PHARMACODYNAMICS AND PHARMACOKINETICS
Why do we need pharmacokinetic studies? Eigill F. Hvidberg, MD Copenhagen, Denmark, Data on the fate of sex steroids in the human organism, such as absorption, distribution, total clearance, and elimination routes, are necessary to understand and predict drug action. However, except for a few exceptions, such data are sparsely available. It is necessary to apply several approaches (descriptive, mathematic, and analytic) to describe variability and dose-response correlations, all of which are important for individualized treatment, and therefore of therapeutic relevance. In addition, such data are now unavoidable requirements for the evaluation of safety, efficacy, and quality performed by the regulatory authorities. Therefore human kinetic information is an integral part of the knowledge that forms the basis for any treatment with sex steroids. (AM J OBSTET GYNECOL 1990;163:316-8.)
Key words: Pharmacokinetics, dose response, variability, sex steroids The question, "Why do we need pharmacokinetic studies? ," is not easily answered whether it concerns sex steroids or any other preparation, and particularly not if seen in a clinical context. However, to address the problem in general, it is necessary to discuss some details of the pharmacokinetic universe.
Definition While pharmacodynamics are characterized as the action of a drug in the organism, pharmacokinetics deal with the fate of a drug. However, a more operational description of pharmacokinetics is all the processes that determine the concentration of the active substance at the receptor site. This definition implies the connection with pharmacodynamics, without which kinetics may easily develop into a nonclinical playground.
Study approach To obtain the kinetic characteristics of a drug, several types of studies are needed. The usually overlapping approaches may be classified into the following three basic ones: (1) The descriptive approach, by which all the processes involved are described, for example, how the absorption, distribution, and elimination take place and how the different organs and physiologic conditions influence these processes; (2) the mathematic approach, which includes calculations of compartments and rate constants, generation of models, and other types of "pharmacomathematic" exercise; and (3) the analytic apFrom the Department of Clinical Pharmacology, University Hospital (Rigshospitalet). Reprints not available.
6/0/18222
316
proach, which tries to analyze the generated data
in the context of other pharmacologic and clinical information. The unifying concept is to explain and predict drug action in the human body. All three approaches are based on the measurements of concentrations in body fluids of the parent compound and its metabolites, most often by establishing plasma concentration/time curves. Therefore the value of such studies is heavily dependent on analytic assays that require a high degree of sensitivity, reproducibility, and specificity.
Parameters and data Much uncertainty seems to exist about which pharmacokinetic parameters are essential. Table I shows what generally is required, but for more information, recent handbooks must be consulted. 1 It would be of interest to see how much kinetic data on sex steroids are actually available in the literature. In most recent source of such information,2 data on clearance, T'/2 , Vd , and protein binding are given for only ethinyl estradiol, levonorgestrel, medroxyprogesterone acetate, and norethisterone. Even in the original kinetic studies, little data exist, at least compared with other groups of drugs. The paucity of information is striking. Variability Pharmacokinetic data are usually presented as an average of results from a studied population.'-5 Naturally, such general information is important for the common characterization of tbe drug in question but cannot be used to predict, for example, plasma concentrations in individual patients. A range is often of greater interest
Pharmacokinetic studies
Volume 163 Number I, Part 2
than a mean value, and kinetic data should therefore include information on the variability between individuals. For most drugs, the variability in kinetic parameters is more than lO-fold, even if the study population is quite homogenous and the dose is corrected for body weight. Basically, this can originate from variability in absorption and from differences in the metabolizing capacity of the liver caused by genetic or environmental factors. Presystemic metabolism seems to be an important determinant for the plasma levels of progesterone. 6 On the basis of individual kinetic data, it may be possible to sort out such factors. In addition, intraindividual variability might be large (see Fotherby, this supplement).
