FUNDAMENTALS
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`nleral Drugs I. Intravenous and Intramuscular
`
`FRANCIS L. S. TSE‘ and
`PETER G. WELLINGF“
`
`‘School of Pharmacy
`University of Wisconsin
`Madison, Wisconsin
`
`4‘-‘College of Pharmacy
`Rutgers, The State University
`Piscataway, New Jersey
`
`Whatever the mode of action of a systemi-
`cally acting drug, the efficiency and also the
`rate of its absorption into the circulation are
`of primary importance. During the last 10
`years there has been a proliferation of litera-
`ture related to the biological availability, or
`bioavailability, of systemically acting com-
`pounds. Thc impetus for this has derived firstly
`from a growing awareness among clinicians
`and biological scientists of a relationship be-
`tween drug bioavailability and therapeutic
`effect, and secondly, from the recent increase
`in the number of rnultiplosource drug prod-
`ucts and also the expiration of patents on many
`proprietary drug formulations. The combined
`effect of these perhaps diverse interests has
`been to generate a vast amount of data, and
`also rhetoric, on drug bioavailability and its
`importance in therapy.
`The term bioavailability has been defined
`in the United States Federal Register (1) as
`“the rate and extent to which the active drug
`ingredient or therapeutic moiety is absorbed
`from a drug product and becomes available at
`the site of action”—~normally estimated by its
`concentrations in body fluids, rate of excretion,
`or acute pharmacological effect.
`Although a number of methods inttolving
`the use of pharmacological response have been
`described for measuring drug bioavailability,
`the majority of studies is based on the chemi-
`
`409
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`Astrazeneca Ex. 2108 p." 1
`Mylan Pharms. Inc. V. Astrazeneca AB
`
`IPR20 16-0 1325
`
`Introduction
`
`_
`
`It has long been recognized that the men»
`sity and duration of pharmacologic effect of
`' a systemically acting drug are functions, not
`only of the intrinsic activity of the drug, but
`also of its absorption, distribution, and elimi-
`".-nation characteristics.
`'
`To exert a required pharmacological action,
`:21 drug must be absorbed at rt rate and to an
`extent that will produce adequate drug con-
`centrations at the site(s) of action during a
`‘certain time period. The relationship between
`rirug concentration at the receptor site and
`pharmacological effect depends also on the
`type of action the drug exerts.
`For example, present knowledge suggests
`that the bacteriocidal action of antibiotics is
`nlirectly related to the drug levels at the site of
`‘
`e infection, and the bacteriocidal effect is
`at when antibiotic levels fall below the min-
`um inhibitory concentration of the invading
`Eorganisms. On the other hand, the effect of the
`ticoagulant warfarin on blood clotting is
`nsiderably delayed relative to the circulating
`g profile, and the relationship between
`rcnlating levels of this compound and its
`erapeutic effect is less well defined.
`
`Dr. Tso is at The College of Pharmacy, Rutgers, The
`tate University, Piscataway, NJ 08854.
`
`‘-i ember-Dctobcr, i980, Vol. 34. No. 5
`
`
`
`

`
`cal determination of drug or metabolites in
`biological fluids.
`While the bioavsilebility of drugs adrnin~
`istered via the oral or enteral route has been
`investigated to a great extent, few studies have
`attempted to address the bioavailabillty
`problems associated with drugs which are
`closed parenterally. Drugs given by parenteral
`routes are not subject to enzyme degradation
`in the gastrointestinal tract or to hepatic me-
`tabolism during their “first-pass” through the
`hepato-portal system. Nevertheless, with the
`possible exception of intravenous doses, drug
`absorption from parenteral administration is
`often incomplete, and bioavaliability consid-
`erations therefore are necessary.
`This review addresses the problem of the
`systemic availability of drugs which are ad-
`ministered by parenteral routes. The review is
`divided into two parts. The first considers drug
`pharmaeokinetics and bioavailability in gen-
`eral, and also drug bioavailability from in«
`traveno-us and intramuscular doses in partic-
`ular. The second part considers drug bio-
`availability from other parenteral dosage
`routes.
`
`Basic Phrzrmacokinetic Concepts Governing
`Drug Levels in Blood
`Drug Absorption
`In all except the intravascular routes of
`administration, the drug must be absorbed in
`order to enter the systemic circulation. A
`prerequisite of absorption is that the drug be
`released from the dosage form. Drug release
`depends on the physical and chemical prop-
`erties of the drug, the dosage form, and also
`the body environment at the site of sdminis—
`tration.
