`DRUG DISPOSITION
`0"“PhO'mO8§I@T:$.B%’;t35‘3;%‘sIiisééiéié
`© Adis International Limited. All rights reserved.
`
`Pharmacokinetics of Alendronate
`
`Arturo G. Porms, Sherry D. Holland and Barry ]. Gertz
`
`Merck Research Laboratories, Clinical Pharmacology and Drug Metabolism, Rahway,
`New Jersey and West Point, Pennsylvania, USA
`
`Contents
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`Abstract
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`I. Mechanism of Action .
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`2. Preclinical Pharmacokinetics .
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`2.1 Metabolism .
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`2.2 Absorption .
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`2.3 Distribution .
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`2.4 Elimination .
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`3. Clinical Pharmacokinetics
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`3.1 Disposition of Intravenous Alendronate .
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`3.2 Reproducibility of Intravenous Pharmacokinetics
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`3.3 Oral Dose Proportionality and Bioavailability .
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`3.4 Influence of Food, Beverages and Calcium on Absorption .
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`3.5 Influence of Gastric pH on Absorption .
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`3.6 Potential for Drug Interactions
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`4. Pharmacokinetic—Pharmacodynamic Relationships with Alendronate .
`5. Conclusion .
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`AbSl'I'GCl'
`
`Alendronate (alendronic acid; 4-amino-1-hydroxybutylidene bisphosphonate)
`has demonstrated effectiveness orally in the treatment and prevention of post-
`menopausal osteoporosis, corticosteroid-induced osteoporosis and Paget’s dis-
`ease of the bone. Its primary mechanism of action involves the inhibition of
`osteoclastic bone resorption. The pharmacokinetics and pharmacodynamics of
`alendronate must be interpreted in the context of its unique properties, which
`include targeting to the skeleton and incorporation into the skeletal matrix.
`Preclinically, alendronate is not metabolised in animals and is cleared from
`the plasma by uptake into bone and elimination Via renal excretion. Although
`soon after administration the drug distributes widely in the body, this transient
`state is rapidly followed by a nonsaturable redistribution to skeletal tissues. Oral
`bioavailability is about 0.9 to 1.8%, and food markedly inhibits oral absorption.
`Removal of the drug from bone reflects the underlying rate of turnover of the
`skeleton. Renal clearance appears to involve both glomerular filtration and a
`specialised secretory pathway.
`Clinically, the pharmacokinetics of alendronate have been characterised al-
`most exclusively based on urinary excretion data because of the extremely low
`concentrations achieved after oral administration. After intravenous administra-
`
`tion of radiolabelled alendronate to women, no metabolites of the drug were
`detectable and urinary excretion was the sole means of elimination. About 40 to
`
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`

`Porms et al.
`316
`
`
`60% ofthe dose is retained for a long time in the body, presumably in the skeleton,
`with no evidence of saturation or influence of one intravenous dose on the phar-
`macokinetics of subsequent doses.
`The oral bioavailability of alendronate in the fasted state is about 0.7%, With
`no significant difference between men and women. Absorption and disposition
`appear independent of dose. Food substantially reduces the bioavailability of oral
`alendronate; otherwise, no substantive drug interactions have been identified.
`The pharmacokinetic properties of alendronate are evident pharmacodynam-
`ically. Alendronate treatment results in an early and dose-dependent inhibition of
`skeletal resorption, which can be followed clinically with biochemical markers,
`and which ultimately reaches a plateau and is slowly reversible upon discontin-
`uation of the drug. These findings reflect the uptake of the drug into bone, where
`it exerts its pharmacological activity, and a time course that results from the long
`residence time in the skeleton. The net result is that alendronate corrects the
`
`underlying imbalance in skeletal turnover characteristic of several disease states.
`In women With postmenopausal osteoporosis, for example, alendronate treatment
`results in increases in bone mass and a reduction in fracture incidence, includ-
`ing at the hip.
