PERGAMON
`
`European Journal of Cancer 37 2001 15901598
`
`European
`Journal of
`Cancer
`
`wwwejconlinecom
`
`Cremophor EL the drawbacks and advantages of
`vehicle selection for drug formulation
`H Gelderblom J Verweij K Nooter A Sparreboom
`
`Department of Medical Oncology Rotterdam Cancer Institute Daniel den Hoed Kliniek and University Hospital Rotterdam
`3075 EA Rotterdam The Netherlands
`
`Received
`
`26 February 2001 received
`
`in revised form 26 March 2001 accepted
`
`3 May 2001
`
`Abstract
`
`Cremophor EL CrEL is a formulation vehicle
`used for various poorly water soluble drugs including the anticancer agent
`paclitaxel Taxol
`to earlier reports CrEL is not an inert vehicle but exerts a range of biological effects some of which
`In contrast
`have important clinical
`implications Its use has been associated with severe anaphylactoid hypersensitivity
`reactions hyperlipi
`lipoprotein patterns aggregation of erythrocytes and peripheral neuropathy
`The pharmacokinetic behaviour of
`daemia abnormal
`CrEL is dose independent although its clearance
`is highly influenced by duration of the infusion This is particularly important
`since CrEL can affect
`the disposition of various drugs by changing the unbound drug concentration through micellar encapsulation
`In addition it has been shown that CrEL as an integral component of paclitaxel chemotherapy modifies the toxicity profile of
`than kinetic interference A clear understanding of the biolo
`certain anticancer agents given concomitantly by mechanisms other
`role of CrEL is essential
`gical and pharmacological
`to help oncologists avoid side effects associated with the use of paclitaxel or
`other agents using this vehicle With the present development of various new anticancer agents it
`is recommended that alternative
`should be pursued to allow a better control of the toxicity of the treatment and the pharmacological
`formulation approaches
`interactions related to the use of CrEL
`2001 Elsevier Science Ltd All rights reserved
`
`Keywords Cremophor EL Formulation vehicles Paclitaxel Pharmacokinetics
`
`Pharmacodynamics
`
`such as
`some drawbacks
`the morbidity
`use despite
`associated with gaining iv access risk of iv catheter
`and
`related infection thrombosis
`and extravasation
`therapy when
`
`effective 3 Important reasons for choosing iv use for
`
`patients
`
`preference
`
`for oral
`
`equally
`
`1 Introduction
`
`The choice of a suitable pharmaceutical
`formulation
`is an essential step in anticancer drug development This
`development starts with the acquisition of a chemical
`entity from either natural sources or entirely synthetic
`the compound is screened
`routes Subsequently
`cytotoxic activity in vitro and in vivo Once the screening
`process has been completed the compound should be
`pharmaceutically formulated
`and produced
`properly
`before entering animal
`toxicology and pharmacokinetic
`studies and subsequently human phase I
`and III
`II
`studies 12 In our opinion pharmaceutical
`formula
`tion is a seriously underrated aspect of anticancer
`development
`With only a few exceptions most new anticancer
`for intravenous iv
`compounds are initially developed
`
`drug
`
`for
`
`initial
`
`drug development are the fact
`
`that usually less
`immediate
`toxicity occurs
`there is
`gastrointestinal
`100 bioavailability and instantaneous pharmacody
`namic effects and there is a possibility to modify the
`the infusion if necessary Solu
`dosing rate or even halt
`bility of the compound is a specific demand for iv
`administration even for
`the newer
`chemotherapeutic
`agents which are known to be poorly watersoluble
`Classical solubility approaches which will be discussed
`subsequently include the use of colloidal systems pro
`drug development or solubilisation techniques
`Colloidal systems such as liposomes microcapsules
`or macromolecule com
`microspheres
`nanoparticles
`drug from premature
`plexes may protect
`the anticancer
`degradation or chemical
`inactivation within the sys
`temic circulation Prodrugs are inactive derivatives that
