The Utility of Pharmacokinetics to the Pharmaceutical Industry ROBERT 1. NELSON. M.D.

Indidndpoiir, Ind.

ITHIN the past decade, the science of pharmacokinetics has grown rapidly as a field of interest and has played an expanding role in the rational design of drug therapy in man.l The application of pharmacokinetic principles in the solution of problems related to bioavailability and bioequivalence of marketed products is well known and represents an example of the utility of pharmacokinetics to both the drug industry and drug regulatory agencie~.~,~ However, pharmacokinetic data are often also quite useful in the developmental stages of pharmaceutical research. This discussion highlights a few examples in which knowledge of the kinetics of a new compound influences its future preclinical development and prorides a rational basis for the formulation of appropriate dosage forms and dosage regimens for initial clinical trials. Ideally, kinetic data should be compiled as soon as a potential new drug enters initial animal toxicology testing. The feasibility of this depends upon whether a sensitive and selective assay for the drug in biologic fluids or a radiolabeled drug is available for use. The spiraling interest in pharmacokinetics recently is certainly

due to the development of new sensitive assay techniques such as radioimmunoassay for measuring drug kinetics, since the mathematical principles employed in pharmacokinetic analysis have already been in use for several hundred years.' The initial goal of these early kinetic studies is the elucidation of the simplest model which explains the observed data. At this early stage, the measurements of most importance are the volumes of distribution and the respective rates of distribution and elimination. When first testing a drug, rapid single-bolus intravenous injection is the preferred route of drug administration. It is relatively easy to mathematically analyze kinetic data generated by this method because all absorption variables are eliminated which can only obscure the distribution and elimination data.'.2s4 Following a single-bolus rapid intravenous injection, blood, urine, feces, and, if possible, cerebrospinal fluid and bile should be collected at frequent intervals for a period of at least 96 hours. The next steps in pharmacokinetic analysis consist in plotting the plasma or serum concentration-versus-time data semilogarithmically, making a visual estimate of the least number of straight lines, and conFrom The Lilly Laboratory for Clinical Research, Wishard Memorial Hospital, Indianapolis, Ind. structing a model which will fit to a sys16202. Presented a t a Symposium on Bioavailabil- tem of differential equations that define ity and clinical Pharmacokinetics, held at the the model by using a nonlinear regression Fifth Annual Meeting of the American College A of Clinical Pharmacology in Philadelphia, Penn., program such as NONLINs or IVILAB.~ graphic analysis must always be done on April 30, 1976. October, 1976

from the SAGE Social Science Collections. All Rights Reserved

565

NEL#SON ANIMAL TOXICOLOCY ___) RAPID IV BOLUS STUDY

EARLY K I E T I C DATA

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ABSORPTI ON, W!TABaITE GEI%ZRATICU, 1 MICHAELIS-HEWEN K1)IRIC SWDIES

MODEL AWPLIPICATIM

CMPUTER SIMIIIATIM OF VARIOUS DOSE REGIXENS

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EARLY HUMAN KINETIC STUDIES

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Fig. I . Flow chart for the process involved in the pharmacokinetic work-up of a potential new drug.

prior to computer fitting since serious errors may be made if the computer is simply used to process data in an assembly line fashion.'** After defining the kinetic model for the unchanged drug given by bolus injection, the model can be amplified to include the metabolism, distribution, and elimination of the drug in the urinary, biliary, and enterohepatic circulation for both unchanged drug and metabolites, if possible. Next, an oral, subcutaneous, intramuscular, or rectal absorption study may be done, and the respective absorption constants and fractions of dose absorbed computed.2 A 9ow diagram depicting the process of generating pharmacokinetic data for a new drug is shown in Fig. 1. At this point in the analysis, a great deal is known about the potential new ,568

drug in the animal teat species. This analysis should yield the various volumes of distribution, the distribution and elimination half-lives, and the rate constants for absorption, distribution, elimination, and the metabolism of the drug. It is important that these data be fit directly to a system of differential equations instead of to coefficients of a multiexponential decay equation. While the exponential decay equation is ideal for initial definition of the multicompartment model, the hybrid coefficients derived from it are dependent on the variables associated with the animal under study (weight and renal and hepatic function), and it is difficult to compare coefficients among several animals.' By contrast, the transfer constants associated with a system of differential equations are not dependent on such variables as weight and are much more directly comparable among several test animal^.^ Statistical analysis performed on the variables which are directly comparable will provide an estimation of how well the model fits data derived from several test animals?-" What can be said about the future development and clinical use of the potential new drug from the animal kinetic model? Has initial kinetic analysis provided any leads o r clues which might obviate a great deal of expensive and unnecessary research in higher animals or man? As one example, consider a potential new antibiotic under study for deep-seated t h e infections. Kinetic analysis in animals, and perhaps in one or two human volunteers, shows the drug to have a minimal distribution and a rapid elimination half-life, and renal excretion kinetics indicate that it is eliminated by both glomerular fltration and tubular secretion. Simulation of frequent multiple doses or even constantrate infusion of the drug on a cornputer12-14 by using parameters derived from the kinetic model reveals that high serum and tissue levels of this drug could never realistically be achieved, and thus, The J o d of Clinical Pharmacology

