Clinical Pharmacokinetics 5: 105-136 (1980) 0312-5963/80/0300-0105/$08.00/0 ©ADIS Press Australasia Pty Ltd. All rights reserved.
Clinical Relevance of Pharmacokinetics G. Tognoni, C. Bellantuono, M. Bonati, M. D'incalci, M. Gema, R. Latini, M. Mandelli, M.G. Porro and E. Riva Laboratory of Clinical Pharmacology arid Lombardy Regional Centre for Drug Information, Istituto di Ricerche Farmacologiche 'Mario Negri', Milan
Summary
The importance of a more therapeutically oriented perspective for pharmacokinetics has been repeatedly advocated and stressed during the past few years. ReView of recent publications in this field reveals that the search for solutions to clinically relevant problems is merely a secondary goal in many studies. Hence, to obtain reliable information which can be applied safely in therapeutic practice. studies need to be interpreted critically. After careful analysis of publications on some of the most representative drugs and drug groups (anti-infective agents, antiepileptic drugs, psychotherapeutic drugs, antiarrhythmic agents, digoxin, propranolol, theophylline, warfarin, anticancer agents), tentative guidelines are given for datafor which the clinical relevance is well established, for findings for which the relevance should be checked in routine practice, for areas where much research is still needed before kinetic knowledge can result in improved therapeutic outcome, and for fields where only minor therapeutic advances can be expected fro,!, extended kinetic investigations. Within the general framework of clinical pharmacology, it appears that the use of pharmacokinetics is a fundamental research tool and a useful aid to therapeutic practice only if its limitations are clearly recognised, and if priority is given to creating favourable, controlled conditions for good diagnostic practice, general patient care and compliance of the patient with treatment. A restricted attitude is suggested toward the natural expansion of blood level monitoring, because of the risk that doctors and institutions become 'dependent' on this technique and 10lie their critical capacity in the use of both clinical and kinetic data.
The logical and historical background to this review can briefly be traced to a now classic editorial by Dollery () 973), and more recently to the editorial note with the first issue of this Journal (Avery, 1976). On both occasions, a plea was made for a more therapeutically oriented perspective for pharmacokinetics. In view of the time which has elapsed since then, it is
worth evaluating current. developments in -thiS area, which is now an important part of clinical pharmacology. The interest in the topic has been stressed recently, in an authoritative commentary (Gross, 1978), a review article (Richens and Warrington, 1979), and by the publication of a new journal on therapeutic drug monitoring (Pippenger, I 979a,b).
Clinical Relevance of Pharmacokinetics
106
The selection and organisation of the material given in the present review was based on the following oonsiderations: a) A pharmacokinetic approach can help in understanding the mechanism(s) of drug action and drug response in physiological and pathological states, with a view to improving the efficacy and safety of therapy (Levy, 1974; Gillette and Mitchell, 1975; Sjoqvist et al., 1976; Benet, 1976). b) The literature leaves the impression that repetition largely prevails over acquisition of new knowledge. c) Contrary to what is increasingly happening in other fields of medicine and therapeutics (Chalmers et al., 1977; Selzer, 1978), oomparatively little effort and attention is being directed toward evaluation of the impact of pharmacokinetic knowledge on quality of care in actual clinical practice. d) The few papers critically reviewing published data suggest that the need for careful, systematic validation of results of previous studies is at least as important as the accumulation of data, which are often only publication oriented (Lasagna, 1976; Ingelfmger and Goldman, 1976). e) The application of the data from the literature to the work of practising doctors, both inside and outside hospitals, often leaves the unoomfortable impression that the kinetic information hardly fits the actual
clinical situation, where confounding but unavoidable factors such as complicated and/ or ill defined diseases, compliance, organisation of patient care and diagnostic inaccuracy, often over-ride application of sophisticated kinetic knowledge (Liverpool Therapeutics Group, 1978, Boethius and Sjoqvist, 1978). o The application of kinetic knowledge to therapeutics should be questioned frequently and directly to check its immediate and educational advantages (Ogilvie and Ruedy, 1972; Peck et al., 1973). In this review, attention is focused and considerations are based on the drugs and drug groups that have been most extensively investigated over the last few years, and is organised as follows: 1) General principles and concepts frequently used in defming the kinetic prome of a drug, with an assessment of their clinical importance and the need for future investigation (see sections 1 and 2). 2) A quantitative and partially qualitative evaluation of the literature published over the last 3 years to indicate the degree of innovation and change of clinical interest in the pharmacokinetic literature (see section 3). 3) An analysis of individual drugs and drug groups with regard to the clinical relevance of their kinetic properties (see section 4).
.....--- Pharmacokinetics - - - - ,
Dose - - - - - - Blood - - - concentration
+
Receptor site- - - concentration L--_ _ _
-+
Pharmacological - - - response
+
Clinical response Therapeutic outcome
Pharmacodynamics-_ _ _ _ _ _ _~
Fig. 1. Schematic representation of principal factors and terms involved in drug dosage and response.
107
Clinical Relevance of Pharmacokinetics
Table I. Main variables and kinetic parameters in drug disposition Main variables
Kinetic parameters
Absorption
Pharmaceutical formulation Gastrointestinal motility Gastrointestinal pH Blood flow in gastrointestinal tract Permeability constants Presence of active saturable transport
Rate constant of absorption Bioavailability Area under the plasma concentration-time curve
Distribution
Body size and composition Blood flow in various organs Binding (plasma and tissue) Permeability constants
Apparent volume of distribution Plasma protein binding
Elimination
Kidney and liver function Blood flow in eliminating organs
Rate constant of elimination Slope of last linear phase of the plasma concentration -time curve Michaelis-Menten equation parameters for saturable elimination processes (V max; Km) Apparent plasma clearance Apparent plasma (elimination phase) half-life
Plasma protein binding
1. General Principles The question posed in the title is readily understood when the sequence from drug dose to drug response is analysed according to the classic scheme in figure I (see further Sheiner and Tozer, 1978). The question can be reformulated as follows: how and how far is and/ or can the information gained in the pharmacokinetic phase be used to optimise and explain pharmacodynamic aspects? The definition of kinetics accepted here is fairly comprehensive. It only excludes: a) Construction of models and their mathematical interpretation. b) Clinical studies where drug concentrations to be reported (if at alI) are one of many items of information set out in the research protocol, without any specific discussion of their relationship with clinical effects.
The step 'dose to blood concentration' has been extensively investigated; as the importance of overcoming or at least describing and quantifying interindividual differences in drug disposition became evident at an early stage. The rapid development of reliable analytical methods and of mathematical models more fitted to actual pathophysiological situations was both a prerequisite and a consequence of this work (Koch-Weser, 1972; Gillette and Mitchell, 1975; Rowland, 1978). The 'dose to blood concentration' relationship is divided into its component parts in table I, which indicates the main variables and relevant kinetic parameters. Research in this area has provided much insight and some solutions, butit has also identified further variability factors which define new areas of research and indicate both the possibilities and the limitations of fmding a direct relationship between pharmacokinetics and pharmacodynamics.
Clinical Relevance of Pharmacokinetics
2. Some Problems Encountered in Clinical Pharmacokinetic Investigation 2.1 Analytical Methods The widespread adoption of chromatographic techniques (GLC, HPLC and GLC-MS) should gradually minimise problems of lack of specificity (e.g. quinidine; Kessler et al., 1974) and/ or sensitivity (see propranolol and tricyclic antidepressants). Reproducibility has become a matter for major concern as measurement of drug concentrations in biological fluids enters routine clinical practice. Comparison of data obtained by assay procedures with impressive coefficients of variation can be dangerously misleading. Quality control programmes have been proposed to ensure reliability in easy and economical techni. ques (Richens, 1978; McCormick et al., 1978).
2.2 Protein Binding Alteration in protein binding has been found to influence the kinetics and relationship of plasma total drug concentration (Le. bound + unbound drug) to clinical effect· of some drugs; the free fraction of which can be modified by pathophysiological states and by endogenous and exogenous substances. The potential value of measuring the free drug concentration in clinical practice has been discussed by many authors for some drugs and groups of patients (e.g. phenytoin in uraemia; disopyramide in ventricular arrhythmias; imipramine in endogenous depression).
