Toxicologic Pathology

http://tpx.sagepub.com/ Differences Between Pharmacokinetics and Toxicokinetics

Peter G. Welling Toxicol Pathol 1995 23: 143 DOI: 10.1177/019262339502300207 The online version of this article can be found at: http://tpx.sagepub.com/content/23/2/143

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Differences Between Pharmacokinetics and Toxicokinetics*

PETER G. WELLING
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48106
ABSTRACT

Pharmacokinetics has evolved into a highly interactive discipline in which the dispositional characteristics of an administered drug are often compared to the time course of observed drug effects. The more recent discipline of toxicokinetics is undergoing a similar, although belated, evolution. While toxicokinetic studies were first intended to demonstrate merely that toxicology test animals received drug, they now provide a critical evaluation of drug disposition at toxicologic doses and also the relationships between toxicokinetic values and the occurrence and time course of toxic events. Different dose levels used in toxicokinetics, compared to pharmacokinetics, give rise to technological changes in such factors as solubility, stability, absorption, presystemic clearance, protein binding, and metabolism that may be influenced by dose size, and may give rise to profound differences in the design and interpretation of studies. Pharmacokinetic and toxicokinetic studies also have different objectives. While preclinical pharmacokinetic and pharmacodynamic studies provide correlates, based on generally well-established parameters, that may provide useful but perhaps not essential information to guide drug dosage in man, information from toxicokinetics and toxicodynamic studies, which is difficult to obtain because of capricious interspecies differences in dispositional characteristics and organ/tissue sensitivities, is critical to predict the behavior and safety of compounds in
man.

Key words.

Drug discovery; pharmacokinetics; toxicokinetics; drug development

INTRODUCTION

Pharmacokinetics and toxicokinetics, together with the closely related disciplines of pharmaco-

from both technological and philosophical perspectives.

PHARMACOKINETICS
Pharmacokinetics has been with us for just over 50 yr and has advanced from the very early concepts of Torsten Teorell ( 19, 20) to the sophisticated pharmacokinetic approaches that are used today. During the 1950s and 1960s, the discipline of pharmacokinetics was landmarked by major contributions from Goldstein (6), Dost (5), Nelson ( 10), Wagner (~ 1 ), and others. During the 1970s, there was rapid expansion in pharmacokinetics, which paralleled advances in analytical instrumentation and computer technology. The rapid growth of pharmacokinetics was accompanied by similar, although somewhat slower, growth in metabolism technology. Pharmacokinetic studies are now conducted dur-

dynamics and toxicodynamics, are rapidly emerging

important components of the drug discovery and development process (12). Pharmacokinetics has played an ever-increasing role in discovery and development during the last 30 yr and is now a critical and highly interactive discipline, contributing to knowledge regarding drug disposition and activity throughout preclinical and clinical drug developas

ment.

Toxicokinetics, on the other hand, is of more reorigin and is currently the topic of much debate. The study of toxicokinetic-toxicodynamics relationships is in its infancy but is evolving rapidly as both technology and acceptance increases for this critical relationship, relevant to all therapeutic areas. The objective of this paper is to compare the disciplines of pharmacokinetics and toxicokinetics
cent
*Address correspondence to: Dr. Peter G. Welling, ParkeDavis Pharmaceutical Research Division. Warner-Lambert Company, Ann Arbor. Michigan 48105.

ing

all

phases of drug discovery

and

development.

from earl/ preclinical bioavailability studies prior

to Lead

Compound declaration

to

the

study ofphar-

macokinetic parameters in patient populations leading to marketing approval submission (2). By definition, pharmacokineuc studies are conducted at 143

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pharmacologic or therapeutic doses in order to characterize drug disposition in experimental animals and humans at therapeutically relevant doses.
PHARMACOKINETICS
AND