The dose-response concept As emphasized, kinetic data only have a meaning when related to pharmacodynamic data. The pharmacologic way of expressing this is by dose-response curves, in which the dose may be substituted by plasma concentrations or other kinetic parameters. To generate meaningful and relevant concentration-response curves in patients is an extremely difficult task and therefore often neglected. However, if the concept became better understood, more energy would be put into this work. For sex steroids, only a few, if any, such human dose-response curves exist. This is also related to the difficulty in grading the effect parameter, although this may be overcome by the use of the percentage of "failures/successes" related to plasma concentration. However, both measuring and grading the effects are still the main obstacles for setting up reliable dose-response curves/,8 and very sparse kinetic information makes this even more problematic. Another important use of dose-response curves is that they are necessary for meaningful comparisons between analogous drugs. Regulatory requirements The basic idea in drug regulation is that only drugs for which safety, efficacy, and quality have been evaluated-and found acceptable-are released for general use. The requirements should, of course, reflect profesional thinking and clinical relevance. Kinetic information must be presented for the evaluation of both safety and efficacy, because it will be required for most drugs to estimate toxic plasma concentrations and minimum plasma levels for efficacy. This means that kinetic studies should not be limited to healthy volunteers but be extended to relevant patient categories including risk groups, such as renal and hepatic insufficiency, and old age. Today drug regulation is increasingly involving demands on the conduct of clinical trials. In Europe rules
317
Table I. Pharmacokinetic parameters required Characteristics Absorption: Distribution: Elimination: Steady-state: Special features:
Parameter Absorption fraction (F), T rna" C,nax Vd , protein binding Route, Tl/2~, Cl w " pattern of metabolites, saturation phenomena Area under the curve (e.g" AVC 24 h,j, therapeutic plasma concentration range Kinetic interactions, influence of hepaticlrenal insufficiency and age, autoinduction, and active metabolites
for good clinical (research) practice-the so-called Good Clinical Practice rules-will be the foundation of the authorities' future demands regarding trials of new drugs,9 as in the United States.
Therapeutic relevance As previously stated, it should also be possible to use data from pharmacokinetic studies in humans as a prognostic instrument. Without this objective, pharmacokientics may be reduced to a sophisticated, academic exercise and, therefore, ethically questionable. Only a few examples within sex steroids exist, but to demonstrate the concept of the beneficial use of plasma concentrations, an example from cytostatics will be given. Methotrexate plasma levels were used to predict therapeutic outcome,1O and it was found that patients with levels above a discriminating limit had a much greater chance of remission despite the fact that the same dose was given. This can, of course, be developed into a regular therapeutic drug monitoring system, but even without it, this line of thinking could be applied to existing data on sex steroids. 5 Therefore it would be a reasonable question whether such data could be used as a predictor of therapeutic outcome. Some efforts have been made in the treatment of breast cancer with medroxyprogesterone." Furthermore, some data for prophylactic treatment of osteoporosis 12 may eventually be used in this connection. Finally, the induction of estrogen metabolism by phenobarbital or rifampicin should be better investigated in terms of kinetic data to define special risk groups, that is, those who lose the contraceptive effect because of this drug interaction. In conclusion, the response to the question, "Why do we need pharmacokinetic studies?" is as follows: (1) A general characterization of the drug in humans includes kinetic information. (2) An estimation of the kinetic contribution to the variability of drug response is essential both between and within individuals. (3) Meaningful dose-response curves must be based on pharmacokinetics to design optimal dose regimens and to compare analogous drugs. (4) Regulatory authorities require kinetic data for a thorough evaluation of safety,
Hvidberg
efficacy, and quality. (5) General measures may be developed on basis of kinetic studies to predict the outcome of a given drug treatment in individual patients on a safer basis. (6) Finally, sex steroids constitute no exception to these requirements.