PHARMACOKINETICS A N D T E E PHARMACEUTICAL INDUSTRY

theoretically, the drug would not be useful for deep-seated tissue infections. However, the renal excretion kinetics suggest that the drug could have great utility in treating urinary infections, and future research by the pharmaceutical company would be along the lines of developing an antibiotic specificially to treat urinary infections. By this analysis, many costly and needless clinical studies would be circumvented. As another example, consider a potential antiarrhythmic agent which has shown excellent efficacy when used by constantrate intravenous infusion, but is now considered for development into an oral dosage form. If initial kinetic studies disclose that the drug has a large volume of distribution but an elimination half-life of only 30 minutes, developing a compressed-tablet oral dosage form would be impractical. Clearly, the most rational clinical use of this antiarrhythmic drug would be to give an initial loading dose achieving a rapid filling of the large volume of distribution, followed by a constant-rate intravenous infusion to maintain a steady-state therapeutic level. A somewhat different situation arises for drugs which have relatively long elimination half-lives.16 A potential anticonvulsant drug that has undergone the aforementioned kinetic analysis reveals that when given orally, it is rapidly and completely absorbed from the gastrointestinal tract, distributed in a space compatible with total body water, and has an elimination half-life of 43 hours. Such a drug might rationally be used by giving a loading dose of 30 mg initially, followed by a single daily maintenance dose of 10 mg. If the drug were given daily without the loading dose, therapeutic serum levels of the drug would not be present for the first three days of treatmenkan unacceptable situation in the clinical management of seizures. On the other hand, if the effective initial dose of 30 mg were used for October, 1976

daily maintenance, serious toxicity might occur in a few days because of the higher steady-state serum concentration. It is clearly advantageous to establish the pharmacokinetic characteristics for this drug early in animal studies or Phase I human trials, as the design of a rational dosage schedule for early efficacy studies in epileptic patients is largely dependent on the knowledge of drug kinetics. In this way, many dosage regimens can be ruled out, needless clinical trials using these regimens circumvented, and developmental research costs saved by the pharmaceutical company. Another example of the fruitful application of pharmacokinetic data arises in the formulation of drug combinations. This basically involves closely matching the disposition kinetics of two or more drugs to create a fixed-ratio combination dosage form. Because of convenience to the patient, such combinations are frequently useful in treating pain, hypertension, asthma, and other clinical conditions. I n each situation, clinical testing will be required to demonstrate that the combination has a potentiating o r at least an additive therapeutic effect for the condition being treated. In some instances, matching kinetics is critical for efficacy. Consider trimethoprim-sulfamethoxazole,3 a new fixed-ratio combination antibiotic containing trimethoprim and a sulfonamide. I n vitro microbiologic studies indicated that trimethoprim augmented the antibacteria1 action of the sulfonamides because the combination produced a competitive sequential blockage of two consecutive steps in the microbial nucleic acid biosyntheses.l6 To impede the development of resistance, both agents had to be present simultaneously in the medium. After the pharmacokinetics of the new drug trimethoprim were determined,17 the question was which of the available sulfonamides would most closely match the distribution and elimination kinetics of 567

NELSON

trimethoprim. Sulfamethoxazole proved to be nearly, although not perfectly, so, on the basis of its kinetic grounds, and waa chosen for incorporation into the combination drug. Additional kinetic studies were required to demonstrate that neither agent in the combination affected the disposition kinetics of the other. When these studies showed no effeect,18 the combination was tested clinically and found effective in chronic urinary tract infections as well aa other syatemic infections. In this instance, pharmacokinetic studies played a crucial role in the development of a rational, fixed-ratio antibiotic combination. "here are other examples to show that a knowledge of pharmacokinetics may facilitate early clinical drug testing. Kinetic studies in man may indicate that while the therapeutic range for a drug such aa coumarin is quite narrow, the elimination kinetics vary widely among patients, making individual monitorng a necessity to tailor a dosage schedule for each patient.le A highly protein-bound drug forewarns of the potential of displacement by other drugs and the hazard of increased toxicity.2O A large first-pass effect indicates that the effective intravenous dose might be considerably smaller than the effective oral dose?' Drugs with a high rate of renal excretion will require dosage modifications for patients with renal impairment.22 Finally, despite the broad utility of pharmacokinetics, kinetic data alone are frequently insufficient to explain certain biologic effects.2J1 For certain drugs for cancer chemotherapy and immunostimulatory or immunosuppressive therapy, the blood and tissue level curves may not parallel the biologic responses. More basic and detailed pharmacologic and biochemical studies may be required to elucidate the mechanism and time course of drug dose and response. However, kinetic data are often necessary to solve the clinical puazle. For example, the use of pharma668

cokinetic data is essential in designing cellcycle synchronization protocols for the treatment of acute

Summary Pharmacokmetic -studies done early in the course of drug development can favorably influence the course of research by suggesting optimum dosage regimens, drug delivery methods, and fixed-ratio combinations and by alerting the clinical pharmacologist to potential problems. Pharmacokinetic data can be useful in the design of rational clinical drug research and thereby expedite clinical trials and save research costs. Thus, in addition to their value in the area of comparative bie availability, pharmacokinetic studies carried out by the pharmaceutical industry are useful economically as well aa scientifically.