`
`Alendronate (alendronic acid) is one of a growing
`class of bisphosphonate compounds in clinical use
`or under investigation.[1>2] Bisphosphonates are non-
`hydrolysable analogues of inorganic pyrophosphate
`in which the bridging oxygen has been replaced by
`a carbon, with, most commonly, an aliphatic side
`chain. They were developed after the discovery
`that pyrophosphate inhibits both the formation and
`dissolution of calcium phosphate crystals.[3] These
`properties suggested a potential utility as an inhib-
`itor of bone resorption or ectopic calcification. How-
`ever, the nearly ubiquitous presence of inorganic
`pyrophosphatase prevents the direct use of the in-
`organic compound as a modifier of bone metabo-
`lism. In contrast, the bisphosphonates have demon-
`strated biochemical stability and pharmacological
`activity as inhibitors of bone resorption and, thus,
`have an expanding role in the clinical management
`of patients with bone disease.
`Intravenous alendronate has been used investi-
`
`gationally for the management of hypercalcaemia of
`malignancy. [4'6] Alendronate is approved as an oral
`medication for both the treatment and prevention
`of postmenopausal osteoporosis,[7'13] corticosteroid-
`induced osteoporosism] and the treatment of Paget’s
`disease.[15'18] Alendronate is approved for use orally
`in over 80 countries worldwide.
`
`Alendronate is mono sodium 4-amino- 1 -hydroxy-
`butylidene bisphosphonate (fig. 1). The amino
`group in the side chain appears to yield much
`higher potency and far greater selectivity for inhib-
`iting bone resorption, over reducing mineralisation,
`than is observed with etidronate, one of the first
`
`bisphosphonates used clinically and one which
`
`does not contain nitrogen.[19l
`This review provides some background on the
`biochemical mechanism of action of bisphosphon-
`ates, focusing on studies with alendronate, as it is
`relevant to a complete understanding of the pharma-
`cokinetics and pharmacodynamics of alendronate
`and their relationship to each other. Furthermore,
`because some of the properties of alendronate are
`characteristic of the bisphosphonate class, notably
`its limited oral bioavailability and prolonged resi-
`dence in the target organ of interest (i.e. the skele-
`ton), a brief summary of the preclinical pharmaco-
`kinetics of alendronate is provided as several
`important pharmacokinetic questions with alendron-
`ate can only be addressed within animals. Finally,
`the pharmacokinetic-pharmacodynamic relation-
`ship Will be reviewed as it relates mo st importantly
`to the beneficial effects of alendronate for the treat-
`
`ment of postmenopausal osteoporosis.
`
`© Adis International Limited. All rights reserved.
`
`Clin Phormocokinet 1999 May; 36 (5)
`
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`
`
`Alendronate 317
`
`
`
`Fig. 1. Structure of alendronate (alendronic acid; monosodium
`4—amino—1—hydroxybutylidene bisphosphonate).
`
`l. Mechanism of Action
`
`Although all the details of the pharmacological
`action of bisphosphonates have not been clearly
`defined, the datapermit a general description ofthe
`mechanism of action of alendronate.
`
`Alendronate is rapidly cleared from plasma, either
`eliminated in the urine or taken up by the skele-
`ton.[2°] However,
`this uptake is not uniform
`throughout bone; rather, it is focused in areas of
`high physiological activity, where bone turnover is
`greatest.[21] Specifically, alendronate concentrates
`in a relatively selective manner at sites of bone
`resorptionlzhzzl
`Following binding to the hydroxyapatite of
`bone exposed at sites of bone resorption, alendron-
`ate can be mobilised by osteoclasts as these cells
`generate acidic conditions and dissolve the inor-
`ganic phase, thereby solubilising the bound alend-
`ronate.[23] Alendronate is then taken up by the
`osteoclasts and, through biochemical effects, rend-
`ers the osteoclast inactive for bone resorption.[21]
`This is observable on electron microscopy as a loss
`of the ‘ruffled border’ of the osteoclast, a sign that
`they are no longer active.