`
`Abraxis EX2004
`Actavis LLC v Abraxis Bioscience LLC
`1PR201701101 1PR201701103 1PR201701104
`
`1003
`
`fax + 3110439
`
`Corresponding author Tel +31104391754
`Email address gelderblomonchazrn1 H Gelderblom
`see front matter C 2001 Elsevier Science Ltd All rights reserved
`0959804901$
`PIT S0959 80490100171X
`
`

`

`H Gelderblom et al European Journal of Cancer 37 2001 15901598
`
`1591
`
`nonionic surfactant CrEL is a
`The heterogeneous
`white to offwhite viscous
`liquid with an approximate
`
`molecular weight of 3 kDa and a specific gravity
`
`release the active drug following spontaneous
`degrada
`tion or enzymatic reactions Solubilisation is the process
`of uptake of drugs through complex formation into for
`eg oligomers of dextrose and fatty acids through co
`solvent systems such as ethanol polyethyleneglycol and
`glycerol or through surfactant systems The surfactant
`systems consist of either amphoteric compounds eg
`lecithin or gelatin ionic surfactants eg sodium pal
`mitate or nonionic surfactants eg Tween
`80 and
`Cremophor EL CrEL 45 This review focuses on
`properties of CrEL
`and pharmacological
`biological
`which is the formulation vehicle of various hydrophobic
`drugs including the anticancer
`
`agent paclitaxel
`
`2 Paclitaxel
`
`formulation
`
`ingredient
`Western
`
`After
`
`the identification
`
`as the active
`of paclitaxel
`in crude ethanolic extracts of the bark of the
`Yew tree Taxus brevifolia against several
`murine tumours 6 the development of the drug was
`for more than a decade due to problems
`suspended
`associated with the solubilisation of the drug Paclitaxel
`less than 003 mgml slightly
`is insoluble in water
`soluble in octanol propylene glycol and butanol solu
`ble in CrEL ethanol methanol chloroform acetone
`and ether and freely soluble in dimethyl acetamide The
`formulation approach using 50 CrEL and 50 dehy
`drated ethanol United States Pharmacopeia USP was
`chosen for further development 7 The pharmaceutical
`
`formulation of paclitaxel
`paclitaxel BristolMyers
`Squibb contains 30 mg paclitaxel dissolved in 5 ml of
`this 11 vv mixture
`
`a
`
`OH
`
`°°11
`
`25°C25°C of 105106 and it
`is produced by the
`reaction of castor oil with ethylene oxide at a molar
`ratio of 135 4 Castor oil
`is a colourless or pale yellow
`fixed oil obtained from the seeds of Ricinus communis
`with an extremely high viscosity and consists mainly of
`and
`the glycerides of
`ricinoleic isoricinoleic stearic
`dihydroxystearic acids CrEL is usually of highly vari
`able composition with the major component
`identified
`ie poly
`as oxylated triglycerides of ricinoleic acid
`oxyethylene glycerol triricinoleate 35 Fig 1 Polyvinyl
`chloride PVC free equipment
`for CrEL administration
`is obligatory since CrEL is known to leach plasticizers
`from PVC infusion bags and polyethylene lined tubing
`toxicity 5
`sets which can cause severe hepatic
`CrEL is being used as a vehicle for the solubilisation
`of a wide variety of hydrophobic
`drugs including
`sedatives immunosup
`photosensitisers
`and experimental
`anticancer
`Table 1 The amount of CrEL administered with these
`range 15103 ml although
`5 ml
`drugs averages
`is an exception as the amount of CrEL is
`paclitaxel
`much higher per administration approximately 26 ml
`is important to understand the biological
`Therefore it
`and pharmacological behaviour of CrEL especially in
`the formulation of paclitaxel
`
`anaesthetics
`
`pressive
`
`agents
`
`drugs
`
`3 Biological effects of Cremophor EL CrEL
`3 Anaphylactic hypersensitivity reactions
`
`The most well known biological
`effect of paclitaxel
`formulated with CrEL is a clinical acute hypersensitivity
`characterised by dyspnoea
`flushing rash
`reaction
`angiooedema
`chest pain tachycardia
`hypotension
`con
`and generalised urticaria Despite premedication
`sisting of high dose corticosteroids H1 and H2 antago
`nists minor reactions flushing and rash still occur
`
`in
`
`Table 1
`Examples of surfactant systems using CrEL
`
`Agent
`
`Therapeutic class
`
`Amount administered m1
`
`Aplidine