`
`When a drug solution is administered, or
`foilowing the dissolution of a solid dosage
`form, drug molecules diffuse into the circu-
`lation by crossing one or more biological
`membranes. Theories regarding the basic
`structure of biological membranes are con—
`stantly changing, and one of the most recent
`and generally acecptabie concepts which has
`been proposed by Singer and Nicolson (2) is
`shown in Figure 1. In this modei the basic
`
`-"'
`
`+
`
`—+"'
`..
`
`ill4*
`
`it
`it
`
`Figure l~wThe lipid-globular protein mosaic mozfet
`ofmembrane structure: schematic cross—sectiomz! view.
`The pizasphoiiprds are depicted as a discontinuous
`bilayer with their polar heads oriented outward. fie
`integral proteins are shown as globufar moiecuies
`partially embedded in andprotruafingfram the mem-—
`brane. Reproduced. by permissiomfrom Science 175,
`720-731 (1972).
`
`structure is a discontinuous bilayer of phos—
`pholipids, oriented so that their poiar heads are
`in contaet with the external aqueous environ-
`ment. Assoeiated with the lipid bilayer are
`globular proteins, which are embedded into
`and protrude from the bilayer, in some cases
`passing from one side of the bilayer to the
`other. The charged portion of the protein
`protrudes from the membrane surface while
`the uncharged portion is embedded within the
`Iipoidal portion of the membrane. Although
`there are other theories regarding membrane
`structure, the model proposed by Singer and
`Nicholson appears to be consistent with the
`relative membrane penetration characteristics
`of Iipophilie and hydrophilic molecules.
`The mechanisms of drug absorption include
`passive diffusion and specialized transport
`processes, the former being far more common.
`In the case of passive diffusion, the drug in
`aqueous solution at the absorption site dis-
`solves in the lipid material of the membrane,
`and passes through the membrane to reach an
`aqueous environment on the other side. Thus;
`effective absorption is favored when a drug
`molecule has both lipophilic and hydrophilie
`properties. Most drugs are organic weak
`electrolytes, whose ionized forms are soluble
`in water but almost insoluble in lipids, while .
`the unionized forms have the converse solu-
`
`bilities (3). Therefore, the plia of the drug and ..
`
` Astrazeneca EX. 2108 p. 2
`
`410
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`Journal of the Parenteral Drug Association
`
`

`
`
`
`{ABLE I.
`5
`
`pKa Values of Some Medicinal Acids and Bases Which May be Administered Par-
`enterally (4)
`
`Acid
`
`Ptcetazolarnide
`Carbenicillin
`Cefazolin
`Cephaloridine
`Cephalothin
`Diazoxide
`Fluorouraeil
`Fnrosemide
`Methioillin
`Moxalaetam
`Nafcillin
`Phenobarbital
`Phenytoin
`Snlfisoxazole
`Thiopental
`
`plia
`
`7.2
`2.6
`2. 1
`3.4
`3.6
`8.5
`8.0, 13.0
`3.9
`3.0
`2.5
`2.7
`7.4
`8.3
`5.0
`7.5
`
`Base
`
`Adriamycin
`Aminophylline
`Chlordiazepoxide
`Cimetidine
`Codeine
`Diazepam
`Dipyridamole
`Erythromycin
`Gentamicin
`Metoprolol
`Pentazocine
`Procainamide
`Propranolol
`Trifluoperazine
`Vinhlastine
`
`1:-Kn
`
`8.2
`5.0
`4.8
`6.8
`8.2
`3.4
`6.4
`8.8
`8.2
`9.7
`8.8
`9.2
`9.5
`8.1
`5.4, 7.4
`
`the pH at the absorption site will determine
`the extent of drug being unionized and ab-
`sorbable. The pKa values of some acidic and
`basic drugs, which may be administered par-
`enterally, are listed in Table I (4) while nom-
`inal pH values of some body fluids and sites
`are given in Table II. Acidic compounds are
`predominantly in the unionized form at pH
`values below their pKa while basic compounds
`are predominantly unionized at pH values
`above their pKa, so that comparison of the
`dsta in Tables I and II will give an indication
`of the fraction of drug which is in the union~
`
`TABLE II. Nominal pH Values of Some
`Body Tissues and Fluids (4)
`
`Site
`
`Blood, arterial
`Blood, venous
`Blood, maternal umbilical
`Cerebrospinal fluid
`Milk, breast
`Muscle, skeletal
`Prostatic fluid
`Saliva
`Sweat
`Urine
`
`pH
`
`7.4
`7.39
`7.25
`7.35
`7.0
`6.0
`6.5
`6.4
`5.4
`5.8
`
`lipophilie form at various sites. The
`ized,
`percentage of drug which is unionized, the ii»
`pophilieity of the unionized species, and also
`the adsorption of drug to the membrane sur-
`face, are principal factors governing drug-
`memhrane penetration.