`Two recently described biochemical effects in-
`clude an inhibition of protein tyrosine phospha-
`tase[24'26] and inhibition of protein prenylation.[27>28]
`This latter mechanism appears to result from the
`inhibition in osteoclasts of enzyme(s) involved in
`cholesterol biosynthesis by nitrogen—containing
`bisphosphonates.[27>28] Although numerous other
`biochemical effects have been described which
`
`may lead to the inhibition of osteoclast resorptive
`capabilities and its structln'al changes, inhibition of
`prenylation is most likely the one responsible for
`
`yielding a quiescent cell.[2>19] Not only is osteoclast
`activity reduced, but the number of osteoclasts is
`also significantly reduced after long te1m adminis-
`tration of alendronate. Whether this is secondary
`to the reduction in bone resorption and the dynam-
`ics of bone turnover, or a separate effect to reduce
`osteoclast recruitment and/or differentiation, or in-
`duce osteoclast apoptosis,[29] or all of the above, is
`not certain. Furthermore, some investigators have
`proposed that bisphosphonates, such as alendron-
`ate, must interact with the bone forming cells, the
`osteoblasts, in order to exert their inhibit01y influ-
`ence on the osteoclasts.[30]
`
`The alendronate deposited at sites of bone turn-
`over, if not taken up by the osteoclasts, is ultimately
`incorporated within the matrix as newly formed
`bone encases it.[19’21] This is similar to the tetracy-
`clines, which are deposited in bone along the
`mineralisation front, a characteristic exploited by
`investigators who study its fluorescence in bone as
`amarker ofbone formation. The alendronate incor-
`
`porated in the mineralised bone matrix is no longer
`pharrnacologically active until the time when bone
`resorption removes the overlaying layers of bone,
`bringing the alendronate back to the surface and
`allowing it to interact with osteoclasts again.
`Most importantly, these data indicate that the
`primary effect of alendronate on the skeleton is to
`inhibit bone resorption. Other manifestations of its
`skeletal influence after long term administration,
`such as reduced bone formation and turnover, de-
`rive from this primary pharmacological activity.
`
`2. Preclinical Pharmacokinetics
`
`2.1 Metabolism
`
`As with most other bisphosphonates, alendron-
`ate appears not to be metabolised in mammals.[31]
`Following administration of a dose of radiolabelled
`alendronate, Lin et al.[20] demonstrated, by high
`performance liquid chromatography (HPLC), that
`unmodified alendronate accounts for all the radio-
`
`activity recovered in urine of rats, dogs and mon-
`keys, as well as that deposited in the skeletons of
`
`© Adis International Limited. All rights reserved.
`
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`
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`
`

`

`318
`Forms 81‘ al.
`
`rats and dogs, indicating that metabolism of alen-
`dronate in vivo is absent or at most negligible.
`It has recently been reported that other bisphos-
`phonates, for example clodronate, may be metabo-
`lised by mammalian cells in vitro to yield an ana-
`lo gue of adenosine triphosphate; this could play a
`role in the mechanism of action of that drug.[32] In
`contrast, such metabolism was not demonstrable
`with alendronateml
`
`Because of its high potency, the relatively low
`oral dosages used clinically produce plasma con—
`centrations of alendronate which fall below the
`
`limit of reliable quantification of the assay. The
`absence of discernible metabolism thus proved es-
`sential to examination of the pharmacokinetics of
`this compound, given that plasma pharmacokinet—
`ics after oral administration could not be quanti-
`fied. Drug uptake was, therefore, characterised by
`following deposition in bone of radiolabelled ding.
`For example, bioavailability was examined by de-
`telmining the ratio of 14C and 3H in bone following
`administration of a 14C-labelled oral dose and a
`3H-labelled intravenous dose.[20]
`
`2.2 Absorption
`
`As with other bisphosphonates, the oral absorp-
`tion of alendronate in animals is limited under fast-
`
`ing conditions and negligible in the presence of
`food. The fasting oral bioavailability of alendron-
`ate was estimated as 0.9% in rat, 1.8% in dog and
`1.7% in monkey.[20] Oral administration to rats in
`the presence of food decreases bioavailability
`about 6- to 7-fold.[30] Since alendronate is highly
`polar and charged at physiological pH, absorption
`across the gastrointestinal tract has been proposed
`to occur primarily by the paracellular, rather than
`transcellular, route.[33] Alendronate is better ab-
`sorbed from segments of the gastrointestinal tract
`with larger surface areas, that is the j ejunum > duo-
`denum > ileum.[33]
`
`2.3 Distribution
`
`Over the concentration range of 0.1 to 0.5
`mg/ml, alendronate is approximately 80, 73 and
`70% protein bound in rats, dogs and monkeys, re-
`sp ectively. Albumin is the predominant protein that
`binds alendronate, with pH and calcium concentra-
`
`. Concentration in bone
`0 Dose remaining in soft tissue
`
`9 -O
`
`.