108
2.4 Drug Metabolite(s) and Optical Isomers Development of this area of research depends on the availability of specific and sensitive analytical methods. Different intrinsic activity of metabolite(s) should be taken into account in the overall activity of drugs administered (e.g.· many antitumour agents; procainamide; carbamazepine; ~-adrenoceptor blocking drugs such as propranolol, alprenolol, acebutolol). Analytical problems are still a limitation to more thorough investigation of optical isomers (e.g. warfarin).
2.5 Mechanism of Action at Receptor Site Irreversible binding to (e.g. alkylating agents) or irreversible modification of the receptor (e.g. antibiotics) could be reasons for time courses of effects which are hardly reflected by the time course of drug concentration in the blood.
2.6 Multiple Pharmacological Actions Often the detectable response is the sum of discrete elementary actions of the drug (e.g. ~-blockers); sometimes modulated by host physiological feedback mechanisms. In this case, any search for a correlation between blood concentration and response is not only difficult, but also even theoretically unsound.
2.7 Intrinsic Variability of the Receptor· 2.3 Drug Transfer to the Site of Action An active transport system is known to exist for some drugs (e.g. methotrexate and 5-fluorouraciJ). The 'blood concentration-response' relationship·can be assumed to be more complex than afirst order rate process. Only indirect studies in man can be expected and findings· must be extrapolated from animal models.
A different degree of affinity and an unpredictable pattern of response of the receptor are often evoked to explain matters when a study fails to document a satisfactory relationship between blood concentration and pharmacological response. Because of the lack of knowledge about most receptors, and consequently about their interactions with drugs, these hypotheses are likely to remain issues for speculation and basic research for a good while yet.
Clinical Relevance of Pharmacokinetics
109
Table II. Survey of clinical pharmacokinetic literature from 4 clinical pharmacology journals and 4 general medical journals Drug
Digoxin Phenytoin Procainamide Propranolol Theophylline Warfarin Phenobarbitone Lignocaine
Clinical pharmacology
General
CPT
JCP
BJCP
20
4
5 6
13
17
2
8
9
9
5 2
2 2
EJCP
JAMA
9
8 2
7
11 4
3 1
6
1
4
BMJ
3
Lancet
6 19 1 3
2
5 2
NEJM
4
6
2
2
1
3
2
3
3
Abbreviations CPT Clinical Pharmacology and Therapeutics JCP Journal of Clinical Pharmacology BJCP British Journal of Pharmacology EJCP European Journal of Clinical Pharmacology JAM A = Journal of the American Medical Association NEJM New England Journal of Medicine BMJ 'British Medical Journal
2.8 Quantitative Measurement of Clinical Drug Effects In general, the outcome of therapy can hardly be measured with the same reliability as drug concentrations in biological fluids. The extreme example of this situation can be· seen with psychotherapeutic drugs. The same problem, though to different degrees, exists with most of the drugs discussed in this review.
b) Ratio of unchanged drug to active metabolite(s), and relative concentrations of isomers . c) Physiological control mechanisms d) An irreversible response can also become proportional to steady-state blood concentrations (see section 2.5).
3. Survey of Published Literature (J975-1978)
A representative but not exhaustive, analysis of published papers has been made to give a quantitative Repeated administration of a drug (constant intra- and partially qualitative description of the distribution venous infusion or multiple dosing) is closer than of interests in kinetic research. The general assumpother regimens to the conditions of use of most drugs tion was that a synopsis of scientiflc output over a in therapeutic practice. When steady-state blood con- certain period of time could supply useful informacentrations are attained or blood concentrations are . tion in areas of innovation, degree of transfer and use maintained constant for a deflnite period of time the of kinetic knowledge from pharmacological to medifollowing variables can reasonably be expected to cal literature and research trends and needs. The following (necessarily oversimplifled) criteria stabilise to a signiflcant degree: were adopted to select and screen the literature: a) Drug concentration at the site of action 2.9 Appropriate Experimental Dosage Regimens
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and also to age. Different key words had to be used for subject areas in a) and b). as articles from the two sources do not lend themselves to the same classification. The classification of articles under ·efficacy· is restricted to b), because those reviewed for a) do mostly take efficacy into account but only as part of the general scheme recommended for reviews, not as a specific goal of
states: Tobramycin kinetics in kwashiorkor· to antibiotics and pathophysiological states; Tetracyctine kinetics in elderly people and in patients with achlorhydria· to both the above areas
Criteria for classification of articles The main explicitly stated objective(s) of each paper determines its allocation to one or more subject areas. e.g.: ·Drug kinetics in protein malnutrition· is allocated to pathophysiokl2ical
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Fig. 2. Survey of literature from the journal Clinical Pharmacokinetics. al Articles published in Clinical Pharmacokinetics bl Current literature references section of Clinical Pharmacokinetics
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111
Oinical Relevance of Pharmacokinetics
a) 'Clinical Pharmacokinetics' was analysed first as the journal formally oriented to the questions dealt with in this review (Avery, 1976). Articles and reviews published in that journal from January 1976 to December 1978 were examined and grouped according to pathophysiological state, drug, drug class, clinical effect, etc. (fig. 2). b) The same criteria were applied to the references published in each issue of this journal (representing the period 1975 to 1978) under 'Current Literature References' (fig. 2), which were assumed to represent a selection of papers falling within the definition of kinetics accepted in section I. The pattern of distribution of drugs does not differ significantly between a and b. The impressive number of articles devoted to antibiotics contributes substantially also to the investigative effort within the context of 'disease state' and 'age' in b above. Far from being
40
30
38
an indication of advanced development in this field, these data are the sum of repetitive articles and special issues where the profile of an antibiotic (often new) is built up of many small reports obtained in patients (mainly renal) and in various age groups. The term 'efficacy' has been used to classify studies dealing explicitly with whether a correlation exists between kinetic behaviour (mainly blood concentrations) and therapeutic outcome. Psychotherapeutic drugs are the most represented drug group under this heading. A more detailed analysis of the number (table II; fig. 3) and contents (table III) of articles on some of the kinetically most interesting drugs was made by screening 4 leading journals in the field of clinical pharmacology and 4 of the most authoritative general medical journals. The quantitative evidence in figures 2 and 3 and table II is in itself support for the selection of drugs discussed under specific subheadings in section 4. Further explanation of the choice of drugs to ~ dis-
40
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Fig. 3. Analysis of literature on clinical pharmacokinetics published in (a) 4 clinical pharmacology joumalsand (b) 4 general medical joumals.