`The rate of passive diffusion of drug
`through the lipid membrane depends on the
`concentration gradient across the membrane.
`Based on Fields first law, the flow across an
`area A per unit time is proportional to the
`concentration gradient, dC/dx, such that:
`
`Flow = -D-A- dC/dx
`
`(Eq. 1)
`
`where D is the diffusion coefficient, and the
`
`negative sign indicates that flow occurs down
`a negative concentration gradient.
`Equation 1 can be written as:
`
`Flow : 'D‘A‘ (Coutside ““‘ Cinside)/’ h
`(E61. 2)
`
`where the C symbols represent drug coI1een~
`trations on either side of the membrane and It
`is the membrane thickness. If one assumes that
`drug is carried away from the membrane by
`the surrounding fluids as soon as it has crossed,
`then Comgde >> Cinside and Eq. 2 can be written
`as:
`
`September-October, i980, Vol. 34. No. 5
`
`411
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`Astrazeneca Ex. 2108 p. 3
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`

`
`Flow = hkcoutsidve
`
`(Eq. 3)
`
`in which 1), A, and 11 have been combined into
`a new first-order permeation constant k. In
`general, absorption and membrane penetra-
`tion of drugs can be described by a simple
`first-order expression of the form of Eq. 3.
`
`Drug Distribution
`A drug entering the systemic circulation
`rapidly distributes throughout the blood or
`plasma. The drug leaves the circulation via the
`capillary walls, and passes into other body
`fluids and tissues, depending on its lipophill—
`city, the permeability of tissue membranes, the
`affinity of drug to particular tissues and fluids,
`and on the rate at which blood is supplied to
`the tissues.
`
`to which a drug distributes
`The extent
`throughout the body is often described (fre-
`quently incorrectly) in terms of its apparent
`volume of distribution, V, which may be ob-
`tained by expressions of the form:
`
`V _ Amount of drug in the body
`‘ Concentration of drug in plasma
`(Ea. 4)
`
`Another important property influencing the
`distribution characteristics of a drug is its
`binding to plasma proteins, primarily albumin.
`Plasma protein binding is reversible, and the
`percent of dose bound is dependent on the
`nature of the drug molecule, the capacity of
`the protein, and the concentration of total drug
`in plasma. The drug which is bound to plasma
`proteins at any time cannot cross the capillary
`walls, and is not free to distribute into body
`tissues. Therefore, for a drug which is exten-
`sively plasma protein bound, the plasma con-
`centration of total drug will be unduly high
`compared to free drug in extravascular fluids,
`resulting in underestimates of true distribution
`volumes.
`
`Although the percentage of circulating drug
`which is bound to proteins is influenced to
`some extent by drug concentration, the degree
`of binding by most drugs is constant over the
`normal therapeutic range.
`The binding of individual drugs to plasma
`
`412
`
`
`
`TABLE III. Plasma Protein Binding
`Some Antimicrobial Agents
`(5)
`
`l. Highiy bound (80-I00%)
`Dxacillin
`Erythrornycin
`Nafcillin
`Lincomycin
`Cefazolin
`Clindamycin
`Doxycycline
`Chlortetracycline
`
`2. Moderately bound (50~80%)
`Penicillin G
`Cefoxitin
`Carbenicillin
`Cephalothin
`Ticarcillin
`Minocycline
`Cefarnandole
`Chloramphenicol
`
`3. Weakly bound (<50%)
`Methicillin
`(lentamiein
`Cefuroxirne
`Arnikacin
`Cephaloridine
`Tetracycline
`Cefotaxime
`Streptomycin
`
`
`
`
`
`-'
`
`proteins is difficult to determine accurately,
`and reported values often vary from different
`laboratories. It is convenient therefore to dill
`ferentiate compounds into those which are
`highly bound (80—10()%), moderately bound
`(50-8095), and weakly bound (<50%). Some
`parenteral antimicrobial agents which fall into
`these categories are listed in Table Ill (5).
