of
`dialyzable component(s) of uremic blood on phenobarbital concentrations in rats at
`onset of loss of righting reflex. J. Pharmaco). Exp. Ther., 2.34, 180-183.
`Klockowski, P., and G. Levy (1988). Kinetics of drug action in disease states. XXIII. Effect
`of acute hypovolemia on the pharmacodynamics of phenobarbital in rats. J. Ph arm. Sci.,
`77, 365-366.
`
`12
`
`13
`
`

`

`Kutt, H., W. Winters, R. Kolenge, and F. McDowell (1964). Diphenylhydantoin metabolism,
`blood levels and toxicity. Arch. Neuro)., ll, 642-648.
`Levy, G. ( 1985). Variability in animal and human pharmacodynamic studies. In M. Rowland,
`L. B. Sheiner, and J.-L. Steimer (Eds.), Variability in Drug Therapy: Description,
`Estimation, and Control, Raven Press, New York, pp. 125-138.
`Nagashima, R., R. O'Reilly, and G. Levy (1969). Kinetics of pharmacologic effects in man:
`The anticoagulant action of warfarin. Clin. Pharmacol. Ther., 10, 22-35.
`Ramzan, I. (1990). Pharmacodynamics of phenytoin-induced ataxia in rats. Epilepsy Res.,
`.5., 80-83.
`Ramzan, I. M., and G. Levy (1987). Kinetics of drug action. XVIII. Effect of experimental
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