Clinical Relevance of Pharmacokinetics
112
Table III. Survey of literature. Investigative aims of pharmacokinetic studies
Drug
Phenobarbitone Plasma vs CSF vs brain levels Plasma vs saliva levels Kinetics vs age Methods of dose adjustment Plasma levels vs clinical effects Phenytoin Bioavailability Plasma protein binding (normal and pathological) Plasma vs saliva levels Plasma vs CSF vs brain levels Kinetics in 'normal', subjects Kinetics vs age
Clinical pharmacoiogy journals
General medicai journals
Study of brain levels possibly relevant 1
3
Special disposition in neonates well studied
2
7 10
3
2
2
1
Dose-dependent kinetics well studied in adults and children
6
1 B
Plasma levels vs clinical effects
3
10
Procainamide (PA) Bioavailability Acetylator phenotype and methods of dose adjustment Kinetics in disease
5
Lignocaine (lidocaine) Kinetics of active metabolites
Kinetics in disease Models Methods of dose adjustment Plasma levels vs clinical effects Digoxin Bioavailability Plasma vs saliva levels Milk excretion Plasma vs myocardium levels Kinetics in disease
Many, mainly repetitive, studies on bioavailability Decreased protein binding in disease seems to have clinical relevance Study of brain levels possibly relevant
2 5
Kinetics in disease Methods of dose'adjustment
Models Procainamide (PAl and N-acetylprocainamide (NAPA; active metabolite)
Yield in information
Kinetics of PA and its active metabolite NAPA well studied
6 1 15
Kinetics vs activity of PA plus NAPA needs further study Use of NAPA as a drug itself needs study
2 3
Methods for predicting dose regimens widely criticised
5
Kinetics and effects of the drug, and its active metabolites needs further study Kinetics well studied in different' conditions
3 2
9 2
3 4
6
Kinetics well studied in different conditions
ainical Relevance of Pharmacokinetics
113
Table III, (continued) Drug
Clinical pharmacology joumals
General medical journals
Kinetics vs age Methods of dose adjustment Plasma levels vs clinical effects
2 2 3
9 9
Yield in information
Measurement of plasma levels helpful in suspected under-or overdosage Overlap between toxic and therapeutic levels
Propranolol Bioavailability and first-pass effect Plasma protein binding Kinetics in normal individuals Kinetics in disease Kinetics in old age Models Levels vs effects
3
2
3 2
5 1 2 9
3
High interindividual variability in disposition Kinetics well studied in different conditions
3
Good correlation of plasma levels with pharmacological effects (~-blockade) but not with therapeutic effect (blood pressure lowering)
7
Kinetics well studied in different conditions
Theophylline Bioavailability Placental transfer Metabolism Kinetics in disease Kinetics vs age Methods of dose adjustment
4 1 4
3 4
Therapeutic range well established for asthma; to be verified for apnoeic prematures
Warfarin Plasma protein binding Milk excretion Kinetics and interactions of optical isomers Kinetics in disease Clearance (or levels) vs effects (prothrombin time)
3
Relevance of protein binding shown clearly in various conditions
2
3
Kinetics and activity of optical isomers is still an open field of research Levels vs effects (prothrombin time) studies have investigational but not direct clinical significa nce
Methods of dose adjustment
The first column lists the main aim of research, Figures in columns 2 and 3 refer to the frequency of their appearance in the literature screened, The brief comments in the last column are a suggestion of the most interesting lines of further investigation, The pathological conditions reported under the word 'disease' for different drugs are as follows:
Phenytoin: Haemodialysed patients Procainamide: Renal. hepatic, cardiac failure Lignocaine: Renal, hepatic and cardiac failure, myocardial infarction Digoxin: Renal failure, hepatitis, thyroid dysfunction
Propranolol: Liver, thyroid and renal dysfunction, coeliac and Crohn's disease, ulcerative colitis, rheumatoid arthritis, staphylococcal pneumonia ' Theophylline: Pulmonary oedema, haemodialysed patients, asthma, obesity, cirrhosis, viral respiratory illness Warfarin: Iron deficiency ,
114
Clinical Relevance of Pharmacokinetics
Table IV. Papers on antibiotic kinetics
Antibiotic class or problem
Year of publication
Aminoglycosides Cephalosporins Penicillins Antituberculosis drugs Tetracyclines Other antibiotics Protein binding and tissue distribution Bioavailability Renal failure and dialysis Uver and other pathologies Total
1 From Clinical references section).
1976'
1977'
29 18 11 2 9 16 14
35 22 21 9 18 12 25
3
18 8
3 27 8
128
180
Pharmacokinetics (current
literature
cussed is nevertheless necessary in order to understand the approach adopted. Drugs are selected to represent (not to cover; e.g. propranolol for ~-adrenoceptor blocking drugs) largely different therapeutic classes, which are used in and refer to heterogeneous clinical situations, and which can be considered a good indicator of the whole spectrum of questions faced by kinetics when applied to clinical problems. The information published in the 8 journals considered (table II) is by no means exhaustive (for instance, a substantial amount of data on cardiovascular drugs is published in specialty cardiology journals), but it has been assumed to be a rough indicator of how information is exchanged and distributed between clinical pharmacology and medical research (which cannot yet be considered the same as clinical practice!). The proftles proposed for each drug in section 4 refer, however, to the broader spectrum of all rerevant literature. Table II shows that much attention is still focused on 'old' drugs (e.g. phenytoin and digoxin), on which
data have been accumulating for many years, suggesting that enough information should have been available for an evaluation of it" impact on the quality of clinical care. The qualitative analysis in table III does not include antibiotics, psychotherapeutic drugs or anticancer agents. More frequently than is the case for other drugs, data for these groups are published in specialty journals, which have been included under the subheadings in section 4.
4. Analysis of the Clinical Relevance of Kinetic Studies 4.1 Anti-infective Agents The non-pharmacological criteria usually considered when evaluating the clinical relevance of pharmacokinetics appear particularly important in the field of anti-infective therapy. Factors such as the accuracy of the clinical and bacteriological diagnosis, patterns of microbial resistance, localisation of the infective process, immune status of the patient and the confounding effect of concomitant therapy and/or pathologies (mainly in 'at-risk' patients), are likely to be more relevant in determining the course (length and severity) of the disease; the outcome of which can be the only reliable measure of the efficacy of the treatment (Mattie, 1977; Ellis Pegler, 1978; Kunin, 1974; Lorian, 1977). Within the limitations imposed by these factors, the kinetic approach to anti-infective therapy has attracted considerable attention in the last few years (Smith and Tucker, 1977; table IV). Each of the main antibiotic classes has been the subject of investigation for specific kinetic properties (table V).
4.1.1 Tissue Penetration and Distribution Most studies of antibiotic kinetics have involved tissue penetration and distribution. Four questions summarise the present state· of research. 1) How to ensure the presence of the appropriate anti-infective agent in adequate concentration in 'deep seated' and/or poorly irrigated sites of infection?
Oinical Relevance of Pharmacokinetics
115
Table V. Outline of kinetic knowledge on anti-infective agents Problem
Antibiotic class
Degree of clinically relevant knowledge
References 1
Absorption
Penicillins; tetracyclines; urinary tract antiseptics
Absorption: Bioavailability of different brands of tetracyclines still a problem? Non-irritating nitrofurantoin preparations possibly useful
Rosenberg and Bates (1976); Melander (1978); Hamilton-Miller (1978)
Protein binding
Cephalosporins; isoxazolylpenicillins; sulphonamides
Still undefined with respect to diffusion in specific sites and tissues (see text)
Craig and Welling (1977)
Tissue distribution
All
Insufficient (see text)
Craig and Welling (1977)
Metabolism
Isoniazid; rifampicin; chloramphenicol; thiamphenicol
Good
Reidenberg (1977); Bond (1978); Acocella (1978)
Elimination
Aminoglycosides; cephalosporins; penicillins
Good. Influence of all degrees of renal impairment more thoroughly investigated. Relation of tissue concentration to toxicity needs more data
Fabre and Balant (1976); Dettli (1976); Yaffe et al. (1977); Philipson (1977); Gibson and Nelson (1971); Duchin and Schrier (1978); du Souich et al. (1978)
Age
All
Good
Wallace and Watanabe (1977); Tognoni (1977); Mandelli and Tognoni (1977); Eichenwald and McCracken (1978); McCracken and Eichenwald (1978)
1 These papers and reviews are complementary to those quoted in the text, as they give additional detailed information on the specific problems considered here. Kinetic findings do not have always the seme clinical relevance. The following are but few examples of: Definite clinical interest: isoniazid and rifampicin should.be given hours apart from meals to avoid interference with absorption (Melander, 1978); higher dosages of ampicillin are needed in pregnant women (Philipson, 1977); an increased dosage of methicillin and dicloxacillin is needed in patients with cystic fibrosis (Yaffe et aI., 1977); caution is required when administering chloramphenicol to patients with hepatic dysfunction (Boston, 1978). . Not proven clinical importance: a longer half-life of amikacin is described in neonates with respiratory acidosis (du Souich et al., 1978). as it is for carbenicillin and clindamycin in serious liver disease (Bond, 1978; Blaschka, 1977); obesity or fasting can modify disposition of sulphonamides (Reidenberg, 1977).