`As drug which is bound to plasma proteins
`is essentially restricted to the plasma volume,
`the degree of binding may influence drug
`availability to extravascular sites. For exam-
`ple, drug which is protein bound cannot cross
`the blood-brain barrier. However, the once
`popular notion that highly bound drugs cannot
`reach extravascular sites, has been shown to
`be incorrect for many compounds. For ex-
`ample,
`the cephalosporins cefazolin and
`cephalothin are 75—85% bound to plasma
`proteins, and yet have larger apparent distri-
`bution volumes than cephalexin and ce-
`phaloricline, which are only 20% bound to
`plasma proteins. This relationship is shown in
`Figure 2. Clearly, the binding of compounds
`to tissue proteins and other extravascular
`macromolecules also plays an important role
`in drug distribution.
`
`Two other compounds which are highly
`
`Journal of the Parenteral Drug Association
`
`Astrazeneca Ex. 2108 p. 4
`
`

`
`
`
`
`
` Apparentvolumeofdistribution
`
`‘°-)
`
`
`
`
`
`offreedrucll.peri.73m
`
`43) O
`
`O’: D
`
`-5O
`
`O 20 40 60 30 I00
`Percent bound to serum proteins
`
`is a function not only of the intrinsic abiiity of
`the eliminating organ to handle a particular
`drug but also of the drug distribution volume
`and binding characteristics.
`For drugs that are eliminated by glomcrular
`filtration, plasma protein binding delays their
`excretion, since only unbound drug is filtered.
`Similarly, hepatic metabolism is retarded
`because bound drugs generally do not have
`access to metabolic sites. On the other hand,
`plasma protein binding has no direct effect on
`kidney tubular secretion, because of the rapid
`dissociation of drug—prctcin complex during
`the drug secretion process.
`Within the usual range of therapeutic levels
`for many drugs, elimination is a first-order
`process, the rate being proportional to the
`concentration of drug in plasma, and governed
`by the elimination rate constant key. For drugs
`which are cleared wholly or partially by he-
`patic metabolism however, saturation of drug
`metabolizing enzymes may occur at high drug
`concentrations. Under such circumstances,
`metabolism is governed by Michaelis-Menten
`kinetics as:
`
`Rate of metabolism =
`
`Vmax’C
`
`Km + C
`
`where C is the concentration of drug at the
`metabolic site, I/gm is the maximum velocity
`at which a particular metabolic step can occur,
`and Km is the Michaelis~Menten constant.
`From this equation it is clear that, at low drug
`concentrations the rate of metabolism is ap-
`proximated by V,,mcC/Km or kc;-C‘, where ks;
`Vmax/Km, i.e., a pseudo iirsborder rate. At
`high drug concentrations however, the rate of
`metabolism is approximated by VWXC/C =
`I/max. This is the maximum velocity with
`which the metabolic step can occur, and the
`process becomes zero-order in nature. Two
`compounds that undergo this type of saturablc
`elimination in the therapeutic concentration
`range are phenytoin and salicylate.
`
`Effect offizarmacokinetic Behavior on
`Drug Biaavoilability
`The plasma profile of an administered drug
`
`Figure 2-The relationship between serum protein
`= binding and the distribution volume offree dmgfor
`our different cephalosporitu‘. CFZ m cephazolin, CLT
`cephalothim CLD = cephaloridine, and CXN == ce-
`hrrlexfn. Correlation coefficient —- -t-0.998. Repro-
`uced, by permission, from Clin. Pharmacokinet., 2,
`.- 252468 (I9??).
`
`
`
`
`
`' bound to plasma proteins, and yet distribute
`
`extensively into cxtravascular tissues and
`fluids, are crythromycin and trimcthoprim.
`5 While erythromycin is 90% bound, and tri-
`methoprini 60% bound to plasma proteins,
`5‘ more than 95% of the total body load of both
`of these compounds is distributed in extra-
`rascular tissues and fluids. Changes in drug
`binding, due to drug—drug interactions or
`discase conditions, may cause drug redistri~
`hution in the body. These types of changes,
`_ however, are of clinical significance only for
`drugs which are normally highly bound to
`plasma proteins.
`
`Drug Elimination
`Drugs are eliminated from the body pri-
`marily by hepatic metabolism and /or renal
`excretion. Other mechanisms, usually less
`important, include excretion via the bile, lungs,
`sweat, saliva, and breast milk. The elimination
`characteristics of each drug depend largely on
`its physico-chemical properties. In general,
`watensoluble drugs are readily cleared by the
`kidneys, while lipid—solohlc compounds are
`primarily metabolized in the liver.