References 1. Greenblatt, D. J., and Koch-Weser, J.: Clinical pharmacokinetics (part I). Nm England J . Y e d . 293 :702 (1975). 2. Greenblatt, D. J., and Koch-Weser, J.: Clinical pharmacokinetics (part II). Neco England J . Med. 293:964 (1975). 3. Koch-Weser, J.: Bioavailability of droga New England J . Y e d . 291:233 (1974). 4. Gibaldi, M.: Effect of mode of adminiahtion on drug distribution in a twocompartment open system. J . Phonn. 8Oi. 58:321 (1969). 5. Metzler, C. M.: NONLIN, a Computer hogram for Parameter Estimation in Nonlinear Situations. The Upjohn Company, Kalamazoo, Mich., 1969. 6. Knott, G. D., and h e c e , D. K.: U: a civilized curve-fitting m m . In Proceeaings of the 0 " E 1972 Inkmational Conference, Vol. I. Brnnel University, England, 1972, pp. 497426. 7. Wagner, J. G.: Biopharmsceutica and Mevant Pharmacokinetica, 1st ed. Hamilton, Ill., Drug Intelligence Publications, 1971, pp. 318-324. 8. Wagner, J. 0.: Use of computese in pharmacolrinetica. Clin. PhMmaaol. !l'harap. 8 : 201 (1967). 9. Westlake, W. J.: Problema aaaociated with analyses of pharmacokinetic modela J. Pharm. S&. 60 :882 (1971).

Th0 Journal of Clinical Pharmacology

PHARMACOKINETICS A N D T E E PHARMACEUTICAL INDUSTRY 10. Boxenbaum, H. G., Riegelman, S., and Elashoff, R. M.: Statistical estimations in pharmacokinetics. J. P h a m o k i n e t . BW-

pharm. 2:123 (1974). 11. Fell,-9. J., and Stevens, M. T.: Pharmacokinetics: uses and abuses. Eur. J. Clin. Pharmcol. 8 :241 (1975). 12. Kruger-Thiemer, E.: Continuous intravenous infusions and multi-compartment accumulation. Eur. J. Pharmcol. 4:317 (1968). 13. Wagner, J. G.: A safe method for rapidly achieving plasma concentration plateaus. Clin. Pharmcol. Therap. 16 :691 (1974). 14. varnssum, J. M.: Pharmacokinetics of accumulation. J. Pharm. Sci. 57 :2162 (1968). 15. Goldstein, A,, Aronow, L., and K h a n , 8. M.: Principles of Drug Action, 2nd ed. New York, Wiley, 1974, pp. 311-332. 16. Brumfitt, W., Hamilton-Miller, J. M. T., and Kosmidis, J. : Trimethoprim-sulfamethoxazole : the present position. J. Infect. Dis. 128 :778 (Supplement 1973). 17. Welling, P. G., Craig, W. A., Amidon, G. L., and Kunin, C. M.: Pharmacokinetics of trimethoprim and sulfamethoxazole in

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19. 20. 21.

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normal subjects and in patients with renal failure. J. Infect. Dk. 128:556 (Supplement 1973). Kaplan, 8. A., Weinfeld, R. E., Abruzzo, C. W., McFaden, K., Jack, M. L., and Weissman, L. : Pharmacokinetic proiile of trimethoprim-sulf amethoxazole in man. J. Infect. Dis. 128:547 (Supplement 1973). Koch-Weser, J.: Serum drug concentrations as therapeutic guides. New England J. Y e d . 287:227 (1972). Anton, A. H.,and Solomon, H. M., Eds.: Drug-protein binding. Ann. New Pork Acad. Sci. 226: (1973). Gibaldi, M., Boyes, R. N., and Feldman, 8.: Influence of first-pass effect on availability of drugs on oral administration. J. Pharm. Sci. 60:1338 (1971). Wagner, J. G.: Biopharmaceutics and Relevant Pharmacokinetics, 1 s t ed. Hamilton, Ill., Drug Intelligence Publications, 1971, pp. 222-233. DeVita, V. T.: Cell kinetics and the chemotherapy of cancer. Cancer Chemother. Rep. 3:23 (1971).

The utility of pharmacokinetics to the pharmaceutical industry.

The Utility of Pharmacokinetics to the Pharmaceutical Industry ROBERT 1. NELSON. M.D. Indidndpoiir, Ind. ITHIN the past decade, the science of pharm...
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