`Q
`I
`
`T
`' 60
`
`3
`3
`a:
`
`E
`
`E
`E
`E
`8
`c
`8
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`- 10
`
`I
`4
`
`CIJ
`6
`
`I
`24
`
`I
`48
`
`0
`
`72
`
`Fig. 2. Distribution of alendronate to soft tissues and bone in rats (n = 3 to 4) following administration of a single intravenous dose
`of 1 mg/kglzol
`
`Time (h)
`
`© Adis International Limited. All rights reserved.
`
`Clin Phormocokinet 1999 May; 36 (5)
`
`AstraZeneca Exhibit 2105 p. 4
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`
`
`
`
`- 50
`
`E’
`a
`_ 40 S
`
`3.
`
`E$
`
`3
`
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`3:
`2.
`— 20 3
`
`

`

`319
`Alendronate
`
`
`tion modulating the extent of alendronate bind-
`ing.[31,34]
`An intravenous dose of alendronate 1 mg/kg in
`rats is quickly and widely distributed throughout
`the body followed by redistribution to its ultimate
`site of sequestration (bone) or elimination. About
`63% of the dose is present in noncalcifled tissues
`at 5 minutes post-dose. This is reduced to about 5%
`by 1 hour and about 1% at 6 to 24 hours post-dose.
`Areciprocal pattern is evident in bone, where about
`30% of the dose can be found 5 minutes after ad-
`
`ministration, reaching some 60 to 70% of dose by
`1 hour, and remaining constant for the next 71
`hours (fig. 2).[20]
`Distribution of alendronate within bone is de-
`
`termined by blood flow and favours deposition at
`sites of the skeleton undergoing active resorption.
`Thus a larger proportion of the dose is taken up by
`trabecular as compared with cortical bone, and in
`the latter at the metaphysis compared with the dia-
`physis.[20] The uptake of alendronate in the skele-
`ton was linear (proportional to dose) in rats which
`received radiolabelled alendronate (0.2,
`1 or 5
`mg/kg intravenously or 1, 5 or 25 mg/kg orally).[20]
`When multiple intravenous doses (totalling 35
`mg/kg) were given to rats every 3 days for 21 days,
`the bone deposition of the first (3H-labelled) and
`last (MC-labelled) doses was similar. Thus, the up-
`take of drug in bone was not saturated with re-
`peated doses, nor did prior administration of al-
`endronate affect the distribution of subsequent
`doses, at least up to the extent of drug delivered in
`this experiment.[35]
`
`2.4 Elimination
`
`Alendronate is cleared from plasma by deposi-
`tion in bone and urinary excretion. Only a negli-
`gible amount of the drug (<0.2%) is detected in
`faeces after intravenous administration, suggesting
`little, if any, is excreted in bile. About 30 to 40%
`of a 1 mg/kg dose in rats is eliminated in the urine
`by 24 hours post-dose.[20] About 60 to 70% of an
`alendronate dose is sequestered in bone over the
`short term. The drug is then slowly released from
`the skeletal deposits, accounting for the prolonged
`
`multiple-phase elimination of this drug.[20] The ter-
`minal half-life (tI/zy) of alendronate is related to the
`rate of bone turnover in each of the species studied;
`thus a half-life of approximately 300 days in rats
`and at least 1000 days in dogs has been esti-
`mated.[20]
`The observation that the renal clearance of alen-
`
`dronate in the rat exceeded that expected from the
`glomerular filtration rate and unbound concentra-
`tion of the drug suggested that a secretory mecha-
`nism was involved in renal elimination. Renal ex-
`
`cretion of alendronate appears to utilise an active
`secretory system with a maximum rate of about 25
`mg/min/kg in the rat.[36] High concentrations of
`classical inhibitors of the secretion of acidic (pro-
`benecid, p-aminohippuric acid) and basic (quinine
`and cimetidine) compounds do not influence uri-
`nary excretion of alendronate in the rat.[36] How-
`ever, etidronate, a structurally related member of
`the bisphosphonate class, did reduce the renal
`clearance of alendronate in a dose-dependent man-
`ner, as did high concentrations of inorganic phos-
`phate.[36] Dose-dependent decreases in renal func-
`tion induced in rats by administration of increasing
`doses of uranyl nitrate produced graded reductions
`in renal clearance of alendronate with increases in
`
`bone deposition.[36]
`In summary, the preclinical pharmacokinetics
`of alendronate are similar to those of other bisphos-
`phonates and permit construction of the model de-
`picted in figure 3. Many of the experiments sup-
`porting the model cannot be performed in humans.