`The rate at which drug elimination occurs
`
`v
`
`
`
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`Sept.:ml‘R:I'«Oct0ber. i980, Vol. 34, No. S
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`413
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`Astrazeneca Ex. 2108 p. 5
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`

`
`is affected by the rate and extent of absorption,
`the rate of elimination and also the drug dis-
`tribution volume. The types of effects that may
`occur are summarized in Figure 3. Decreasing
`the absorption rate will result in lower and
`more prolonged drug levels, with no change in
`the overall area under the drug-level curve.
`Similar variations in drug profiles may be
`obtained with variable absorption rates when
`drug appearance is zero-order in nature. As in
`the first-order case, slower zero-order, or
`constant rate, release of drug over a prolonged
`period will result in lower but more prolonged
`circulating drug levels. Decreasing the fraction
`F of drug which is available to the circulation
`however, results in lower drug levels and a
`reduced area under the drug-level curve, the
`reduction being directly proportional to the
`fraction of bioavailsble drug. A reduction in
`the elimination rate constant kc; will result in
`increased and more prolonged drug levels, and
`the degree by which levels are increased also
`becomes greater with repeated doses. A
`change in drug distribution may affect circu-
`lating drug levels, the concentration of drug
`in plasma being inversely related to distribu-
`tion volume. However, the clinical implica-
`tions of this type of change depend on whether
`the site of drug action is within the vascuiar
`compartment and those body Fluids in equi-
`librium with the vascular compartment, or in
`other tissues. The apparent distribution vol-
`ume of digoxinin roan is approximately 500
`liters, due to extensive tissue binding. In severe
`uremia however, the distribution volume de-
`creases to 200 liters. However, the action of
`digoxin on the myocardium appears to be as-
`sociated with tissue drug levels, so that a
`similar plasma digoxin level in a uremic indi-
`vidual to that in a person with normal renal
`function may be associated with a reduced
`relative therapeutic effect.
`Of the four parameters considered in Figure
`3, the two values commonly affected by drug
`bioavailability characteristics are the effi-
`ciency of absorption, F, and the rate constant
`for appearance of drug into the circulation ka.
`or kg when appearance is zero-order in na-
`ture.
`
`
`
`DRUGCONCENTRAYIONiNPLASMA
`
`"°""°°‘5"9 ha
`
`increasing kg]
`
`GGGVBWHQ F’
`
`increasing V
`
`TIME
`
`Figure 3—Effecr ofchanges in (a); the absorption rate
`constant kg, (25): the elimination rate constant lc,;(
`,
`the fraction of dose absorbed F, and (d); the drug
`distribution volume V on circulating drug profiles.
`
`Intravenous Administration
`Introducing the drug directly into the ve-
`nous circulation results in complete drug bio-
`availability, but the shape of the plasma drug
`profile is determined by the rate of injection.
`A bolus injection (Fig. 4) gives an almost in-
`stantaneous peak plasma level, and this dosage;
`route is useful when a prompt response is do» =
`
`LOGonus
`
`CONCENTRAWON
`
`DR36CONCENTRATSON
`
`t
`
`rm:
`
`Figure 4- The plasma concentration vs. time cwruefor
`a drug which is administered by bolus intravenous .
`injection, and is eliminated inflrsr-order manner. The I
`insert shows the same curve plotted on a remiloga
`rithmic scale.
`
`Journal of the Parenteral Drug Assuvmtion
`
`Astrazeneca EX. 2108 p. 6
`
`

`
`
`
`sired. A good example of this method of ad-
`, ministration is the use of intravenous lidocaine
`in the emergency treatment of ventricular
`arrhythmias, encountered during cardiac
`E surgery or resulting from myocardial infarc-
`tion.
`The duration of action of a drug in the body
`is affected by its half-life. The anesthetic effect
`'
`- of a single intravenous dose of thiopental {t 1 g
`= 49 min {6}} disappears within minutes. The
`anti-cancer agent 5-fluorouracil is another
`drug with an extremely short half-life [£1/2 =
`if} min (7)). On the other hand, drugs with
`long half-lives such as digoxin [t V; = 42 hr
`{8}} have a prolonged duration of action.