Clinical Relevance of Pharmacokinetics
2) How and to what extent does protein binding modify between serum and other fluids and tissues in actual clinical situations? 3) Does knowledge of patterns of tissue accumulation give a better basis of understanding organ toxicity and/or drug specificity for a given compartment? 4) Can models (either in vitro, in situ or mathematical) help in optimising dosage regimens? Favourable clinical data have been published on bone penetration of clindamycin and lincomycin after repeated treatment (Schurmann et al., 1975; Schneider and Visconti, 1977). No consistent data are available for cephalosporins although a single high dose of cefazolin has been found to reach satisfactory tissue levels (Parsons et ai., 1978). No systematic studies however, are yet available on comparative groups of patients to permit reliable conclusions on dosage regimens, and/ or on the correlation of dose with therapeutic efficacy. The same is true for the much debated question of antibiotic diffusion in exudative and inflammatory areas (Editorial, 1973; Craig and Kunin, 1976; Kunin, 1974; Peterson and Gerding, 1978; Wise et al., 1978). The degree of binding has been claimed both to be and not to be, a major limiting factor. The physicochemical properties of various molecules, local conditions of blood flow and of tissue organisation and necrosis also have an important role in influencing antibiotic diffusion (Craig and Welling, 1977; Gillett and Wise, 1978; Mennheimer and Brorson, 1976). The wide interest in protein binding (see table IV; the number of articles could also be assumed to reflect the ease of such measurements) has not yet produced conclusive evidence that the degree of binding has direct therapeutic or toxicological consequences. This is not surprising, however, as antibacterial activity even at sub-inhibitory levels, has been documented (Shah· et al., 1976; Mattie, 1977). Animal and human data published to date suggest accumulation of aminoglycosides in renal tissue, which is possibly correlated with toxicity (Edwards et ai., 1976; Schentag et al., 1978). Predicted and measured concentrations correspond to a kinetic
116
model of a biphasic decline, including gentamicin storage in a deep compartment (Schentag and Jusko, 1977a,b). It will be important to see how these findings will be transferred into clinical practice where area under the plasma concentration and trough levels have been usually considered to offer accurate prediction of renal toxicity. The wider use of newer aminoglycosides and the suggested differences in their accumulation in renal tissue will possibly give in the near future interesting information in this field. Peak plasma concentrations corresponding to high perilymph concentrations have been correlated more frequently with ototoxicity. This however, has also been documented with high trough levels, suggesting that the A UC may be a more comprehensive term of reference (Barza and Lauermann, 1978). No consistent data are available on the relationship between concentrations in plasma and CSF and in the infected brain in clinical situations (Barling and Selkon, 1978). The contribution of meningeal inflammation and the role of CSF proteins in diffusion is still open to debate. Therapeutically effective clinical guidelines can therefore be considered to be based on very tentative kinetic information on the degree of permeability. The search for an optimum dosage schedule for different types of urinary tract infection has long looked to kinetics for useful information. An in vitro model of the urinary bladder in which the course of antibiotic concentrations in the urine was reproduced (Greenwood and O'Grady, 1977) has shown that doses lower than normal are equally effective in uncomplicated urinary infection. This is in agreement with evidence from clinical trials. A dosage regimen assuring effective concentrations of the appropriate anti-infective agent in serum and urine is required to control infections involving renal' parenchyma, especially in patients with complicating. fact<:>rs and/or pathologies (Naumann, 1978), or in relapse after multiple treatments. Overall consideration of the data analysed so far and of the more detailed information reported in the literature quoted in table V, fully justifies th~ statements made at the beginning of this section. Im-
Clinical Relevance of Pharmacokinetics
proved analytical techniques will possibly improve the quality and completeness of kinetic knowledge, especially of distribution in biological fluids and tissues.
4.1.2 Plasma Concentration Monitoring The advantages of monitoring plasma drug concentrations (mainly aminoglycosides) are established for a minority of treated patients (Reeves, 1977; Flynn et al., 1978). The cost/benefit ratio should be better established, however, as attention to kinetic properties possibly backed up by the use of appropriate nomograms seems to provide the maximum information for use in clinical practice. Doubts about the universal significance of therapeutic plasma concentration ranges, and the still unanswered question of the correlation between plasma concentration and degree and course of toxicity, further point to the need for assessment of the value of monitoring services (Wilkinson et al., 1977; Noone et ai., 1978).
4.2 Antiepileptic Drugs The study of the clinical pharmacokinetics of antiepileptic drugs has been a major step in the management of epilepsy. Since the first study by Buchthal et al. (1960), the development of more reliable analytical techniques has resulted in accumulation of considerable information about these drugs and the clinical relevance of application of their kinetic properties to therapeutics. The usefulness of a kinetic approach to therapy, possibly linked with plasma concentration monitoring, is well recognised in the following areas (Woodbury et al., 1972; Eadie and Tyrer, 1974; Van der Kleijn et al., 1975; Morselli, 1976; Rane and Wilson, 1976; Eadie et al., 1977; Richens, 1977a; Milano Collaborative Group for Studies on Epilepsy, 1977): a) At the outset of therapy to facilitate selection of the most appropriate dosage regimen. b) Periodic use during long term therapy, taking into consideration age requirements and the course of the disease.
117
c) During pregnancy and the puerperium. d) Any time an intercurrent illness is likely to alter the normal pharmacological control of epilepsy. e) When lack of efficacy and/ or occurrence of side or toxic effects appear to be attributable to drug interaction. f) Where it is necessary to check patient compliance. g) When epileptic symptoms are not controlled and there are no other apparent reasons for therapeutic failure. The individual kinetic characteristics of particular drugs in this class should be considered within the very broad limits of these guidelines. Clinical and comprehensive kinetic profiles of the various drugs have been published in reviews (Eadie, 1976; Hvidberg and Dam, 1976; Pinder et ai., 1976; Pinder et ai., 1977; Bertilsson, 1978; Browne, 1978). For the purpose of this review, table VI contains the kinetic features which should be considered most carefully for each drug in routine clinical practice. In addition to these well known details, clarification of the following areas should improve therapy. J) The contributory role of the active 10, II epoxide metabolite of carbamazepine in the therapeutic and/or side effects of the parent compound (Bertilsson, 1978). 2) A better definition of the therapeutically effective plasma concentration range and of the time course of therapeutic efficacy of clonazepam and valproic acid, together with delineation of the full pattern of their possible active metabolites (Pinder et al., 1976; Pinder et al., 1977). 3) How and whether study of the relationship between plasma and brain concentrations would improve understanding of 'drug resistance'. Data in this field are scarce, and do not constitute conclusive evidence (Sherwin et al., 1973; Sherwin et al., 1977; Morselli et al., 1977; Houghton et al., 1975; Vajda et aI., 1974; Friis and Christiansen, 1978; Porro et aI., unpublished results). The question raised repeatedly in recent years is whether and how appropriate general criteria of diagnosis and follow-
Clinical Relevance of Pharmacokinetics
118
Table VI. Kinetic characteristics of antiepileptic drugs
Drug
Clinical relevance of kinetics
Phenytoin
Well established relationship between plasma levels and therapeutic and toxic effects Absorption depends strictly on the pharmaceutical formulation Dose-dependent kinetics occurs within therapeutic range Increase of free fraction in renal disease, compensated by higher Vd and plasma clearance (Odar"Cederlof and Borga, 1974) and restored to normal by peritoneal dialysis (Andreasen, 1974) and renal transplantation (Odar-Cederlof, 1977) Dosage adjustment not required in liver disease (Blaschke, 1977) Limited clinical value of predictive nomograms (Richens, 1977b; Ludden et al., 1977)
Phenobarbitone
Well established relationship between plasma levels and therapeutic and toxic effects Renal excretion of unchanged phenobarbitone to some extent pH-dependent Careful control of plasma levels suggested especially in neonates and early infancy to minimise (delayed?) side effects (Richens, 1976a) Significance of phenobarbitone as active metabolite of primidone and/or of primidone plasma levels is still under discussion (Richens, 1976a) Conversion of primidone to phenobarbitone a saturable process at large primidone doses? (Gallagher and Baumel, 1972)
Ethosuximide
Well established therapeutic plasma levels See text for indications of monitoring plasma levels, particularly in paediatrics
Carbamazepine
Further evaluation required for proposed therapeutic and toxic plasma levels (Bertilsson, 1978) Unpredictable absorption (Morselli et aI., 1975) Shorter half-life during long term therapy (Bertilsson, 1978) Individual adjustment of daily dosage schedule minimises side effects (Bertilsson, 1978) See text for 'epoxide'
Clonazepam
See text for main open problems requiring study Does cfinically documented 'tolerance' have any relationship with kinetic behaviour? (Pinder et aI., 1976)
Valproic acid
See text for main open problems requiring study
up are applied in routine clinical practice (Hopkins and Scambler, 1977; Reynolds, \978) in order to permit optimum use of kinetic knowledge. This suggests that kinetic investigations do not now have high priority in anticonvulsant therapy, especially in relation to development of new drugs. However, reliable,
sensitive and rapid analytical methods can promote kinetics as a supporting tool in a number of areas such as in testing therapeutic potential of single drug therapy; in carefully planned long term clinical observations of well defined populations; in clinical trials comparing drug efficacy; and with epidemiological
Clinical Relevance of Pharmacokinetics
surveillance data (Coatsworth, 1971; Dam, I 975; Richens, 1976b; Shorvon et aI., 1978; Masland, 1978). This is a limited discussion on proper use of antiepileptic drug measurements in situations where efforts are primarily aimed at optimising the overall 'care' of epileptic patients (Milano Collaborative Group for Studies on Epilepsy, 1977; Reynolds, 1978). 4.3 Psychotherapeutic Drugs The search for a satisfactory correlation between a kinetic approach to drug therapy and clinical response could be expected to be largely frustrating in this field. Intrinsic confounding factors such as lack of diagnostic specificity, high incidence of placebo response, difficulty in quantification of therapeutic efficacy in acute and even more so in long term treatment, combine with the variable criteria of drug utilisation in different clinical settings to produce high unpredictability. When these general statements are applied to individual therapeutic classes some distinctions must be made. Available information suggests a decreasing degree of possible correlation of drug concentrations with clinical response - from lithium, to tricyclic antidepressants, to antipsychotics and benzodiazepines.