REFERENCES 1. Evans EE, Shentag ]], ]usko W], eds. Applied pharmacokinetics: principles of therapeutic drug monitoring. 2nd ed. Spokane, Wash., 1986. 2. Mammen G], ed. Clinical pharmacokinetics. Drug data handbook. Auckland, New Zealand: ADIS Press, 1989:36. 3. Kuhl H, lung-Hoffmann C, Heidt F. Serum levels of 3keto-desogestrel and SHBG during 12 cycles of treatment with 30 f.l.g ethinylestradiol and 150 f.l.g desogestrel. Contraception 1988;38:381-90. 4. Newburger], Goldzieher ]W. Pharmacokinetics of ethinyl estradiol: a current view. Contraception 1985;32:33-5. 5. Orme ML'E. The clinical pharmacology of oral contraceptive steroids. Br] Clin Pharmacol 1982;14:31-42.
July 1990 Am J Obstet Gynecol
6. Madden S, Back D], Martic CA, Orme ML'E. Metabolism of the contraceptive steroid desogestrel by the intestinal mucosa. Br] Clin Pharmacol 1989;27:295-9. 7. Fotherby K. Pharmacokinetics of progestational compounds. Maturitas 1986;8;123-32. 8. Hammerstein], Fotherby K, Goldzieher ]W, Johansson EDB, Schwarts U. Clinical pharmacology of contraceptive steroids. Contraception 1979;20; 187-200. 9. Spilker B. Multinational drug companies. Issues in drug discovery and development. New York: Raven Press, 1989: 108-9. 10. Evans WE, Crom WR, Abromowitch M, et al. Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect. N Engl] Med 1986;314:471-7. 11. Stockdale AD, Rostom AY. Clinical significance of differences in bioavailability of medroxyprogesterone acetate preparation. Clin Pharmacokinet 1989; 16: 129-33. 12. Riis B], Thomsen K, Strom V, Christiansen C. The effect of percutaneous estradiol and natural progesterone on postmenopausal bone loss. AM ] OBSTET GYNECOL 1987;156:61-5.
Selected aspects of the pharmacokinetics and metabolism of ethinyl estrogens and their clinical implications Joseph W. Goldzieher, MD Houston, Texas Careful studies in an adequate sample of subjects show a very marked degree of variability in the pharmacokinetics of ethinyl estradiol-specifically, in parameters such as area under the curve, half-life, and time to peak. This variability is seen in differences between different populations, as well as from one individual to another. These studies also show variability in area under the curve and other parameters in the same person from time to time. Such differences may equal or exceed the differences between low dose (35 fl-g) and high-dose (50 f.l.g) formulations. The levels of plasma ethinyl estradiol produced by a 50 f.l.g dose of mestranol are similar to those from 35 f.l.g of ethinyl estradiol. Thus a high-dose pill may be no higher than a low-dose pill if the nature of the estrogen is not kept in mind. Qualitative differences in the oxidative metabolites of estrogens may be of significance with respect to oncogenic potential. (AM J OBSTET GVNECOL 1990;163:318-22.)
Key words: Ethinyl estrogens, area under the curve, mestranol, ethinyl estradiol, pharmacokinetics
Although the pharmacokinetics of ethinyl estrogens have been studied intensively for more than a decade,' many unresolved problems of practical interest, as they affect contraceptive effectiveness, remain to be examined.
From the Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine. Reprint requests:joseph W. Goldzieher, MD, Department of Obstetrics and Gynecology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. 610118552
318
Table I. Pharmacokinetic parameters for ethinyl estradiol 3-sulfate and 17 -sulfate Parameter
EE 13 -sulfate
EEl I7-sulfate
tlt2 (IV) (hr) AUCo.24 (ng hrlml IV) Bioavailability (%) Conversion to free EE (%) IV po Comparison E, sulfate-E, IV
8.4 4.6 ± 0.5 50 ± 13
9.3 16.9 ± 3.4 23 ± 5
13.7 20.7
3.4 11.7
14
From Goldzieher ]W, et al. Steroids 1988; 51 :63. EE, Ethinyl estradiol; IV, intravenous; po, by mouth; AUC,
area under the curve; E 1 , estrone.
