Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
Tyson JE, Furzan JA, Reisch JS, et al. An evaluation of the quality of therapeutic studies in perinatal
medicine. J Pediatr 1983;102(1):10–13.
Greenhouse SW. Some historical and methodological developments in early clinical trials at the
National Institutes of Health. Stat Med 1990;9(8):893–901; discussion 903–906.
Bock R. NICHD Renamed for Eunice Kennedy Shriver, advocate for institute’s founding. In: NIH
record. Bethesda, MD: NIH, 2008.
Shirkey H. Editorial comment: therapeutic orphans. J Pediatr 1968;72(1):119–120.
Marks I. Drugs (e.g., hexachlorophene), the FDA, and the AAP. Pediatrics 1972;50(2):338.
American Academy of Pediatrics Committee on Drugs. General guidelines for the evaluation of
drugs to be approved for use during pregnancy and for the treatment of inf ants and children.
Chicago, IL: American Academy of Pediatrics, 1974.
Wilson JT. Pragmatic assessment of medicines available for young children and pregnant or breastfeeding women. In: Garattini S, Morselli PL, Sereni F, eds. Basic and therapeutic aspects of
perinatal pharmacology. New York, NY: Raven, 1975:411–421.
Food and Drug Administration. General considerations for the clinical evaluation of drugs in infants
and children. Washington, DC: Department of Health, Education, and Welfare, 1977.
American Academy of Pediatrics, Committee on Drugs. Guidelines for the ethical conduct of studies
to evaluate drugs in pediatric populations. Pediatrics 1977;60:91–101.
Food and Drug Administration. Labeling and prescription drug advertising: content and format for
labeling for human prescription drugs. Washington, DC: Federal Register, 1979:37434–37462.
US Congress. Orphan drug act public law 97-414. Washington, DC: US Government, 1983.
House Committee on Energy and Commerce. Health care reform, hearing before the Committee on
Energy and Commerce, House of Representatives, One Hundred Third Congress, first session, on
President Clinton’s Proposal to Reform the Nation’s Health Care System—United States. Congress.
House. Committee on Energy and Commerce. Washington, DC: Government Printing Office,
1994:622–623.
Gilman JT, Gal P. Pharmacokinetic and pharmacodynamic data collection in children and neonates. A
quiet frontier. Clin Pharmacokinet 1992;23(1):1–9.
Food and Drug Administration. Specific requirements on content and format of labeling for human
prescription drugs; revision of “pediatric use” subsection in the labeling. Washington, DC: Federal
Register, 1994:64240–64250.
Food and Drug Administration. The content and format for pediatric use supplements.
Washington, DC: Food and Drug Adminsitration, 1996.
American Academy of Pediatrics, Committee on Drugs. Guidelines for the ethical conduct of studies
to evaluate drugs in the pediatric population. Pediatrics 1995;95(2):288–294.
NICHD. Pediatric Pharmacology Research Units (PPRU) Network. 2017.
https://www.nichd.nih.gov/research/supported/ppru.
NICHD. Making medicines safer for children: NICHD-supported research in pediatric
pharmacology. 2013. https://www.nichd.nih.gov/newsroom/resources/spotlight/120313-pediatricpharmacology.
US Congress. Public Law 105-115 Food and Drug Administration Modernization Act.
Washington, DC: Government Printing Office, 1997:86.
Food and Drug Administration. Regulations requiring manufacturers to assess the safety and
effectiveness of new drugs and biological products in pediatric patients. Washington, DC: Federal
Register, 1998:66631.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
US District Count for the District of Columbia. Civil Action130-02898 October 17. 2002.
Washington, DC: US District Court, 2002.
US Congress. Public Law 108-155 Pediatric Research Equity Act. Washignton, DC: Government
Printing Office, 2003.
Stolbeg SG. The biotech death of Jesse Gelsinger. New York Times. New York, NY: New York
Times, 1999:149–150.
Office of Public Health and Science and National Institutes of Health-Office of the Director.
Statement of organization, functions, and delegations of authority. Washington, DC: Federal Register,
2000:37136.
Food and Drug Administration. Additional safeguards for children in clinical investigations of FDA
regulated products. Washington, DC: Federal Register, 2001:20589.