4.3.1 Lithium Clinically satisfactory guidelines are available for lithium (table VII); the narrow therapeutic range of the drug being firmly established (Amdisen, 1977). Only marginal additional information can be expected for this drug. Research is now more concentrated on assessment of the incidence and degree of renal damage in long term users. Data obtained in different series of patients are not in agreement, possibly because they reflect different dosage regimens (Burrows et al., 1978; Hullin et al., 1979). 4.3.2 Tricyclic Antidepressants Tricyclic antidepressants have received the most attention. For a long time they appeared to be the
119
Table VII. Guidelines to monitoring lithium therapy (Amdisen. 1977)
1. Biological half-life 7 to 20h; steady-state reached over 2 to 6 days. Divided daily dosage schedule recommended. preferably with lithium carbonate. 2. Narrow therapeutic range: 0.60 to 1.20mEq/L. Toxicity over 1.5mEq/L. 4.5mEq/L may be lethal. 3. Repeated monitoring of standardised 12h serum lithium concentration 112h -st SU) is mandatory. Whole blood and/or saliva possible altemative to serum? 4. Dose/serum level ratio depending on renal clearance which is reduced by sodium depletion and in impaired renal function.
ideal drugs for documenting the possibility of a quantitative approach to psychiatric care. The amount of data collected, following the 'amine hypothesis' of depression, the impressive evidence of reproducible and predictable individual kinetic proftles, access to 'brain markers' in the cerebrospinal fluid (CSF), and the development of analytical techniques for large scale trials are some of the major factors that have contributed to the interest shown by pharmacologists and clinicians in this field of research. Table VIII summarises the results obtained in 18 of the most notable controlled trials published since 1970. The evidence of a positive correlation between plasma concentration and therapeutic response is contradicted by other authors who draw negative conclusions about the usefulness of kinetic data to improve the therapeutic outcome (Coppen et aI., I 978a). Further disturbing observations relate to the inconsistency of diagnostic classifications, and to disagreement on what should be considered a therapeutic plasma concentration range: a narrow window (50 to 150ng/ml) and 'self-inhibiting action' at higher levels seem to be accepted for nortriptyline in endogenous depression (Kragh-Sorensen et aI., 1976), While contradictory data are given for a 'critical lower limit' for amitriptyline (> 120? or > 200ng/ml?) [Braithwaite et al., 1972; Kupfer et al., 1977) and for
Clinical Relevance of Pharmacokinetics
120
Table VIII. Major controlled trials on plasma concentrations vs therapeutic response of tricyclic antidepressants (1970-1978) No. studies
No. patients
Drug'
Type of depression
Correlation
NTP; IMI AMT; NTP; PTP AMT; PTP; NTP AMT
Endogenous Heterogeneous Heterogeneous Primary
+ + +
Sweden-Denmark USA UK
5 6 3
173 174 64 32
Australia
2
112
NTP
Heterogeneous
54
AMT
Endogenous
WHO Multicentre study 18
609
References The following references include both comprehensive reviews of studies published before 1977 and the more recent original articles: Gram (1977); Montgomery et al. (1978); Coppen et al. (1978a,b); Kupfer et al. (1977); Ziegler et al. (1977); Biggs and Ziegler (1977). 1 Abbreviations PTP = protriptyline; NTP = nortriptyline; IMI = imipramine; AMT = amitriptyline.
imipramine (> 150? or > 240ng/ml?) [Reisby et aI., 1977; Glassman et aI., 1977], but no upper limits are proposed for these two drugs. Monitoring programmes (Editorial, 1978) are likely to add little information. The very recent rmding that a single nortriptyline spot level at 48 hours is a good predictor of steady-state plasma concentrations is stimulating, as it suggests a procedure compatible with most routine practices. Data do not, however, answer the more basic question about the positive correlation between steady-state plasma concentrations and clinical efficacy (Montgomery et al., 1979). The main risk remains that widespread utilisation of blood levels in 'uncontrolled' populations coincides with extended recruitment of 'non-endogenous' depressed patients, in whom a high frequency of placebo response is well documented (Bielski and Friedel, 1976). Simple therapeutic guidelines for selection of dosage regimens, and attention to factors Which influence interindividual variability, should provide sufficient support for a therapeutic strategy where non-pharmacological and non-medical factors will always play a major role.
4.3.3 Antipsychotic Drugs A kinetic approach to the use of antipsychotic drugs has been difficult because of analytical problems in measuring blood concentrations of parent compounds and metabolites (Cooper, 1978). Now that sensitive analytical techniques are available however, they do not appear to contribute greatly to the quality of therapeutic outcome as a consequence of monitoring drug plasma concentrations. Selection and evaluation of an appropriate length of treatment, careful assessment of non-pharmacological factors leading to relapse with and without drugs, and control of short and long term side effects are at present the main questions for which answers are not likely to come from emphasis on kinetics (Vaughn and Leff, 1976). 4.3.4 Benzodiazepines Benzodiazepines have always been so widely used in kinetic studies that it is hard to decide how to deal with them. A recent review gives detailed information on diazepam, the most widely used drug of this group (Mandelli et al., 1978). However, while provid-
121
Clinical Relevance of Pharmacokinetics
ing the basic profile of each new molecule, kinetic knowledge has relatively little to offer towards the improvement of therapeutic outcome with benzodiazepines used as antianxiety drugs. Available evidence on accumulation of the parent drug and active metabolite(s) at a very early age of life (Morselli et al., 1973) and in the elderly, and in patients with liver diseases (Klotz et al., 1975) is possibly the most important information to be considered in order to avoid excessive sedation and adverse effects. The advantages of benzodiazepines with short as opposed to long elimination half-lives in causing less hangover and sedation when used as hypnotics should be verified during actual clinical use in large populations (see further Bellantuono et al., 1980).
4.4 Antiarrhythmic Agents Extensive study of this group of drugs has in recent years produced ample knowledge of their disposition, and accepted dose regimens have been established for most of the individual agents. Despite this, there are still areas of uncertainty and controversy. A complete discussion of this topic can be found in the main reviews published during the last few years (Zipes, 1978; Anderson et al., 1978). The rationale of a clinical pharmacokinetic approach to use of antiarrhythmic drugs and the problems in its application can be summarised as under: I) Recognised relationship between blood concentration and clinical effects. 2) Low therapeutic index (toxic concentrations are usually 2 to 3 times the therapeutic concentrations). 3) Toxicity is frequent, serious and involves the myocardium as much as the therapeutic effects do. 4) A therapeutic range has usually been defined (except for propranolol). 5) Interindividual variability in steady-state plasma levels is often higher than the therapeutic index. 6) Therapeutic effects are well quantifiable and the response is often rapid. Many questions remain to be answered before the relationship between antiarrhythmic drug concentra-
tions and their effects can· be thoroughly defined, and before other factors which make the use of pharmacokinetics questionable can be clarified. Examples of these factors are: 1) The metabolic and cellular events underlying different arrhythmias need further research. 2) There are inter- and intraindividuaJ differences in the pathophysiological basis of the disease to be treated (e.g. a drug may be effective in one patient with myocardial infarction but not in another, or even at one time but not another after myocardial infarction in the same patient). 3) Agreement is incomplete on evaluation of therapeutic efficacy; i.e. for how long and when to record the ECG (since suppression of arrhythmia for definite periods of time such as 24h. is recognised as. being of limited value, ambulatory ECG monitoring is becoming a more reliable tool for 'measuring' the therapeutic outcome) [Harrison et al., 1978]. . 4) Heart failure and low cardiac output states, sometimes associated with serious arrhythmias, can unpredictably alter the kinetics of some of these drugs (e.g. iignocaine,quinidine, procainamide). 5) Important pharmacodynamic interactions (drugs, electrolytes) modify their action. 6) Rapid therapeutic decisions are often required, which makes measurement of blood levels mostly unhelpful since it takes too long to obtain the results; predictive techniques for dose adjustment are thus essential. Table IX reports the characteristics relevant to our discussion of the most widely used antiarrhythmic agents. New drugs, which are continually being developed, are not included in this brief discussion, since adequate clinical pharmacological studies are still lacking (Zipes and Troup, 1978; Anderson et al., 1978). However, some of them are of particular interest; e.g. verapamil and amiodarone.