Why do we need pharmacokinetic studies? Eigill F. Hvidberg, MD Copenhagen, Denmark, Data on the fate of sex steroids in the human organism, such as absorption, distribution, total clearance, and elimination routes, are necessary to understand and predict drug action. However, except for a few exceptions, such data are sparsely available. It is necessary to apply several approaches (descriptive, mathematic, and analytic) to describe variability and dose-response correlations, all of which are important for individualized treatment, and therefore of therapeutic relevance. In addition, such data are now unavoidable requirements for the evaluation of safety, efficacy, and quality performed by the regulatory authorities. Therefore human kinetic information is an integral part of the knowledge that forms the basis for any treatment with sex steroids. (AM J OBSTET GYNECOL 1990;163:316-8.)
Key words: Pharmacokinetics, dose response, variability, sex steroids The question, "Why do we need pharmacokinetic studies? ," is not easily answered whether it concerns sex steroids or any other preparation, and particularly not if seen in a clinical context. However, to address the problem in general, it is necessary to discuss some details of the pharmacokinetic universe.
Definition While pharmacodynamics are characterized as the action of a drug in the organism, pharmacokinetics deal with the fate of a drug. However, a more operational description of pharmacokinetics is all the processes that determine the concentration of the active substance at the receptor site. This definition implies the connection with pharmacodynamics, without which kinetics may easily develop into a nonclinical playground.
Study approach To obtain the kinetic characteristics of a drug, several types of studies are needed. The usually overlapping approaches may be classified into the following three basic ones: (1) The descriptive approach, by which all the processes involved are described, for example, how the absorption, distribution, and elimination take place and how the different organs and physiologic conditions influence these processes; (2) the mathematic approach, which includes calculations of compartments and rate constants, generation of models, and other types of "pharmacomathematic" exercise; and (3) the analytic apFrom the Department of Clinical Pharmacology, University Hospital (Rigshospitalet). Reprints not available.
6/0/18222
316
proach, which tries to analyze the generated data
in the context of other pharmacologic and clinical information. The unifying concept is to explain and predict drug action in the human body. All three approaches are based on the measurements of concentrations in body fluids of the parent compound and its metabolites, most often by establishing plasma concentration/time curves. Therefore the value of such studies is heavily dependent on analytic assays that require a high degree of sensitivity, reproducibility, and specificity.
Parameters and data Much uncertainty seems to exist about which pharmacokinetic parameters are essential. Table I shows what generally is required, but for more information, recent handbooks must be consulted. 1 It would be of interest to see how much kinetic data on sex steroids are actually available in the literature. In most recent source of such information,2 data on clearance, T'/2 , Vd , and protein binding are given for only ethinyl estradiol, levonorgestrel, medroxyprogesterone acetate, and norethisterone. Even in the original kinetic studies, little data exist, at least compared with other groups of drugs. The paucity of information is striking. Variability Pharmacokinetic data are usually presented as an average of results from a studied population.'-5 Naturally, such general information is important for the common characterization of tbe drug in question but cannot be used to predict, for example, plasma concentrations in individual patients. A range is often of greater interest
Pharmacokinetic studies
Volume 163 Number I, Part 2
than a mean value, and kinetic data should therefore include information on the variability between individuals. For most drugs, the variability in kinetic parameters is more than lO-fold, even if the study population is quite homogenous and the dose is corrected for body weight. Basically, this can originate from variability in absorption and from differences in the metabolizing capacity of the liver caused by genetic or environmental factors. Presystemic metabolism seems to be an important determinant for the plasma levels of progesterone. 6 On the basis of individual kinetic data, it may be possible to sort out such factors. In addition, intraindividual variability might be large (see Fotherby, this supplement).