`While the duration of a drug in the body is
`not necessarily related to its hioavsilability, the
`drug hall‘-life does affect the area under the
`plasma concentration vs. time curve, AUC.
`which is a parameter commonly used as an
`index of drug bioavailability. The relationship
`between the AUC value and other phar-
`rnacokinetic parameters is shown in Eq. 6:
`
`AUG = (l.44)F—D- .t1;3[V (Eq. 6)
`
`where 11;; is the drug biological half~life and
`Vits distribution volume in the body. It is clear
`that, besides its dependence on F, D, and V,
`the AUC is also directly proportional to :1 ;2,
`so that any variations in this value must be
`taken into consideration when the AUC is used
`in bioavailahility assessment.
`The intravenous route should not be used to
`deliver drugs with low aqueous solubility,
`which may precipitate in blood and cause
`embolism. Another major disadvantage of the
`intravenous route is that once injected, the
`dose cannot be withdrawn. It is therefore in-
`jected slowly, over a period of l to 2 min, or
`longer, to avoid excessively high transient
`concentrations of drug in plasma, which may
`produce undesirable cardiovascular and cen-
`tral effects.
`Precise and continuous drug therapy is
`provided by intravenous infusion at a eonstsnt
`rate, which can be controlled by using an in-
`travenous drip or an infusion pump. Generally,
`Flow rates of 2 to 3 ml per minute are em-
`ployed. This method is particularly useful for
`
`drugs with a narrow therapeutic index, and
`when the effective blood levels are well de-
`fined, as in the case of arninophylline in
`treating asthma. Adequate bronchodilation
`with minimum adverse effects is usually
`achieved within an aminophylline plasma
`concentration range of 8 to 20 ng/ml (9).
`The circulating steady-state drug level CS,
`which is achieved during intravenous infusion
`is related to the infusion rate kg, the drug
`distribution volume V, and its biological
`half-life, as in Eq. 7:
`
`C533 (1.44) [(0-hf;/V (Eq.'?)
`
`The value of C5, increases in direct proportion
`to both the drug infusion rate and the drug
`half-life, but is inversely proportional to the
`distribution volume. Clearly, if the infusion
`rate or the drug biological ha1f—life is doubled,
`the latter being due perhaps to saturable me-
`tabolism or competition by some other drug
`for elimination mechanisms, then Cs, will also
`be increased to twice the original value.
`While the steady— state drug level achieved
`by an intravenous infusion is thus influenced
`by several factors, the time taken to reach the
`steady-state is controlled by only one factor,
`the drug half—life in the body. Regardless of
`the rate at which a drug is infused, it will take
`approximately 4.5 drug half-lives to approach
`steady—state levels. This may be particularly
`important
`for drugs with long biological
`half-lives. For example, comparing the drugs
`already mentioned in the intravenous injection
`case, steady«state levels of 5-fluorouracil will
`be achieved within one hour of the start of
`infusion, while it will take up to 8 days to
`achieve steady-state circulating levels of di-
`goxin.
`The above concepts apply also to drugs
`which are given intermittently, for example by
`repeated intravenous or intramuscular injec-
`tion. Regardless of the way in which a drug is
`administered, it will take four to five drug bi-
`ological halillives to reach steady-state levels
`in the bloodstream.
`For many drugs which have long biological
`half-lives, loading doses have to be adminis-
`tered at the start of therapy in order to avoid
`
`
`
`Septemhenflctoher, 1980, Vol, 34, No. 5
`
`415
`
`Astrazeneca Ex. 2108 p. 7
`
`

`
`
`
`DRUGCONCENTRATFON
`
`TIME
`?
`Figure 5~Plasmn concentration or. time curves for
`drugs with (:2); a short biological half-lzgfe, and (I: ): a
`long biological half—life during continuous intravenous
`infusion. The infusion rates are adjusted according to
`Eq. 7 to obtain the some (35, values.
`
`the delay in achieving the desired drug levels
`in the body. Typical plasma profiles during
`intravenous infusion of drugs which have short
`and long biological haltllives are shown in
`Figure 5.
`
`Intramuscular Administration
`
`Intramuscular injection usually, but not
`always, provides quantitative drug delivery to
`the body with less hazard than the intravenous
`route. Drug effects are less rapid, but generally
`of longer duration. The intramuscular route
`
`
`
`SfiflflP!fl4%l8Bl'VAvL.DlDOVl'l“l
`
`mt mm
`
`Figure 6-Mean serum levels ofphenebarbital during
`21 days following single oral doses ofphenobarbital
`(30 mg) and single intramuscular injections ofsodium
`phenobarbital (equivalent to 27.4 mg phenobarbital).