4.5 Digoxin Digoxin pharmacokinetics have been extensively studied since the 1960's (Doherty et aI., 1961; Doher-
Acute treatment (intravenous infusion)
Few data
Well described High variability Predictive 120 times) in methods proposed steady-state levels
Phenytoin (10-20 "g/mll
Propranolol 140-BOng/mll
High variability (dose-dependent kinetics, drug interaction)
Not well established
Few data
Disopyramide 12-4 or 3-S"g/mll
High variability (10 times) in steady-state levels
High variability
As for lignocaine though fewer studies
Active metabolites
4-0H propranolol antiarrhythmic activity (?)
None
N-dealkylated metaboIite derivative: antiarrhythmic /less potent}
Dihydroquinidine: antiarrhythmic
NAPA: antiarrhythmic (similar). wider therapeutic range, double t1/2
Not employed MEGX: antiarrhythmic (extensive first-pass (similar activity) metabolism) GX: antiarrhythmic /less potent) + convulsant
Maintenance (orall
NOloften Quinidine 12.3-5.0"g/mll employed (circulatory depression)
Procainamide (4-8"g/ml)
Ugnocaine Loading and /lidocaine) infusion rate ( lo6-6.0"g/mll adjustment Predictive methods proposed
Drug (therapeutic range)
Liver and renal disease
Liver and renal disease (protein binding)
Cardiac and renal fa~ure
liver and renal disease
Renal and liver disease Heart failure NAPA accumulation in renal failure
liver disease Heart failure
Diseases affecting kinetics
Table IX. Outline of the characteristics of the main antiarrhythmic agents
Seldom (large therapeutic range)
than total drug concentration)
more relevant
Suspected overdose Drug interaction and disease (free fraction
Not well established
Intravenous treatment 'Risk' patients
. Resistance' • suspected toxicity Renal failure (PA + NAPA) Myocardial infarction Prophylactic treatment
Rate adjustment during long term (12h) infusions
monitoring
Indications for plasma level
Better definition of therapeutic range
Shand (1974a,b); Bianchetti et al. ( '976); Branch and Shand (1976); Johnsson and Regardh (19761
Bigger et al. (1968); Gerber and Wagner (1972)
Danilo and Rosen (1976k Hinder1ing and Garrett (1976k Cunningham et al. (1977)
Kessler et al. (19:14); Gaughan et al. (1976); Conrad et af. (1977); Greenblatt et al. (1977)
As for lignocaine New agents, less toxic than quinidine
Much to be done on its activity and kinetics (dosedependent elimination, concentration dependent protein binding)
Koch-Weser and Klein (1971); Gibson et al.(1976k Drayer et al. (1977a,b); Atkinson et al. (1977k Kar1sson (197Sk Lima and Jusko (197St Woosleyet al. (1978)
Thomson et al. (1973t Halkin et al. (1975k Greenblatt et al. (1976t Benowitz and Meister (197S)
References
Acetylator phenotype vs lupus syndrome NAPA as altemativedrug Therapeutic concentration for different arrhythmias
Better definition of activity of metabolites and kinetics in normal and disease states
Prospects for further study
N N
'"
CD g.
::J
i!r.
0
.,n3
.,~
2-
CD
n
::J
.,
m <
CD
:II
i''i" !!!.
Q
s·
123
Clinical Relevance of Pharmacokinetics
ty, 1968). A large amount of data on its kinetics in plasma, and distribution in tissues in different pathophysiological conditions, has been produced (Chamberlain, 1975; Iisalo, 1977; Wettrell and Andersson, 1977). Predictive methods (nomograms or equations) for dosage adjustment in renal failure were first devised in 1972 (JeliitTe et al., 1972; Sheiner et al., 1972). Correlations have been found between digoxin concentrations, its cardiac therapeutic effects and its toxicity (Butler and Lindenbaum, 1975; Smith, 1975; Weintraub, 1977; Biddler et al., 1978). These studies have made digoxin a 'model drug' in clinical pharmacology. In view of the broad scattering of studies on this drug, it is useful to summarise the present discussion and knowledge on digoxin clinical pharmacokinetics under 4 main headings: 1) Descriptive: The kinetics of digoxin are now reasonably well known in most pathophysiological conditions. Extensive studies on bioavailability has made it possible to standardise its dosage (Chamberlain, 1975). 2) Patient monitoring: There is still debate about the role or even the value of measuring blood drug concentrations in optimising therapeutic etTects and in preventing toxicity (Smith, 1975; Ingelfinger and Goldman, 1976). 3) Predictive: All proposed methods have some limitations because of their excessive complexity or lack of flexibility (Aronson, 1978). Very careful evaluation in real clinical situation is needed for these procedures (Peck et al., 1973). 4) Educational: Application of pharmacokinetic knowledge can help the clinician make sound adjustments in digoxin dose regimens in individual patients, with a consequent decrease in related toxic events (Ogilvie and Ruedy, 1972; Peck et al., 1973; Liverpool Therapeutics Group, 1978). The main problem in digoxin therapy at present seems to be, as Lasagna (\976) underlines, that we still cannot define a reliable therapeutic plasma concentration range for this drug. The reason is that we have no way of making unequivocal decisions on its efficacy and toxicity, independently of drug concentrations. In this search, even sophisticated studies
on myocardial muscle digoxin concentrations (Hartel et al., 1975; Biddler et al., 1978), or red blood cell rubidium uptake (Aronson et aI., 1977) have not been of significant help. However, an undesired consequence of the emphasis on digit~lis toxicity has been a tendency among many clinicians to underdose their patients (Tunstall Pedoe, 1978). In conclusion, monitoring of digoxin plasma concentrations can be helpful in management of the cardiac patient when used in conjunction with clinical and laboratory data. Such monitoring is necessary in patients with renal failure and in cases of suspected digitalis toxicity or possible non-compliance (Johnston et al., 1978). 4.6
~-Adrenoceptor
Blocking Drugs
These drugs comprise a large group of individual compounds used for various diseases such as angina, arrhythmias, hypertension and hyperthyroidism. The present discussion will be limited to the use of propranolol in essential hypertension, where data have contributed to an increased understanding of the basic mechanisms involved. Present knowledge on the clinical pharmacology (see also Routledge and Shand, 1979) of propranolol in essential hypertension can be summarised as follows: I) Steady-state plasma concentrations during long term treatment are highly variable (up to 20 times) due to interindividual ditTerences in clearance and hepatic first-pass metabolism (Chidsey et al., 1975). 2) An active metabolite (4-hydroxypropranoloI), about equipotent but with a shorter half-life than the parent drug, is detectable only after oral administration, and can contribute to the overall activity of the drug (Paterson et al., 1970; Fitzgerald and O'Donnell, 1971). 3) A correlation has been found between propranolol plasma concentrations and degree of ~ blockade, measured as inhibition of tachycardia after exercise (the best index at present available) or after isoprenaline (McDevitt and Shand, 1978). 4} Plasma concentrations lower than 100ng/ml produce ~-blockade (Zacest and Koch-Weser, 1972)
Clinical Relevance of Pharmacokinetics
but much higher levels are required for the membrane stabilising' effect (Coltart et aI., 197 O. 5) No clear correlation has been found between plasma concentrations and therapeutic effect, measured as lowering of. arteriaI blood pressure (LeWinter et aI., 1975; Hollifield et aI., 1976; Lehtonen et al., 1977; Clement et aI., 1977). 6) The therapeutic index is large. Total daily doses ranging from 80 to 600mg are well tolerated (Prichard, 1978). Based on these considerations, the role and contribution of pharmacokinetics in this area may be summarised in the following way: I) Pharmacokinetic studies shed some light on the mechanisms of action of these drugs (e.g. ~-blockade vs membrane stabilising effect of propranolol). 2) Propranolol and other ~-blockers with different relative selectivity for ~ I and/ or ~2-adrenoceptors, or also for a-adrenoceptors (e.g. labetalol), are a good tool for better understanding and pathophysiology of hypertension (e.g. the role of renin, a and ~ blockade, sympathomimetic action). 3) Even though the high interindividuaI variability in disposition of propranolol may appear to suggest the usefulness of monitoring plasma concentrations, its large therapeutic index and the lack of correlation between plasma concentrations and therapeutic effects make this approach of no routine vaIue. Moreover, the dosage of propranolol in hypertension can be readily titrated to the desired clinical endpoint. Thus, it is only necessary to recognise that the effective dose can vary widely.