`However, as the data will show, the available in-
`formation strongly indicate that this model also
`applies to the pharmacokinetics of alendronate in
`humans.
`
`3. Clinical Pharmacokineiics
`
`The pharmacokinetics of bisphosphonates in
`humans have been characterised to a limited extent.
`
`These compounds are difficult to measure in bio-
`logical fluids and their disposition characteristics
`make it difficult to examine their pharmacokinetic
`behaviour in plasma. Concentrations in plasma
`following therapeutic doses generally fall below
`
`© Adis Inlernolionol Limiled. All rights reserved.
`
`Clin Phormocokinel l999 May; 36 (5)
`
`AstraZeneca Exhibit 2105 p. 5
`
`

`

`320
`Forms 81‘ al.
`
`
`
`Non-calcified
`tissues
`
`
`
`
`
`Furthermore, alendronate was found to be elimi-
`nated exclusively through urinary excretion. These
`findings allowed for the use of urinary excretion
`alone to monitor the disposition of doses of alen-
`dronate delivered systemically.
`The pharmacokinetics of intravenous alendron-
`ate have been examined for doses ranging from
`20ug to 10mg.[39>40] Independent of dose, a sub-
`stantial fraction of the administered drug was
`found to be promptly excreted in urine (approxi-
`mately 45% of an intravenous dose in the first 8
`hours), with subsequent excretion proceeding much
`more slowly (approximately 5% of the dose be-
`tween 8 and 72 hours) as can be seen in figure 4.
`By 72 hours post-dose, 40 to 60% of administered
`drug has been recovered in urine, leaving the re-
`mainder still resident in the body. By this time,
`however, urinary excretion has fallen to exceedingly
`low concentrations, indicating that the remaining
`alendronate has been tightly sequestered in a com-
`partment from which it is released very slowly.
`By analogy with the results in animals, alendron-
`ate is probably bound to the mineral phase of the
`skeleton, from which it is released at a rate that is
`proportional to the rate of bone turnover. This hypo-
`thesis was examined in 11 patients who were ad-
`ministered 7.5mg intravenous doses of alendronate
`once daily over 4 days (totalling 30mg) and closely
`followed for 18 months to provide an estimate of
`the tI/Zy.[40] Approximately 48% of the total intrave-
`nous dose was initially retained. Elimination was
`then multi-phasic, with approximately one-third of
`the alendronate initially retained excreted over the
`first 6 months. Subsequent slow excretion yielded
`
`an estimate of tl/2y with a mean value of 10.5 years
`(95% confidence interval : 7.9, 13.2 years). It is
`not possible from these data to rule out even slower
`phases of elimination. Even so, an estimate of this
`
`magnitude is consistent with the very long tl/fl ob-
`served preclinically (approximately 300 days in
`rats and >1000 days in dogs) and, therefore, in
`agreement with the hypothesis derived from pre-
`clinical work that alendronate is sequestered in the
`skeleton.