`Bars indicate one standard error (n = 5). Reproduced,
`by permission,from J. Clin. Pharmacol, 18, wow I05
`(1928).
`
`Figure ?—lnjecn‘on sire in gluteus muscle. ?“}ii.rjlgure,
`and also Figures 8, 9, and I 0. are reproduced by pen
`mission from R. I). Muster and J. J. O'Neill, Phar-
`macology and Therapeutics. 4th at, Macmillan. New
`York, NY, 1971.
`
`is often used to administer drugs that are
`poorly absorbed from the gastrointestinal
`tract. For example, piperacillin, a new semi-
`synthetie aminobenzyl penicillin derivative
`which is poorly absorbed orally‘ is rapidly and
`reliably absorbed after intramuscular ad»
`ministration (10).
`However, drugs are not always completely
`available following intramuscular injection.
`Slow or incomplete absorption from lntra~
`muscular sites has been reported for clilordi-
`azepoxide, diazepam, digoxin, phenytoin, and
`phenobarbital, and the extent of absorption
`may also be influenced by the patient’s age.
`Although phenobarbital appears to be com
`pletely bioavailable following intramuscular
`injection to children, it is only 80% available
`compared to oral doses in adults (I 1). Serum
`levels of phenobarbital obtained during 21
`days following oral and intramuscular doses
`are shown in Figure 6. Note the very long du~
`ration of this drug in serum from both dosage
`routes. The biological half-life of phenobar-
`bital from these data was approximately 90
`hours.
`
`Intramuscular injections are made deep into
`the skeletal muscles, preferably far away from
`major nerves and blood vessels. In adults, the
`upper portion of the gluteus rnaxirnus is a
`frequently used site for this purpose. In infants
`and young children, the deltoid muscles of the
`upper arm or the midlateral muscles of the
`thigh are usually preferred. The usual sites for
`
`Journal of the Parenteral Drug Association
`
`Astrazeneca EX. 2108 p. 8
`
`

`
`Gluwun Nuxlmu
`Gr-at-r mum.
`at you can
`(Nu iltmmr-eh
`Scion: mm
`
`
`
`Figtire 7 vlnjeclioli site in gluteux mtlscle. This figure,
`and also Figures R, 9, and /0, are reproduced by per-
`misrion from R. I).
`/Muss:-r and J. J. 0‘Neill, Phar-
`macology and Therapeutics, 41/: ml. Macmillan. New
`York. NY, l‘)7l.
`
`is often used to administer drugs that are
`poorly absorbed from the gastrointestinal
`tract. For example. piperacillin. a new semi-
`synthetic aminobenzyl penicillin derivative
`which is poorly absorbed orally, is rapidly and
`reliably absorbed after intramuscular ad-
`ministration (10).
`
`However, drugs are not always completely
`available following intramuscular injection.
`Slow or incomplete absorption from intra-
`muscular sites has been reported for chlordi-
`azepoxide, diazepam, digoxin. phenytoin, and
`phenobarbital. and the extent of absorption
`may also be influenced by the patients age.
`Although phenobarbital appears to be com-
`pletely bioavailable following intramuscular
`injection to children, it is only 80% available
`compared to oral doses in adults (I 1). Serum
`levels of phenobarbital obtained during 21
`days following oral and intramuscular doses
`are shown in Figure 6. Note the very long du-
`ration of this drug in serum from both dosage
`routes. The biological half-life of phenobar-
`bital from these data was approximately 90
`hours.
`
`Intramuscular injections are made deep into
`the skeletal muscles, preferably far away from
`major nerves and blood vessels. In adults, the
`upper portion of the gluteus maximus is a
`frequently used site for this purpose, In infants
`and young children. the deltoid muscles of the
`upper arm or the midlateral muscles of the
`thigh are usually preferred. The usual sites for
`
`416
`
`Journal of the Parenteral Drug Association
`
`Astrazeneca Ex. 2108 p. 9 _
`
`
`
`DRUGCONCENTRATION
`
`TIME
`T
`Figure 5»Plasma concentration vs. time curves for
`drugs with (a),'a.thort biological halj-life, and (h);a
`long biological half-life during continuous intrarenous
`infusion. The infusion rates are adjusted according to
`Eq. 7 to obtain the same C” valuar.