4.7 Theophylline Theophylline was one of the first drugs for which it was recognised that blood concentrations were worth measuring, since toxicity was common and often serious and concentrations correlated well with the therapeutic and toxic effect. The main mechanism of action of theophylline is relatively simple (smooth muscle relaxation due to an increase in intracellular cyclic AMP content), and probably for this reason, a
124
good quantitative correlation is found experimentally in man between blood concentrations and percentage lowering of airways resistance (Mitenko and Ogilvie, 1973). A therapeutic range (to to 20J.1g/ml), on which most authors agree, has been established for the treatment of reversible obstructive airways diseases. Toxicity, often serious, is related to blood concentrations, giving a narrow therapeutic index (Hendeles et al., 1978; Ogilvie, 1978). Hence, since 1972 many authors have concentrated on adjustment of the intravenous loading dose and maintenance infusion rates for the treatment of acutely ill patients (Mitenko and Ogilvie, 1972; Weinberger et aI., 1976; Koup et al., 1977). Despite the number of published studies over the last few years, poor predictability of these methods has been demonstrated (Hendeles et al., 1977; Koup et aI., 1977). Measurement of theophylline plasma concentrations can help in the treatment of the elderly, patients with liver disease and/ or heart failure, and acutely ill patients needing intravenous infusions. Such patients are at most risk of toxicity (Hendeles et aI., 1977; Piafsky et aI., 1977). Theophylline has recently been used in the treatment and prevention of apnoea in premature neonates. Since studies have shown a marked prolongation of elimination haIf-life in neonates, a new safe dose regimen (Aranda et aI., 1976) has been established with which toxic concentrations. should not be easily reached. Tachycardia seems a sufficiently reliable index of overdose in the. absence of blood concentration measurements. The main outstanding question now seems to be what is the lower effective blood concentration, since the slower elimination in the newborn, the narrower therapeutic index and, most recently the possible additive effect of caffeine produced from theophylline, suggest the need for a dosage regimen lower than that employed for asthma which had aIso been considered applicable in apnoea of prematurity (Shannon et aI., 1975; Kattwinkel, 1977; Latini et aI., 1978; Aranda and Turmen, 1979). It is important to note that the emphasis on theophylline for the treatment of asthma is now decreasing since selective ~2-adrenoceptor stimulants
Clinical Relevance of Pharmacokinetics
have been introduced (Hartnett and Marlin, I 976), although little is known of their clinical pharmacokinetics. 4.8 Warfarin Warfarin is used clinically in those situations involving thromboembolic problems, particularly in venous thromboembolism, rheumatic mitral valve disease and in patients with artificial heart valves (Wright, 1969; Wessler, 1974; Mackie and Douglas, 1976; Breckenridge, 1976). The pharmacokinetics of warfarin have been widely studied and a wealth of information now exists about the steps involved in the dose-effect relationship discussed in section I. This can be summarised as under: I) Wide interindividual variability in warfarin clearance and volume of distribution causes wide variability in dose-plasma concentration correlations, even though the bioavailability is complete and well reproducible (O'Reilly et aI., 1962). 2) The free fraction of the drug in plasma ranges from 98.11 to 99.56%; meaning that the percentage of unbound drug available for distribution and metabolism and biological activity varies 3-fold (Yacobi et al., 1976). 3) Warfarin is administered as it racemic mixture of 2 optical isomers, S( - ) and R( + ), which have different kinetic properties and potencies (Breckenridge etal., 1974). 4) Warfarin acts by competitively antagonising vitamin K, reducing the concentration of the vitamin K-dependent clotting factors II, VII, IX and X. Thus, serum drug concentrations correlate with the degree of inhibition of synthesis of these factors (Nagashima et al., 1968) but not simply with the prothrombin complex concentration in plasma (prothrombin time) which is the measurable clinical effect (Breckenridge and Orme, 1973). The prothrombin complex concentration depends not only on the synthesis rate but also on the metabolism of the clotting factors, which is not influenced by warfarin. It is thus not surprising that patients with
125
the same level of anticoagulation show 5-fold differences in plasma concentration of warfarin (Breckenridge and Orme, 1973) and that there is no correlation with the free drug plasma concentration (Yacobi et al., 1976). Dosage adjustment of warfarin made on the basis of plasma concentrations instead of prothrombin time are not only useless but may also be dangerous. The only clinical situation in which measuring the plasma concentration of warfarin might be directly useful is in patients requiring uncommonly high doses of the drug to achieve therapeutic anticoagulation. This situation can be determined by very rare cases of genetic resistance (O'Reilly et aI., 1964) or by concomitant administration of microsomal enzyme inducing agents, such as barbiturates. It is important to distinguish between these two situations, because withdrawal of the inducing agent is a reason for dosage regimen readjustment. Study of warfarin is, at least, a very interesting model for acquiring knowledge of basic pharmacokinetic and pharmacodynamic principles. An example is the re-examination of how this drug interacts with acidic anti-inflammatory agents, in the light of the existence of the 2 optical isomers mentioned (Sellers and Koch-Weser, 1971; Coldwell et al., 1974; Schary et al., 1975; O'Reilly, 1976). 4.9 Anticancer Drugs Two points in clinical research with anticancer agents appear to be of prime importance today - to obtain more selective compounds and to use those already available as well as is possible. There is a need to answer the question whether the results of research over the past years have provided any evidence that information about blood concentrations of these drugs can improve their experimental and clinical use? Our answer is to apply the scheme used for the other classes of drugs, first summarising the applications of pharmacokinetics on which most authors already agree: 1) Preliminary studies ('phaSe 1'), which establish maximum tolerated dose (MTD), and peculiar points
Clinical Relevance of Pharmacokinetics
of toxicity at different dose regimens should now include blood concentration measurements (Williams and Carter, 1978). 2) In subsequent phases (II and III) of development of new compounds this approach can give advance information on dosage schedules. Cytarabine (Ho and Frei, 1971; Wan et al., 1974), with its short half-life, and doxorubicin (Benjamin et al., 1972; 1974) and actinomycin (Tattersall et al., 1975), with their long half-Jives, are good examples. 3) High dose methotrexate chemotherapy, shown to be effective in many cases (Jaffe and Paed, 1972; Djerassi et al., 1972), can now be employed with greater safety since pharmacokinetic studies (Stoller et al., 1977; Nirenberg et al., 1977) make it possible to identify these patients most likely to develop toxic effects. These can consequently be reversed by appropriate folinic acid treatment. In other areas, research has not yet produced enough knowledge to permit us to speak of 'application of pharmacokinetics'. The main findings seem to be as follows: I) Organ failure can alter the disposition of anticancer agents, as it does with other drugs. Relatively few studies have been made in this field but we can note the decreased metabolic clearance of doxorubicin in liver. failure of various degrees (Benjamin et al., 1974), and the influence of kidney failure on methotrexate (Kristensen et aI., 1975) and bleomycin renal clearance (Broughton et al., 1977; Crooke et al.,
126
1977). The importance of this area must be viewed in the light of the high frequency of organ failure in these patients and of the direct toxicity of some of these drugs on liver or kidneys (see cisplatin which is often combined with bleomycin for testis Carcinoma treatment). Dose regimen prediction systems have been proposed for doxorubicin, based on serum bilirubin concentrations, and for methotrexate, based on creatinine clearance, but their clinical application must still be extensively verified. 2) Since the target cancer cells are often within tissue, study of the distribution of these agents assumes great importance. The approach in animals has been to construct perfusion models to predict concentrations in blood and tissues and also in the tumour, with satisfactory accuracy at each time (Bischoff et al., 1971; Chan et aI., 1978). The cell kinetics of target tissues have also been included (Zaharko et al., 1974; Dagnino et al., 1979). Few studies have been made in man to collect data on drug concentrations in accessible extravascular compartments such as CSF, exudates, surgical specimens, etc (Evans and Pratt, 1978; Hayakawa et al., 1976). 3) The variables influencing the relationship between dose and blood levels are summarised in table X and the relationship between blood levels, tissue. levels and therapeutic effects in table XI. These tables, together with the particular complexity of the analytical methods required, illustrates why study of the
Table X. Factors which can influence the relationship of dose to blood concentrations of antitumour drugs in cancer patients
Absorption
Distribution
Metabolism and elimination
Compression of gastrointestinal tract by tumour masses
Presence of peculiar compartments such as pleural effusion or ascites
Hepatic renal metastases
Gastrointestinal tumours
Circulatory modifications caused by compression
Toxicity to liver or kidneys by toxic substances released by tumour; previous or concomitant radiotherapy or chemotherapy Compression on eliininating organs
Possible drug interaction with other antitumour agents employed in combination chemotherapy regimens or other drugs such as analgesic cocktails, antibiotics and corticosteroids may also affect the dose-blood concentration relationship.