US Congress. Best Pharmaceuticals for Children Act. Public Law No. 107-109. 2002.
US Congress. Public Law 110-85, The Food and Drug and Administration Amendment Act of
2007 (FDAAA). Washington, DC: US Federal Government, 2007.
US Congress. FDA Reauthorization Act (FDARA). Washington, DC: US Federal Government,
2017.
Food and Drug Administration. FDA pediatric exclusivity statistics. 2019.
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.htm.
National Institutes of Health. Clinical trial definition. https://grants.nih.gov/policy/clinical-trials/CT-
Definition-Case-Studies_1.7.19.pdf.
Ashcroft R. Equipoise, knowledge and ethics in clinical research and practice. Bioethics 1999;13(3–
4):314–326.
Sioutos N, de Coronado S, Haber MW, et al. NCI Thesaurus: a semantic model integrating cancer-
related clinical and molecular information. J Biomed Inform 2007;40(1):30–43.
Kahn MG, Bailey LC, Forrest CB, et al. Building a common pediatric research terminology for
accelerating child health research. Pediatrics 2014;133(3):516–525.
Gipson DS, Kirkendall ES, Gumbs-Petty B, et al. Development of a pediatric adverse events
terminology. Pediatrics 2017;139(1):e20160985.
Hill AB. Conrolled clinical trials. Oxford, England: Blackwell, 1960.
Council MR. Streptomycin treatment of pulmonary tuberculosis: a medical research council
investigation. BMJ 1948;2(4582):769–782.
Austrian R, Mirick GS, Rogers DE, et al. The efficacy of modified oral penicillin therapy of
pneumococcal lobar pneumonia. Bull Johns Hopk ins Hosp 1951;88(3):264–269.
Tucker WB. Experiences with controls in the study of the chemotherapy of tuberculosis. in
Transactions of the 13th Veterans Administration Conference on chemotherapy of
tuberculosis. 1954.
Rheumatic Fever Working Party of the Medical Research Council of Great Britain and the
Subcommittee of Principal Investigators of the American Council on Rheumatic Fever and
Congenital Heart Disease. The evolution of rheumatic heart disease in children. Circulation
1960;22(4):503–515.
Stanley A. The cancer chemotherapy national service center antitumor testing program for
antibiotics. In: Developments in industrial microbiology. Springer Science + Business Media,
1960:86–90.
Gehan EA, Schneiderman MA. Historical and methodological developments in clinical trials at the
National Cancer Institute. Stat Med 1990;9(8):871–880; discussion 903–906.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283(20):2701–
2711.
Sutcliffe AG. Testing new pharmaceutical products in children. BMJ 2003;326(7380):64–65.
Sheiner LB. Learning versus confirming in clinical drug development. Clin Pharmacol Ther
1997;61(3):275–291.
Kauffman RE. Clinical research involving children. Bioethics Forum 2000;16(4):45–46.
Hirschfeld S. Comment—disclosing a diagnosis of HIV in pediatrics: providing the best possible
care. J Clin Ethics 2001;12(2):158–160.
Henney J. Remarks to Pediatric Academic Socieites and American Academy of Pediatrics. 1999.
https://wayback.archiveit.org/7993/20170406163039/https://www.fda.gov/NewsEvents/Speeches/ucm054212.htm.
Food and Drug Administration. Additional safeguards for children in clinical investigations of FDA
regulated products. Washington, DC: Federal Register, 2001:20589–20600.
Food and Drug Administration. Additional safeguards for children in clinical investigations of food
and drug administration-regulated products. Washington, DC: Federal Register, 2013:12937–12951.
International Conference on Harmonisation of Technical Requiremeents for Registration of
Pharmaceuticals for Human Use. E11 Clinical investigation of medicinal products in the pediatric
population. 2017. https://database.ich.org/sites/default/files/E11_R1_Addendum.pdf.
Food and Drug Administration. Pediatric oncology subcommittee meeting notice. Washington,
DC: Federal Register, 2002:61344.
Harvey A, Towner E, Peden M, et al. Injury prevention and the attainment of child and adolescent
health. Bull World Health Organ 2009;87(5):390–394.
Sheiner LB, Steimer JL. Pharmacokinetic/pharmacodynamic modeling in drug development. Annu
Rev Pharmacol Toxicol 2000;40(1):67–95.
Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions
and conceptual framework. Clin Pharmacol Ther 2001;69(3):89–95.
Menetski JP, Austin CP, Brady LS, et al. The FNIH Biomarkers Consortium embraces the BEST.
Nat Rev Drug Discov 2019;18(8):567–568.
Leptak C, Menetski JP, Wagner JA, et al. What evidence do we need for biomarker qualification?
Sci Transl Med 2017;9(417):eaal4559.
Menetski JP, Hoffmann SC, Cush SS, et al. The foundation for the National Institutes of Health
Biomarkers consortium: past accomplishments and new strategic direction. Clin Pharmacol Ther
2019;105(4):829–843.
Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern
Med 1996;125(7):605–613.
Massie BM, Berk MR, Brozena SC, et al. Can further benefit be achieved by adding flosequinan to
patients with congestive heart failure who remain symptomatic on diuretic, digoxin, and an
angiotensin converting enzyme inhibitor? Results of the flosequinan-ACE inhibitor trial (FACET).
Circulation 1993;88(2):492–501.
Packer M, Narahara KA, Elkayam U, et al. Double-blind, placebo-controlled study of the efficacy of
flosequinan in patients with chronic heart failure. Principal Investigators of the REFLECT Study. J
Am Coll Cardiol 1993;22(1):65–72.
Massie BM, Shah NB, Pitt B, et al. Importance of assessing changes in ventricular response to atrial
fibrillation during evaluation of new heart failure therapies: experience from trials of flosequinan. Am
Heart J 1996;132(1 Pt 1):130–136.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
Packer M, Pitt B, Rouleau JL, et al. Long-term effects of flosequinan on the morbidity and mortality
of patients with severe chronic heart failure: primary results of the PROFILE trial after 24 years.
JACC Heart Fail 2017;5(6):399–407.
Cardiac Arrhythmia Suppression Trial Investigators. Preliminary report: effect of encainide and
flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N
Engl J Med 1989;321(6):406–412.
Flecainide and CAST. Lancet 1989;2(8661):481–482.
Bigger JT Jr. The events surrounding the removal of encainide and flecainide from the Cardiac
Arrhythmia Suppression Trial (CAST) and why CAST is continuing with moricizine. J Am Coll
Cardiol 1990;15(1):243–245.
Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide,
flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324(12):781–
788.
Akiyama T, Pawitan Y, Greenberg H, et al. Increased risk of death and cardiac arrest from
encainide and flecainide in patients after non-Q-wave acute myocardial infarction in the Cardiac
Arrhythmia Suppression Trial. CAST Investigators. Am J Cardiol 1991;68(17):1551–1555.
The International Chronic Granulomatous Disease Cooperative Study Group. A controlled trial of
interferon gamma to prevent infection in chronic granulomatous disease. The International Chronic
Granulomatous Disease Cooperative Study Group. N Engl J Med 1991;324(8):509–516.
Mouy R, Seger R, Bourquin JP, et al. Interferon gamma for chronic granulomatous disease. N Engl
J Med 1991;325(21):1516–1517.
Gallin JI. Interferon-gamma in the treatment of the chronic granulomatous diseases of childhood.
Clin Immunol Immunopathol 1991;61(2 Pt 2):S100–S105.
Riggs BL, Seeman E, Hodgson SF, et al. Effect of the fluoride/calcium regimen on vertebral fracture
occurrence in postmenopausal osteoporosis. Comparison with conventional therapy. N Engl J Med
1982;306(8):446–450.
Riggs BL, Hodgson SF, O’Fallon WM, et al. Effect of fluoride treatment on the fracture rate in
postmenopausal women with osteoporosis. N Engl J Med 1990;322(12):802–809.
Kinsella JP, Cutter GR, Walsh WF, et al. Early inhaled nitric oxide therapy in premature newborns
with respiratory failure. N Engl J Med 2006;355(4):354–364.
Ballard RA, Truog WE, Cnaan A, et al. Inhaled nitric oxide in preterm infants undergoing mechanical
ventilation. N Engl J Med 2006;355(4):343–353.