`
`the delay in achieving the desired drug levels
`in the body. Typical plasma profiles during
`intravenous infusion ofdrugs which have short
`and long biological half-lives are shown in
`Figure 5.
`
`Intramuscular Administration
`
`Intramuscular injection usually. but not
`always, provides quantitative drug delivery to
`the body with less hazard than the intravenous
`route. Drug effects are less rapid, but generally
`of longer duration. The intramuscular route
`
`l
`>7 6
`“A
`in
`
`J
`
`Oval 4....
`In-in-uh any
`
`1-
`
`l
`
`*
`
`. l
`
`1'
`..3:
`t
`filb §\ lm;
`.
`T
`p
`
`A‘
`t
`
`t
`
`o
`
`3
`7.
`E"
`5
`
`3
`5
`
`02
`
`b
`
`As
`
`5'
`
`5
`VII‘ tum
`
`IE
`
`is
`
`I!
`
`Figure 6—Mean serum levels ofplzenobarbital (luring
`21 days following single oral doses of phenobarbital
`(30 mg) and single inIramu.vt'u/ar injections 0/sodium
`phenobarbital (equivalent to 27.4 mg phenobarbital).
`Bars indicate one standard error (n = 5). Reproclured,
`by permissiomfrom J. Clin. Pharrnaeol.. I8, I00—I05
`(I 978).
`
`

`
`Arnvl-xv wpcvloc
`like spin:
`{M lnlocfion an
`Gama! tmchamov
`
`-Figure 8-Amerior gluteol injection. The injection site
`is located by placing cmefinger on the {line spine and
`size thumb or anotherjingerjust below the (line crest
`with zlzepalm ofthe hand on (he hip. There is con.ra‘a'~
`erable muscle mass. and no [arge lziood t~e.v.\'ls or nerves,
`in this area.
`
`intramuscular injection are shown diagra-
`matically in Figures 7~lO.
`Aqueous or oleaginous solutions or sus-
`pensions of drugs may be administered intra~
`muscularly. The absorption rates vary widely
`depending on the type of preparation used, as
`well as on other biopharmaoeutical factors.
`These have been discussed in some detail in a
`review article by Ballard (12).
`Some compounds,
`i.e., penicillins and
`oepltalosporins, may oause considerable pain
`when injected intramuscularly and are often
`given intravenously whenever possible.
`Cephalothin is particularly painful when given
`intramuscularly and this drug is routinely
`given by the intravenous route.
`The primary factors which influence the
`
`Figure Qmlnjection site in midanterior region of the
`thigh.
`
`September-October. 1980. Vol. 34, No. 5
`
`Figure I 0x Injection site in the deltoid muscle below
`the acromion process.
`
`rate and extent of intramuscular drug ab-
`sorption are summarized in the following
`sections.
`
`Solubility offlrug
`When solutions of sparingly soluble acids
`and bases are injected into the muscle, they are
`gradually buffered to physiological pH. This
`pl-I shift may cause the drug to precipitate at
`the injection site, often resulting in prolonged
`absorption as the precipitated drug slowly
`redissolves in the tissue fluids. An example is
`the precipitation of quinidine base after an
`intramuscular injection of quinidine hydro—
`chloride solution. Precipitation of drug at the
`injection site, and slow resolubilization to yield
`low and possibly undetectable drug levels in
`the bloodstream, may also explain the rapper»
`ently incomplete hioavailability of intramus-
`cular phenoharbital and other compounds
`discussed earlier. Clearly, the injection of
`larger aqueous fluid volumes will minimize
`drug precipitation at the injection site but
`there are practical limits to the actual volume
`injected, particularly in children.
`
`Solvent Efiect
`Drugs which are poorly wator—soluble, e.g.,
`cliazepam, can be dissolved in non-aqueous
`
`Astrazeneca Ex. 2108 pt. 10
`
`

`
`lilo: crud
`
`Amcvlor uupuvlnr
`illuc Ipim
`
`|M lnincliou xlu
`
`Gm-mu nochanm
`
`
`
`Injection silo
`
`(Dchold much)
`
`Radial nnrvc
`
`'l"I1eiI1jm‘Ir'uIr.riI('
`Figure R».-trirvriur glule-al irije('IioIi.
`is lm"(ll('tll>)']7/£1('iNg' miefinger on the iliac .\'plnc and
`the Ilmmli ur auuIher_/izzgerjust buluw I/re iliuc (rm!
`with the palm ufllw hum! till the /rip