The dose-response concept As emphasized, kinetic data only have a meaning when related to pharmacodynamic data. The pharmacologic way of expressing this is by dose-response curves, in which the dose may be substituted by plasma concentrations or other kinetic parameters. To generate meaningful and relevant concentration-response curves in patients is an extremely difficult task and therefore often neglected. However, if the concept became better understood, more energy would be put into this work. For sex steroids, only a few, if any, such human dose-response curves exist. This is also related to the difficulty in grading the effect parameter, although this may be overcome by the use of the percentage of "failures/successes" related to plasma concentration. However, both measuring and grading the effects are still the main obstacles for setting up reliable dose-response curves/,8 and very sparse kinetic information makes this even more problematic. Another important use of dose-response curves is that they are necessary for meaningful comparisons between analogous drugs. Regulatory requirements The basic idea in drug regulation is that only drugs for which safety, efficacy, and quality have been evaluated-and found acceptable-are released for general use. The requirements should, of course, reflect profesional thinking and clinical relevance. Kinetic information must be presented for the evaluation of both safety and efficacy, because it will be required for most drugs to estimate toxic plasma concentrations and minimum plasma levels for efficacy. This means that kinetic studies should not be limited to healthy volunteers but be extended to relevant patient categories including risk groups, such as renal and hepatic insufficiency, and old age. Today drug regulation is increasingly involving demands on the conduct of clinical trials. In Europe rules
317
Table I. Pharmacokinetic parameters required Characteristics Absorption: Distribution: Elimination: Steady-state: Special features:
Parameter Absorption fraction (F), T rna" C,nax Vd , protein binding Route, Tl/2~, Cl w " pattern of metabolites, saturation phenomena Area under the curve (e.g" AVC 24 h,j, therapeutic plasma concentration range Kinetic interactions, influence of hepaticlrenal insufficiency and age, autoinduction, and active metabolites
for good clinical (research) practice-the so-called Good Clinical Practice rules-will be the foundation of the authorities' future demands regarding trials of new drugs,9 as in the United States.
Therapeutic relevance As previously stated, it should also be possible to use data from pharmacokinetic studies in humans as a prognostic instrument. Without this objective, pharmacokientics may be reduced to a sophisticated, academic exercise and, therefore, ethically questionable. Only a few examples within sex steroids exist, but to demonstrate the concept of the beneficial use of plasma concentrations, an example from cytostatics will be given. Methotrexate plasma levels were used to predict therapeutic outcome,1O and it was found that patients with levels above a discriminating limit had a much greater chance of remission despite the fact that the same dose was given. This can, of course, be developed into a regular therapeutic drug monitoring system, but even without it, this line of thinking could be applied to existing data on sex steroids. 5 Therefore it would be a reasonable question whether such data could be used as a predictor of therapeutic outcome. Some efforts have been made in the treatment of breast cancer with medroxyprogesterone." Furthermore, some data for prophylactic treatment of osteoporosis 12 may eventually be used in this connection. Finally, the induction of estrogen metabolism by phenobarbital or rifampicin should be better investigated in terms of kinetic data to define special risk groups, that is, those who lose the contraceptive effect because of this drug interaction. In conclusion, the response to the question, "Why do we need pharmacokinetic studies?" is as follows: (1) A general characterization of the drug in humans includes kinetic information. (2) An estimation of the kinetic contribution to the variability of drug response is essential both between and within individuals. (3) Meaningful dose-response curves must be based on pharmacokinetics to design optimal dose regimens and to compare analogous drugs. (4) Regulatory authorities require kinetic data for a thorough evaluation of safety,
Hvidberg
efficacy, and quality. (5) General measures may be developed on basis of kinetic studies to predict the outcome of a given drug treatment in individual patients on a safer basis. (6) Finally, sex steroids constitute no exception to these requirements.