Barrington KJ, Finer N, Pennaforte T, et al. Nitric oxide for respiratory failure in infants born at or
near term. Cochrane Database Syst Rev 2017;1:CD000399.
Barrington KJ, Finer N, Pennaforte T. Inhaled nitric oxide for respiratory failure in preterm infants.
Cochrane Database Syst Rev 2017;1:CD000509.
Cole FS, Alleyne C, Barks JD, et al. NIH Consensus Development Conference statement: inhaled
nitric-oxide therapy for premature infants. Pediatrics 2011;127(2):363–369.
Noel CJ. Pick any two-fast, good, cheap. http://mercury.lcs.mit.edu/~jnc/.
Arts SE, Abu-Saad HH, Champion GD, et al. Age-related to lidocaine-prilocaine (EMLA) emulsion
and effect of music distraction on the pain of intravenous cannulation. Pediatrics 1994;93(5):797–
8010.
Chambers CT, Craig KD. An intrusive impact of anchors in children’s faces pain scales. Pain
1998;78(1):27–37.
Johnston CC, Stevens B, Arbess G. The effect of the sight of blood and use of decorative adhesive
bandages on pain intensity ratings by preschool children. J Pediatr Nurs 1993;8(3):147–151.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
152.
Kotiniemi LH, Ryhanen PT, Moilanen IK. Behavioural changes in children following day-case
surgery: a 4-week follow-up of 551 children. Anaesthesia 1997;52(10):970–976.
Lander J, Fowler-Kerry S. TENS for children’s procedural pain. Pain 1993;52(2): 209–216.
Ljungman G, Kreuger A, Andréasson S, et al. Midazolam nasal spray reduces procedural anxiety in
children. Pediatrics 2000;105(1 Pt 1):73–78.
Santavirta N, Björvell H, Solovieva S, et al. Coping strategies, pain, and disability in patients with
hemophilia and related disorders. Arthritis Rheum 2001;45(1):48–55.
Goodenough B, Thomas W, Champion GD, et al. Unravelling age effects and sex differences in
needle pain: ratings of sensory intensity and unpleasantness of venipuncture pain by children and
their parents. Pain 1999;80(1):179–190.
Aho AC, Erickson MT. Effects of grade, gender, and hospitalization on children’s medical fears. J
Dev Behav Pediatr 1985;6(3):146–153.
Bruusgaard D, Smedbråten BK, Natvig B. Bodily pain, sleep problems and mental distress in
schoolchildren. Acta Paediatr 2007;89(5):598–600.
Hirschfeld S. Pain as a complication of HIV disease. AIDS Patient Care STDS 1998;12(2):91–108.
Guite JW, Walker LS, Smith CA, et al. Children’s perceptions of peers with somatic symptoms: the
impact of gender, stress, and illness. J Pediatr Psychol 2000;25(3):125–135.
Chambers CT, Craig KD, Bennett SM. The impact of maternal behavior on children’s pain
experiences: an experimental analysis. J Pediatr Psychol 2002;27(3):293–301.
Food and Drug Administration. General clinical pharmacology considerations for pediatric
studies for drugs and biological products. Silver Spring, MD: Food and Drug Administration,
2014.
Turner MA, Catapano M, Hirschfeld S, et al. Paediatric drug development: the impact of evolving
regulations. Adv Drug Deliv Rev 2014;73:2–13.
Food and Drug Administration. Leveraging existing clinical data f or extrapolation to pediatric
uses of medical devices. Silver Spring, MD: Food and Drug Admininistration, 2016.
Turner MA, Hirschfeld S. Frameworks for evaluating medicines in children. Clin Ther
2017;39(10):1949–1958.
European Medicines Agency. Reflection paper on the use of extrapolation in the development of
medicines for paediatrics. London, England: European Medicines Agency, 2018:20.
Dunne J, Rodriguez WJ, Murphy MD, et al. Extrapolation of adult data and other data in pediatric
drug-development programs. Pediatrics 2011;128(5):e1242–e1249.
Ollivier C, Thomson A, Manolis E, et al. Commentary on the EMA Reflection Paper on the use of
extrapolation in the development of medicines for paediatrics. Br J Clin Pharmacol 2019;85(4):659–
668.