`
`
`
`—> RemOdelling
`
`Inactive
`bone
`
`Fig. 3. Pharmacokinetic model for alendronate based on pre—
`clinical data and assumed to apply to humans. Access to the
`systemic circulation is followed by rapidly reversible distribution
`to noncalcified tissues and the primary competing processes of
`sequestration into the skeleton, from which a slow release can
`occur, and elimination of drug by the kidney. The skeleton is
`depicted as 2 pools of drug, the first of which may be mobilised
`during the process of bone turnover and the second repre—
`senting drug incorporated in the matrix of bone which is rela—
`tively quiescent and not actively turning over.
`
`the limits of sensitivity of the assay. Consequently,
`most of the clinical Pharmacokinetic information
`on bisphosphonates has been derived from urinary
`excretion data. Alendronate is no exception. A sen-
`sitive method has been developed for the quantifi—
`cation of alendronate through fluorescence detec-
`tion (limit of quantification 1 ug/L in urine, 5 ug/L
`in plasma).[37] However, concentrations in plasma
`following oral administration do not rise suffi-
`ciently even after 3 years of daily administration to
`allow examination of plasma kinetics with thera-
`peutically relevant doses (10mg daily).[38] There-
`fore, the pharmacokinetic characteristics of alen—
`dronate in humans have been derived mostly from
`urinary excretion data.
`
`3.1 Disposition of Intravenous Alendronate
`
`The disposition of radiolabelled alendronate
`was studied in 12 patients with bone disease sec-
`ondary to metastatic breast cancer who were given
`single intravenous doses of 10mg of [14C]alendron-
`ate (approximately 26 uCi).[39] Extensive examina-
`tion of plasma, faeces and urine samples collected
`from these patients failed to reveal evidence of
`metabolism, leading to the conclusion that the met-
`abolism of alendronate is negligible or nonexistent.
`
`© Adis International Limited. All rights reserved.
`
`Clin Pharmacokinet 1999 May; 36 (5)
`
`AstraZeneca Exhibit 2105 p. 6
`
`

`

`321
`Alendronate
`
`
`A 10mg intravenous dose is large enough to al-
`low for the analytical detection of alendronate in
`plasma for about 15 hours from the initiation of
`infusion (fig. 5).[39] Given the very long elimina-
`
`tion tl/27 of alendronate, it is clear that figure 5 does
`not depict the complete profile of alendronate in
`plasma, rather a substantial fraction of this profile
`falls below the assay’s limit of reliable quantifica-
`tion. Under these circumstances, exact estimates
`
`of pharmacokinetic parameters are only possible
`for renal clearance, which was found to average
`4.26 L/h. Additionally, systemic clearance was es-
`timated to be no more than 11.94 L/h and the
`
`steady-state volume of distribution (VSS) was esti-
`mated at more than 28L.[39] Given that renal clear-
`
`ance appears to be the sole means of elimination
`
`[therefore giving that plasma clearance (CLp) =
`renal clearance (CLR)], it appears that some two-
`thirds of the area under the concentration-time
`
`curve (AUC) is not detectable because of limits on
`assay sensitivity. Additionally, the calculated or
`apparent VSS would appear to be quite large given
`that alendronate binds to bone with no hint of sat-
`uration.
`
`3.2 Reproducibility of Intravenous
`Pharmacokinetics
`
`As a substantial fraction of a dose is retained
`
`long after administration, the effect ofprevious ex-
`posure to alendronate on the short term (less than
`72 hotu‘s) elimination of intravenous doses was ex-
`amined in 10 healthy postmenopausal women.[39]
`This group were administered a total of 7 intra-
`venous doses of alendronate 125ug over the course
`of 18 days. Urinary excretion following the last
`dose was found to be comparable with that from
`the first dose, demonstrating that previously ad-
`ministered alendronate has no significant impact
`on the disposition of subsequent doses.
`
`3.3 Oral Dose Proportionality and
`Bioavailability
`
`Bioavailability of alendronate was evaluated in
`3 studies in postmenopausal women and in 1 study
`in men.[41] Oral doses ranged from 5 to 80mg and
`intravenous reference doses were 125 or 250ug.