PHARMACODYNAMICS

between the time course of circulating drug [or metabolite(s)] and that of toxic events are setting an entirely new dimension to the conduct, interpretation, and meaning of toxicology studies. TECHNICAL DIFFERENCES BETWEEN PHARMACOKINETICS AND TOXICOKINETICS

end unto itself is essentially redundant. Major emphasis in drug disposition studies now is to obtain relationships and correlations among drug absorption, distribution, metabolism, and excretion (ADME) and observed pharmacologic or therapeutic events (23). These types of studies now occur in both preclinical and clinical environments. Appreciation of the importance of pharmacokinetic-pharmacodynamic relationships has provided added interest and impetus to this area of research and has projected these disciplines into a central and critical position in drug discovery and development. This is particularly so in the case of clinical studies. In Phase 1, Phase 2, and Phase 3 clinical studies, blood level determinations and examination of the relationships between these values and observed pharmacologic or therapeutic end points become an integral part of study design protocols. Much of the initiative for these studies has come from the availability of apas an

Pharmacokinetics

Toxicokinetics is a unique expansion of the sciof pharmacokinetics. The major difference between the 2 disciplines, of course, is that toxicokinetic studies are generally carried out at much higher doses than those used in pharmacokinetic studies. In toxicology, the ability of the body to cope with a drug is extended to the absolute limit, indeed, to the point of toxicity. It would therefore be unrealistic to assume that the body could handle administered compounds and their metabolites from these very high doses in a way similar to therapeutic or pharmacologic doses. Toxicokinetics may thus be different from pharmacokinetics, from a technological perspective, in many ways (22). Some of these are summarized here.
ence

Solubility
high doses used in toxicokireadily encounter solubility problems. These may occur during dosage form preparation and administration and also in terms of drug solubility in the gastrointestinal (GI) tract. More seriously, perhaps, this could give rise to drug precipitation in biological fluids and in organs and tissues giving rise to toxicity that may not be associated with the intrinsic pharmacological or toxicological effects of the drug.
netics,
one can

In view of the very

propriate mixed-effect modeling computer programs (14) but much also from the very high interest shown by the U.S. Food and Drug Administration and other regulatory agencies in this new and unique marriage of disciplines ( 11 ).
TOXICOKINETICS The

discipline of toxicokinetics is of far more re-

cent origin than pharmacokinetics. Until the very recent past, blood drug levels had been determined during toxicology trials merely to ensure that the

Stability
Compound stability may be influenced by concentrations and amounts of substances used in toxicology. Traditionally, in toxicology and toxicokinetic studies, drugs may be administered mixed with feed, and this is realistic in terms of resources. Dosing compounds in toxicology studies by gavage doses is labor-intensive and expensive. However, fine dispersion of drug with feed, with possible storage over considerable periods in this finely dispersed form, can give rise to drug degradation problems.

drug was ingested and was systemically available. Safety assessments were routinely based on doseeffect relationships. The situation is rapidly changing and, in fact, mirroring the recent evolution in pharmacokinetics. Toxicokinetic studies are now a necessary and required component of toxicology studies, and it is now an accepted requirement that the ADME of a drug be well characterized in toxicity species with doses at toxicologic levels (4). The very high doses used in toxicology studies compared to those used in pharmacology or therapeutic studies give rise to extensive technical differences between pharmacokinetic and toxicokinetic disciplines, and these are described in detail later. The closely related discipline of toxicodynamics, as well as the relationship between toxicokinetics and toxicodynamics, is of even more recent origin, and there is a scarcity of clearly established toxicokinetic and toxicodynamic relationships. Nonetheless, this area is changing rapidly, and awareness of the relationships

Absorption
cesses,

While most drugs are absorbed by passive proso that the quantity of drug administered should not influence intrinsic absorption rate or efficacy, the amounts of drug administered:during toxicology studies are almost certain to induce some changes in absorption. This may result from limited solubility in the GI tract, giving rise to slower or less efficient absorption, or from pharmacologic or