Higgins JPT, Chandler J, Cumpston M, et al. Cochrane handbook for systematic reviews of
interventions, 2nd ed. Chichester, England: John Wiley & Sons, 2019:720.
Brown CA, Lilford RJ. The stepped wedge trial design: a systematic review. BMC Med Res
Methodol 2006;6:54.
Mdege ND, Man MS, Taylor Nee Brown CA, et al. Systematic review of stepped wedge cluster
randomized trials shows that design is particularly used to evaluate interventions during routine
implementation. J Clin Epidemiol 2011;64(9):936–948.
Hargreaves JR, Copas AJ, Beard E, et al. Five questions to consider before conducting a stepped
wedge trial. Trials 2015;16(1):350.
153.
154.
155.
156.
157.
158.
159.
160.
161.
162.
163.
164.
165.
Johnson DE, Wolfgang GH. Predicting human safety: screening and computational approaches.
Drug Discov Today 2000;5(10):445–454.
Hirschfeld S, Zajicek A. What could the future of safety monitoring look like? Ther Innov Regul Sci
2019;53(5):590–600.
Hirschfeld S. Pediatric patients and drug safety. J Pediatr Hematol Oncol 2005;27(3):122–124.
Bonhoeffer J, Kochhar S, Hirschfeld S, et al. Global alignment of immunization safety assessment in
pregnancy—The GAIA project. Vaccine 2016;34(49):5993–5997.
Jones CE, Munoz FM, Spiegel HM, et al. Guideline for collection, analysis and presentation of safety
data in clinical trials of vaccines in pregnant women. Vaccine 2016;34(49):5998–6006.
Kochhar S, Bonhoeffer J, Jones CE, et al. Immunization in pregnancy clinical research in low-and
middle-income countries—study design, regulatory and safety considerations. Vaccine 2017;35(48 Pt
A):6575–6581.
Connor EM, Smoyer WE, Davis JM, et al. Meeting the demand for pediatric clinical trials. Sci
Transl Med 2014;6(227):227fs11.
Sheehan J, Hirschfeld S, Foster E, et al. Improving the value of clinical research through the use of
Common Data Elements. Clin Trials 2016;13(6):671–676.
Hirschfeld S, Saint-Raymond A. Pediatric regulatory initiatives. Handb Exp Pharmacol
2011;205:245–268.
White IR. Book review: Nonparametric statistics for health care research. Statistics for small
samples and unusual distributions. Marjorie A. Pett, Page Publications. Thousand Oaks, 1997. No. of
pages: 305. Price: £22. ISBN 0-8039-7039-0. Stat Med 1998;17(19):2287–2288.
Hayden GF. Biostatistical trends in pediatrics: implications for the future. Pediatrics 1983;72(1):84–
87.
Pocock SJ, Hughes MD, Lee RJ. Statistical problems in the reporting of clinical trials. A survey of
three medical journals. N Engl J Med 1987;317(7):426–432.
Hirschfeld S. Common errors associated with FDA submissions. In: DIA Conference on
Electronic Submissions, Washington DC, 1999.
Edmund V. Capparelli
C H A P T E R
2
Clinical Pharmacokinetics in Infants and Children
INTRODUCTION
Considerable growth has occurred in a number of new chemical and biologic
pediatric treatments during the last 30 years. Appropriate use of these agents
in pediatric patients requires determining the safe and effective dosage for
infants and children. A rational approach to determining appropriate dosage
requires understanding the pharmacokinetic (PK) and pharmacodynamic (PD)
properties of a drug in the population in which it is being used. Optimal
therapy uses knowledge of a drug’s PK to determine the dosage with a given
formulation that will achieve desired drug concentrations and effects for a
particular infant or child. In this setting, PK represents the mathematical
description of drug metabolism and movement through a pediatric patient. PD
describes the relationship of drug concentrations at the site of action and the
magnitude of responses, both therapeutic and toxic. In simplified terms, PK
describes what the body does to the drug, and PD describes what the drug
does to the body (Fig. 2.1).
Figure 2.1 Schematic representation of the components that make up the pharmacokinetic–
pharmacodynamic interface.