`Comparison of the dose-adjusted urinary excretion
`profiles of alendronate following various oral
`doses showed no effect of dose on the extent of
`
`1.00 -
`
`0.80
`0.20
`
`0.15—
`
`0.10-
`
`
`
`Excretionrate(mg/h)
`
`0.05 —
`
`. 0
`
`I
`
`I
`12
`
`r
`24
`
`
`1'.1r
`36
`48
`60
`72
`Time (h)
`
`0.00
`
`infused intravenoust over 2 hours, to
`Fig. 4. Urinary excretion of alendronate following administration of a 10mg dose,
`postmenopausal women (n = 6) with metastatic breast cancer (adapted from Coquyt et a|.[39] ).
`
`© Adis International Limited. All rights reserved.
`
`Clin Pharmacokinet 1999 May; 36 (5)
`
`AstraZeneca Exhibit 2105 p. 7
`
`

`

`322
`Forms 81‘ al.
`
`urinary excretion at the individual collection inter-
`vals. Recovery of alendronate in urine was linear
`with dose, indicating that both absorption and dis-
`position are linear with dose over the range studied
`(5 to 80mg). Overall, the bioavailability of alen-
`dronate in postmenopausal women was about
`0.76% of the oral dose. Bioavailability in men was
`similar to that in women (averaging about 0.6%).
`
`3.4 Influence of Food, Beverages and
`Calcium on Absorption
`
`Since alendronate, like other bisphosphonates,
`has very low bioavailability and forms insoluble
`complexes with multivalent cations, the effect of
`the timing of meals, dietary calcium supplements
`and beverages other than water on the bioavailabil-
`ity of the drug were studied. Two studies were car—
`ried out in postmenopausal women to investigate
`the effect of the timing of the meals and of calcium
`supplementation of the meal on the oral absorption
`of alendronate.[41] In one study, 15 women were
`given doses of 20mg at 1 or 2 hours before break-
`fast with or without lg elemental calcium supple-
`ment, or 20mg 30 minutes before breakfast without
`calcium. In the other study, 49 women received
`doses of 10mg at 30 minutes, 1 or 2 hours before,
`immediately after, or 2 hours after, breakfast. Rel-
`ative to administration of alendronate 2 hours be-
`
`250
`
`200
`
`150
`
`100
`
`50
`
`
`
`Concentration(ug/L)
`
`0
`
`0
`
`
`I
`I
`I
`I
`I
`3
`6
`9
`12
`15
`Time (h)
`
`Fig. 5. Plasma concentration profile of alendronate following
`administration of a 10mg intravenous dose to postmenopausal
`women with metastatic breast cancer (adapted from Coquyt et
`a|.[39l).
`
`fore breakfast with no calcium supplement, food
`decreased absorption of the drug to varying de-
`grees depending on the timing. On average, eating
`the meal either 30 minutes or 1 hour after adminis-
`
`tration diminished bioavailability by the same pro-
`portion, about 40%.[41] Taking alendronate either
`immediately after or 2 hours after breakfast low-
`ered bioavailability by about 85 to 90%. Including
`the calcium supplement with the meal given 1 or 2
`hours post-dose had no additional effect beyond
`that of the meal itself.