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toxicologic effects of the compound on other absorption mechanisms and condition of the GI tract.
First-Pass

toxic

this may have a traumatic effect on that may affect drug absorption. distribution. metabolism, or excretion.
events.

physiological feedback

Effect

or

Presystemic

Clearance
The GI or hepatic clearance of drug during absorption is an enzyme-dependent and therefore saturable process. First-pass systemic clearance will inevitably saturate at toxicological doses, giving rise to changes in drug and metabolite systemic availability. There are many examples of this in the literature (1). Bioavailability of compounds may thus be markedly influenced by dose size for these reasons, and it cannot be assumed that bioavailability

Drug Interaction Drug interactions are frequently concentrationdependent, and different types of interactions may occur in toxicity studies compared to pharmacokinetic studies. This is particularly relevant to toxicokinetic studies of drug combinations and of enantiomeric compounds. As already described. most processes in the body, even though they directly involve only passive drug transport, may be affected by saturable processes in
some

in toxicokinetic studies is the same as or even similar to that in pharmacokinetic studies. High drug doses may also give rise to induction of hepatic drugmetabolizing enzymes, which may have toxicokinetic as well as toxicologic sequelae (3).
Protein

Binding Binding of compounds to plasma proteins and other tissues is generally reversible and always saturable (13). Thus, considerable changes may occur in these phenomena at toxicological doses. This can in turn influence drug distribution and penetration into such tissues as the nervous system. This may give rise to different plasma concentration-effect relationships at toxicokinetic doses compared to pharmacokinetic doses. Metabolism As with other enzyme-dependent systems, metabolism of compounds is substrate concentrationdependent (7). Thus, metabolic pathways and metabolic efficiency may differ at toxicological doses relative to therapeutic and pharmacologic doses. This is a critical factor when one considers the importance of comparing the metabolism of a compound in toxicology species to that in humans for toxicology species validation purposes.
Renal Excretion
Renal excretion comprises both saturable and nonsaturable mechanisms and can be markedly influenced by circulating drug concentrations, giving rise to changes in renal excretion efficiency and clearance of drug from the body. This is particularly true for any compound that is actively excreted wholly or partially by the proximal renal tubules.

way or another, and these may affect the toxicokinetics and toxicity profile of an administered compound. Thus, from many technology perspectives, toxicokinetics cannot be considered to be the same as pharmacokinetics but represents an extension of this discipline to examine the behavior of drugs at toxicological doses. PHILOSOPHICAL DIFFERENCES BETWEEN PHARMACOKINETICS AND TOXICOKINETICS

Apart from the preceding technological differmajor difference between pharmacokinetics and toxicokinetics lies in their overall objecences, the

tives. Because toxicokinetic studies are carried out exclusively in animals, it is appropriate to compare the objectives of pharmacokinetic and toxicokinetic studies in these species. The objective of preclinical pharmacokinetic studies is to obtain pharmacokinetic and pharmacodynamic data to provide a link between preclinical studies and humans. The preclinical-clinical link is strengthened if relationships can be established between pharmacokinetic and pharmacodynamic end points in the preclinical species (8). Typically, pharmacologic and pharmacodynamic end points may be used not only to provide additional links between preclinical and clinical studies, but also to better define the activity of the drug. Such quantifiable end points have been described for various therapeutic areas including antiinfectives (minimum inhibitory concentration). cardiovascular agents (blood pressure), central nervous system agents (anticonvulsant effect), immunomodulators (inosine), diabetes (blood sugar). antipsychotics (behavior). analgesics (pain threshold). and cancer che-

motherapy compounds (tumor regression). While the prtclinical--~linical link is useful. and
sometimes v c rv important,. it is seldom essential during a drug development program. Whether or not preclinical information gives sufficient information to accurately predict drug behavior in humans may have little influence on the final decision

Physiological Feedback The high concentrations of drugs used in toxicology studies are, by definition, likely to be toxic to the host. Depending on the site and nature of