Clinical Relevance of Pharmacokinetics
pharmacokinetics (animal and clinical) of anticancer agents is relatively slow. Basic kinetic data are therefore still needed for these drugs even though the real contribution of pharmacokinetics will come not only from the extensive application of 'standard kinetic' studies but also from investigations focused on kinetic models of distribution and non-kinetic determinants of the effect. Kinetic models 0/ distribution: To check the clinical applicability of these models, more information must be obtained about the relationship between blood concentrations of anticancer drugs and their concentrations at the target (tumour and other tissues). Objective difficulties in obtaining samples, and methodological liinitations often mean that such studies are not feasible. These studies should aim to provide a more rational basis for dose schedules of drugs already used in clinical practice and to develop more selective agents for malignant tissues. Non-kinetic determinants 0/ the effect: As discussed in section I and shown in table XI, a direct correlation between drug concentration and effects seems unlikely. Much more knowledge is needed about cell biochemistry, kinetics and sensitivity (Hill and Baserga, 1975; Wolberg, 1977; Sadee and Wong, 1977; Terz et al., 1977; Nichol, 1977; Tannock, 1978; Salmon et al., 1978) before we attempt to correlate concentrations and effects quantitatively. In addition, to better evaluate the efficacy of therapy, we must establish which human malignancies are objectively measurable before and after chemotherapy and are accessible for specimens (external or laparatomically followed tumours).
5. Conclusions It was the intention of this review to systematically answer questions occasionally raised by many authors over the last few years. In choosing this approach, we realise that we expose ourselves to many objections, not only because of the obvious limitations of the analYSis, but also because the in-
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Table XI. Factors which can influence the relationship of plasma concentration to antitumour effect
Intracellular concentration
Sensitivity
Tumour macro- and microcirculation
Cell kinetics
Postradiotherapy or postchemotherapy fibrosis
Normal and neoplastic cell cycle time
Cell size
Percentage of proliferating resting and non-dividing cells
Normal and neoplastic cell membrane characteristics
Biochemistry
Transport mechanism
Repair mechanisms For enzyme inhibitors: enzyme affinity. other substrate concentrations Substances interacting before the drug reaches the site of action Presence of activating and inactivating enzymes Alternative pathways of
tended emphasis on this aspect of kinetics could be interpreted as a disregard or a negative attitude towards other aspects. However, to ensure constructive criticism, these conclusions will attempt to summarise and explain the basic thinking emerging from this work. I) Despite all its temporal and methodological limitations, a survey of the amount and quality of work published in the field of clinical pharmacokinetics demonstrates that a search for solutions to clinically relevant problems was not the main goal of many articles revieWed. The large amount of repetition and the frequent lack of methodological accuracy strongly suggest that only critical evaluation of published data can result in reliable information which is safely applicable in clinical practice. This is by no means a 'new' rroding and will possibly be considered trivial by those in research environments where sound scepticism is the rule. These 'centres of
Clinical Relevance of Pharmacokinetics
excellence', however, are a minority, and have little, if any, control over how kinetic data is 'utilised'. Superficial extrapolation from descriptive data with doubtful significance to ready-to-use guidelines and/ or to promotion of monitoring programmes is well known. Critical review of the reliability of published information and of the clinical significance of blood concentration measurements should be considered a more regular part, not only of educational efforts, but also of research activity. This is increasingly the case in evaluation of clinical drug trials and could be suggested as essential in the field of kinetics also (Chalmers, 1976; Byar et al., 1976; Chalmers et al. 1977; Rennie, 1978). 2) Clinical relevan,ce has been advocated as a term of reference against which the contribution of kinetics has been assessed. It is not our claim to know how to measure clinical relevance, but some tentative definition must be attempted, if for no other reason than to exclude misleading interpretations. To plead for clinically relevant kinetics does not necessarily mean to look for what is directly useful in therapeutic practice. As in all research, evidence is acquired by the cumulative and often contradictory production of data whose links with actual clinical practice can be or appear to be very weak. All these data can be clinically relevant, if their limits are clearly stated, and as long as they are not repeated to the point of overwhelming or diverting basic clinical intelligence. Every time an item of kinetic information contributes to the improvement of ·this intelligence, its relevance is beyond question. Two cases from those analysed in this review give a good example of this. Clinically' relevant use of the puzzling kinetic data available for tricyclic antidepressants (table VIII) could be either, to promote carefully controlled programmes whereby subgroups of patients responding to. different plasma concentrations are identified and possibly even predicted (Asberg, ,1976; Editorial, 1978; Montgomery et al., 1979) or to confirm the. weakness of. the biochemical hypotheses on the pathogenesis and mechanism of drug action in depression. The latter alternative must in our opinion have priority today, as unreliable diagnostic and
128
prescribing practices are prevalent (Gottlieb et aI., 1978; Tyrer, 1978; Tognoni et al., 1978). Both alternatives however, could be considered to contribute to clinical intelligence, in so far as they give kinetic data the role of a research tool to be used under strictly controlled conditions, on limited occasions or within ad hoc projects. As it has been seen, this is not the case when considering the pattern of production of data in the literature (figures 2 and 3). The field of anticancer agents can be used (optimistically!) to describe an opposite situation. Data are still very few. There is a chance that competition for data production. and accumulation will not obscure the need for the comprehensive and cautious approach suggested by the scheme of development in table XI. 3) Kinetics relies in its development and application on mathematical models and measurement of drug concentrations. As stated in the introduction, analysis of the role of models has been excluded from this review. Our competence is not sufficient for an appropriate discussion to fit the framework outlined in point 2 above. If some conclusion has to be drawn, it is a suggestion derived from what has been said about anticancer agents: there is a need for closer feedback between mathematical and statistical tools, and biological, biochemical and pathophysiological data. Successful examples do exist (Zaharko et aI., 1974; Benowitz etaI., 1974a,b) to indicate that, although not easy, this approach can be practised. A restricted attitude towards the 'natural' expansion of blood concentration monitoring has been evident throughout this article. As for most research groups, active involvement in such activities has been part of our interests (Morselli et aI., 1973, 1975; Milano Collaborative Group for Studies on Epilepsy, 1977; Latini et al., 1978). There is a teal risk, however, that doctors and institutions will become 'dependent' on this technique, so giving up a critical attitude in the use of both clinical and kinetic data. Too easily accessible quantitative data can lead to a decreased quality of patient care and to a waste of the real advantages of kinetic knowledge. Periodic research programmes on the criteria of use and interpretation
Clinical Relevance of Pharmacokinetics
of data obtained from the laboratory should become part of the duties of all institutions adopting these resources.
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Clinical Relevance of Pharmacokinetics
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Clinical Relevance of Pharmacokinetics
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Author's address: Dr Gianni Tognoni, Istituto di Ricerche Farmacologiche, 'Mario Negri', Via Eritrea, 62-20/57 Milan (Italy).