`
`The effect of beverages taken with the dose on
`the bioavailability of alendronate was examined in
`42 healthy postmenopausal women who were given
`a 10mg dose with coffee, orange juice or water.[41]
`Ingestion of either coffee or orange juice was found
`to decrease the bioavailability of alendronate by
`about 60% compared with water.[41] Efficacy was
`demonstrated in clinical trials with alendronate ad-
`ministered from 30 minutes to 2 hours before
`
`breakfast and after an overnight fast. Thus, a prac-
`tical and effective recommendation is for alendron-
`
`ate to be taken with water after an overnight fast
`and at least 30 minutes before any other food, bev-
`erage or medication.[42] It is also recommended
`that patients remain upright for at least 30 minutes
`after dlug administration and until eating to mini-
`mise the risk of oesophageal irritation.[42>43]
`
`3.5 Influence of Gastric pH on Absorption
`
`The effect of increased gastric pH on the absorp-
`tion of alendronate was evaluated in a crossover
`
`study in 10 postmenopausal women given simulta-
`neous intravenous (20ug with 0.5 uCi of [14C]alen-
`dronate tracer) and oral (40mg) doses of alendron-
`ate when their stomach pH was less than 2 (native)
`or elevated to more than 6 by administration of
`intravenous ranitidine.[41] Urinary excretion of al-
`endronate and radioactivity were monitored for 30
`hours post-dose. Elevation of stomach pH by rani-
`tidine, in simulation of hypo- or achlorhydria, had
`no measurable effect on the systemic disposition of
`alendronate but increased abs01ption by about 2-
`fold compared with native stomach pH.
`
`© Adis International Limited. All rights reserved.
`
`Clin Pharmacokinet I999 May; 36 (5)
`
`AstraZeneca Exhibit 2105 p. 8
`
`

`

`323
`Alendronate
`
`
`As doses of alendronate greater than the 10mg
`dose used for the treatment of osteoporosis in post-
`menopausal women produce little or no additional
`increases in bone mass or reduction in bone tum-
`
`over,[8>9] it is unlikely that increased gastric pH has
`an important effect on the efficacy or safety of al-
`endronate. Dosage adjustments are, therefore, not
`necessary in such circumstances.
`
`3.6 Potential for Drug Interactions
`
`Although no drug interaction studies have been
`carried out between alendronate and other thera-
`
`peutic agents likely to be used in the target popu-
`lations, a thorough review of concomitant medica-
`tions in the clinical trials data failed to suggest any
`such interactions of significance.[42] The substan-
`tial effects of food and beverages on oral absorp-
`tion[41] argue against administration concurrently
`with other substances. The drug should be admin-
`istered after an overnight fast and no medication or
`nutritional supplement should be administered
`sooner than 30 minutes after alendronate. The very
`low plasma concentrations of alendronate produced
`by therapeutic oral doses make it highly unlikely
`that plasma protein displacement interactions will
`occur.
`
`Alendronate is neither metabolised nor elimi-
`
`nated in bile but is excreted intact exclusively by
`the kidney. [39] The active renal secretory pathway
`that appears to be involved, based on the preclini-
`cal data, is specialised, involving neither the acidic
`nor basic tubular transport processes;[36] therefore
`it is unlikely to contribute to drug-drug interac-
`tions.
`
`In summary, alendronate is believed unlikely to
`interact with other drugs through changes in protein
`binding, metabolism, or biliary or renal excretion.
`Oral administration of other drugs along with al-
`endronate could potentially interfere with the oral
`absorption of alendronate and should be avoided.
`As alendronate is neither metabolised nor ex-
`
`creted in bile, studies in hepatic insufficiency were
`not performed. Dosage adjustments are not neces-
`sary for altered hepatic function.[42] Given the low
`circulating concentrations of drug, and the fact that
`
`50 to 60% of the systemically available drug is
`presumably taken up by the skeleton, even a sub-
`stantial reduction in the renal elimination of alen-
`
`dronate would lead to only a relatively minor frac-
`tional increase in the amount of drug taken up by
`bone, which over a large dose range appears to be
`nonsaturable.[39] Dosage adjustment is therefore
`not necessary in patients with mild-to -moderate re-
`nal insufficiency. There is insufficient clinical ex-
`perience in patients with more severe renal com-
`promise [creatinine clearance <2.l L/h (<35
`ml/min)].
`
`4. Pharmacokinetic-
`
`Pharmacodynamic Relationships
`with Alendronate
`
`The evaluation of the pharmacokinetic-pharma—
`codynamic relationship for alendronate is compli-
`cated by its unique pharmacokinetics, in that its
`plasma concentration profile is neither fully defin-
`able at therapeutic doses nor especially relevant. It
`is the alendronate taken up by bone and the con-
`centration of alendronate present in the resorption
`space between active osteoclasts and bone which
`should determine its inhibition