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forward with clinical studies and on which direction such studies might take. The situation is different in the case of toxicokinetics. The objective of toxicokinetic studies is to attempt to quantify the pharmacokinetics of the compound in toxicology species at toxicological doses, to establish appropriate drug &dquo;exposure&dquo; in these species (15), and to establish, with priority, metabolic profiles of new chemical entities in the toxicity species relative to humans. The objective of linking toxicokinetics and toxicodynamics is to provide additional relationships between drug exposure and toxic events and to predict toxicity and tolerance in humans based on preclinical information. Whereas pharmacokinetic-pharmacodynamic studies are often facilitated by means of well-established end points, toxicokinetic-toxicodynamic studies are extremely difficult because of the very poor and frequently unpredictable end points in experimental animals and also because of the capricious interspecies differences in organ and tissue sensitivity within animal species and between animal species and humans (9, 16-18). Thus, in pharmacokinetics and pharmacodynamics, preclinical to clinical prediction is relatively straightforward but often not critical to a clinical development program. In toxicokinetics and toxicodynamics, prediction is critical but often extremely difficult to achieve.
to go

REFERENCES

1. Balant LP and McAinsh J (1980). Use of metabolite data in the evaluation of pharmacokinetics and drug action. In: Concepts in Drug Metabolism, P Jenner and B Testa (eds). Marcel Dekker, New York, pp. 331-371. 2. Balant LP, Roseboom H, and Gundert-Remy UM (1990). Pharmacokinetic criteria for drug research and development. In: Advances in Drug Research, Vol. 19, B Testa (ed). Academic Press, London, pp. 6139. 3. Cayen MN and Black HE (1993). Role of toxicokinetics in dose selection for carcinogenicity studies. In: Drug Toxicokinetics, PG Welling and FA de la Iglesia (eds). Marcel Dekker, New York, pp. 69-83. 4. de la Iglesia FA (1993). Perspectives and future directions of toxicokinetics in drug development. In: Drug Toxicokinetics, PG Welling and FA de la Iglesia (eds). Marcel Dekker, New York, pp. 381-402. 5. Dost FH (1953). Der Blütspiegel-kinetik der konzentrationsablaüfe in der Kreislauffüsigkeit. G. Thieme, Leipzig, p. 244. 6. Goldstein A (1949). The interaction of drugs and plasma proteins. Pharmacol. Rev. 1: 102-165. 7. La Du BN Jr (1993). Genetic variations in humans and toxicokinetics. In: Drug Toxicokinetics, PG Welling and FA de la Iglesia (eds). Marcel Dekker, New

CONCLUSIONS Pharmacokinetics and toxicokinetics differ in

terms of goals and

technology as well as philosoph-

ical emphasis in the 2 disciplines. Each discipline continues to play an increasing role in drug discovery and development, but their roles are different. Both are now recognized as critical components of the process, but as different components. Each discipline gives rise to different alliances. Pharmacokinetic studies

York, pp. 221-244. Levy G (1993). The case for preclinical pharmacodynamics. In: Integration of Pharmacokinetics, Pharmacodynamics, and Toxicokinetics in Rational Drug Development, A. Yacobi, JP Skelly, VP Shah, and LZ Benet (eds). American Association of Pharmaceutical Scientists, New York, pp. 7-13. 9. Munro A (1994). Toxicokinetics: What one can and cannot do with plasma concentration. Drug Inform.
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research and

development.

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Pharmacol. 8: 67-94. Welling PG (1994). Role of pharmacokineties in drug discovery and development. In: Pharmacokinetics of Drugs. PG Welling and L Balant (eds). Springer-Verlag. Heidelberg. pp. 3-19. 23. Yasuda SU. Schwartz SL. Wellstein A. and Woosley RL (1993). The integration of pharmacodyamics and pharmacokinetics in rational drug development. In:

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