Knowing the right dosage for an individual is as important as selection of
the correct drug. Determining the dosage for an individual patient that
maximizes clinical benefit yet minimizes toxicity requires knowledge of the
general PK and PD properties of the drug in the population, the variability of
these properties, and the important physiologic determinants of this
variability. Some of the PK and PD variability may be explained by
formulation-, genetic-, age-, size-, and disease-related effects. Even when the
sources of PK and PD variability cannot be identified or linked to clinical
characteristics, understanding the range of concentrations and responses to a
dosing regimen is necessary in the development of rational treatment
strategies.
The PK of most drugs can be well described by a few key parameters.
The two most important are volume of distribution, Vd, and clearance, CL.
The elimination half-life, t
1/2
, and associated elimination rate constant, K, are
also widely determined and useful to determine dosing frequency. Following
nonparenteral administration (such as oral, intramuscular, subcutaneous, or
inhaled), bioavailability and absorption rate parameters are also necessary to
describe a drug’s PK behavior. Through these PK parameters, a dosing
regimen can be derived to achieve target drug concentrations or range of
concentrations where the desirable effect is likely and toxicity is minimal.
Clinical PD endpoint measurements and related biomarkers are often highly
variable and can require study of many individuals in multiple studies to
understand the exposure–effect relationship. To develop appropriate target
concentrations, PD models that describe the maximal effect, E
max
, and
concentration that achieves half of the maximal effect, EC50, as either
inhibitory or stimulatory influences on disease processes can be used.
Methods for calculating these parameters and clinical (physiologic and
pathologic) factors that affect them are presented in this chapter.
VOLUME OF DISTRIBUTION
After a drug is administered, it does not stay confined in the circulating blood
pool. The drug diffuses into tissues, organs, and other fluid spaces, where it
exerts its actions. However, when measuring drug concentrations, we are
usually limited to collecting serum or plasma samples from the circulating
blood pool and determining drug concentrations in these matrices. This serves
as a surrogate for the drug concentration at the site of action. Therefore, it is
useful to relate drug concentration measured in plasma to the total amount of
drug in the body. The volume of distribution, Vd, is a proportionality constant
that relates the drug concentration to the total amount of drug in the body and
can be represented as
where A is the total amount of drug in the body and Cp is the drug
concentration in plasma. The direct clinical application of this PK parameter
is that it can determine a loading dose:
Loading dose = C
p-desired
· V
d
It can be defined in relation to blood concentrations, plasma or serum
concentrations, or unbound concentrations (Vdb, Vdp, or Vdu, respectively). For
a given drug, each of these drug concentration measurements may have
different values; thus, Vd is relative to the matrix from which concentrations
were measured. If, after bolus administration, a drug were to equilibrate
incautiously between plasma and tissues, Vdp can easily be estimated as
where Cp0 is the drug concentration in plasma at time zero or immediately
after drug administration (Fig. 2.2). This represents a one-compartment
model with a single fixed Vdp value. Distribution of drug out of blood and into
other fluids and tissues takes time; so “true” one-compartment drug behavior
is almost never encountered. However, if distribution is very rapid relative to
elimination or absorption (following oral administration), a one-compartment
model can adequately describe the drug concentration-versus-time profile.
More commonly, after intravenous administration, a rapid fall in drug
concentrations is followed by a slower disappearance of drug. This
multiphasic pattern of drug concentrations requires more complicated models
characterized by multiple compartments with differential equations describing
the movement of the drug between compartments and overall drug elimination.
The most common model in this situation is the two-compartment model (Fig.
2.3). In this setting, drug concentrations initially fall rapidly because of
distribution of the drug out of blood into tissues followed by a slower decline
because of elimination. The initial distribution phase is also known as the
alpha (α) phase and the elimination period as the beta (β) phase. For a few
drugs, the redistribution out of tissues is a slower process than elimination
through metabolism or excretion. In these settings, the terminal β phase may
represent redistribution rather than elimination. It is important to recognize
that these Vds do not represent true physical tissue or fluid spaces per se but
are greatly influenced by body composition, physiologic processes, and the
chemical and physical properties of the drug. Therefore, a drug that has a
much higher affinity for extravascular tissue than for plasma may have a V
d
that is in excess of true body size (greater than 1 L per kg). However, it is
possible to set a minimum value for Vd at the blood or plasma volume. Thus,
no drug can have a Vd less than total intravascular plasma volume, or about 50