REFERENCES 1. Evans EE, Shentag ]], ]usko W], eds. Applied pharmacokinetics: principles of therapeutic drug monitoring. 2nd ed. Spokane, Wash., 1986. 2. Mammen G], ed. Clinical pharmacokinetics. Drug data handbook. Auckland, New Zealand: ADIS Press, 1989:36. 3. Kuhl H, lung-Hoffmann C, Heidt F. Serum levels of 3keto-desogestrel and SHBG during 12 cycles of treatment with 30 f.l.g ethinylestradiol and 150 f.l.g desogestrel. Contraception 1988;38:381-90. 4. Newburger], Goldzieher ]W. Pharmacokinetics of ethinyl estradiol: a current view. Contraception 1985;32:33-5. 5. Orme ML'E. The clinical pharmacology of oral contraceptive steroids. Br] Clin Pharmacol 1982;14:31-42.
July 1990 Am J Obstet Gynecol
6. Madden S, Back D], Martic CA, Orme ML'E. Metabolism of the contraceptive steroid desogestrel by the intestinal mucosa. Br] Clin Pharmacol 1989;27:295-9. 7. Fotherby K. Pharmacokinetics of progestational compounds. Maturitas 1986;8;123-32. 8. Hammerstein], Fotherby K, Goldzieher ]W, Johansson EDB, Schwarts U. Clinical pharmacology of contraceptive steroids. Contraception 1979;20; 187-200. 9. Spilker B. Multinational drug companies. Issues in drug discovery and development. New York: Raven Press, 1989: 108-9. 10. Evans WE, Crom WR, Abromowitch M, et al. Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect. N Engl] Med 1986;314:471-7. 11. Stockdale AD, Rostom AY. Clinical significance of differences in bioavailability of medroxyprogesterone acetate preparation. Clin Pharmacokinet 1989; 16: 129-33. 12. Riis B], Thomsen K, Strom V, Christiansen C. The effect of percutaneous estradiol and natural progesterone on postmenopausal bone loss. AM ] OBSTET GYNECOL 1987;156:61-5.
Selected aspects of the pharmacokinetics and metabolism of ethinyl estrogens and their clinical implications Joseph W. Goldzieher, MD Houston, Texas Careful studies in an adequate sample of subjects show a very marked degree of variability in the pharmacokinetics of ethinyl estradiol-specifically, in parameters such as area under the curve, half-life, and time to peak. This variability is seen in differences between different populations, as well as from one individual to another. These studies also show variability in area under the curve and other parameters in the same person from time to time. Such differences may equal or exceed the differences between low dose (35 fl-g) and high-dose (50 f.l.g) formulations. The levels of plasma ethinyl estradiol produced by a 50 f.l.g dose of mestranol are similar to those from 35 f.l.g of ethinyl estradiol. Thus a high-dose pill may be no higher than a low-dose pill if the nature of the estrogen is not kept in mind. Qualitative differences in the oxidative metabolites of estrogens may be of significance with respect to oncogenic potential. (AM J OBSTET GVNECOL 1990;163:318-22.)
Key words: Ethinyl estrogens, area under the curve, mestranol, ethinyl estradiol, pharmacokinetics
Although the pharmacokinetics of ethinyl estrogens have been studied intensively for more than a decade,' many unresolved problems of practical interest, as they affect contraceptive effectiveness, remain to be examined.
From the Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine. Reprint requests:joseph W. Goldzieher, MD, Department of Obstetrics and Gynecology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. 610118552
318
Table I. Pharmacokinetic parameters for ethinyl estradiol 3-sulfate and 17 -sulfate Parameter
EE 13 -sulfate
EEl I7-sulfate
tlt2 (IV) (hr) AUCo.24 (ng hrlml IV) Bioavailability (%) Conversion to free EE (%) IV po Comparison E, sulfate-E, IV
8.4 4.6 ± 0.5 50 ± 13
9.3 16.9 ± 3.4 23 ± 5
13.7 20.7
3.4 11.7
14
From Goldzieher ]W, et al. Steroids 1988; 51 :63. EE, Ethinyl estradiol; IV, intravenous; po, by mouth; AUC,
area under the curve; E 1 , estrone.