`C8KC
`
`Clanfenur
`Cyclosporin A
`Diazepam
`Didemnin B
`
`Paclitaxel
`
`Propofol
`
`Antineoplastics
`
`Photosensitisers
`
`Antineoplastics
`
`Immunosuppressives
`
`Sedatives
`
`Antineoplastics
`
`Antineoplastics
`
`Anaesthetics
`
`Teniposide
`
`Antineoplastics
`
`55
`
`103
`
`35
`
`15
`20
`258
`
`15
`
`CrEL Cremophor EL
`a For an average patient
`
`for a single administration of dose
`
`b C
`
`H20CH2CH20x000CH27CH=CHCH2CHOHCH25CH3
`
`HC0CH2CH20y000CH27CH=CHCH2CHOHCH25CH3
`
`CH20CH2CH20z000CH27CH=CHCH2CHOHCH25CH
`
`3
`
`Fig 1 Chemical
`
`oxyethyleneglycerol
`
`x+y+z35
`of paclitaxel a of CrEL poly
`triricinoleate 35 b
`
`structures
`
`

`

`H Gelderblom et al European Journal of Cancer 37 2001 15901598
`4144 of all patients and major potentially
`reactions in 153 810 Mostly the
`
`1592
`
`threatening
`
`life
`
`two
`reaction occurs within the first
`hypersensitivity
`courses of paclitaxel and can be prevented by reducing
`the infusion rate Various preclinical
`observations
`to CrEL as the main contributor
`discussed below point
`to the hypersensitivity reactions
`
`a Using an elegant
`series of in vitro studies com
`plement activation by CrEL was found to cause
`associated with
`the
`reaction
`hypersensitivity
`paclitaxel chemotherapy 11 as well as reactions
`seen to other drugs where CrEL was used as a
`vehicle 1213 Recently it was shown that
`the
`CrELinduced complement activation in human
`serum was clearly concentration dependent with
`a minimum activating CrEL level
`in the order of
`2 jilml
`a concentration readily achieved clini
`cally in the plasma following standard doses of
`paclitaxel 14
`b Histamine release in dogs by CrEL was mainly
`caused by one of its minor constituents
`acid 15 whereas the cardiac
`toxicity attributed
`to paclitaxel mainly asymptomatic rhythm dis
`by CrEL
`be
`caused
`turbances might
`also
`through a mechanism of histamine release 16
`c Improper mixing of high dose cyclosporin A
`infusions caused nonsolubilised CrEL to sink
`to the bottom of vials producing anaphylactoid
`responses because of highly concentrated CrEL
`iv bolus 17 All patients allergic to
`at the initial
`iv cyclosporin A tolerated the CrELfree oral
`formulation 18
`d Finally the fact
`
`are
`
`that CrEL concentrations
`infusion schemes
`lower with prolonged paclitaxel
`see below may be an explanation for the lower
`incidence of hypersensitivity reactions with these
`schemes Collectively these findings indicate that
`CrEL plays a crucial
`of
`role in the occurrence
`hypersensitivity reactions of paclitaxel and other
`drugs using CrEL as a formulation vehicle
`
`oleic
`
`leucocytes
`
`in blood smears
`and a change in shape of
`24 This suggests that manual blood cell count analysis
`is warranted after the administration of preparations
`containing CrEL Whether
`the observed hyperlipidae
`mia after CrEL administration increases
`the risk of
`accidents is as yet unknown
`vascular
`
`33 Neurotoxicity
`
`effect
`
`Axonal degeneration and demyelination one of the
`principal side effects of paclitaxel
`resulting in peripheral
`neuropathy is also supposedly a biological effect caused
`by CrEL The plasma levels of CrEL achieved after
`therapeutic doses of paclitaxel and iv cyclosporin A
`also formulated in CrEL have been shown to produce
`axonal swelling vesicular degeneration and demyelina
`tion in rat dorsal ganglion neurones 25 Interestingly
`in rats treated with CrELfree 3Hpaclitaxel paclitaxel
`was not detectable
`nervous
`in the peripheral
`system
`drug itself might not be
`the anticancer
`indicating that
`toxicity 26 The hypoth
`responsible for the observed
`esis of CrELinduced neurotoxicity
`is further supported
`that iv cyclosporin A causes neurotoxicity
`by the fact
`in approximately 25 of patients 27 while this side
`is rarely seen with oral administration This is also
`consistent with a previous finding that CrEL is not
`absorbed when given orally as a result of
`degradation 28 It
`is also noteworthy that neurological
`symptoms are 10 times less common after
`treatment
`with docetaxel a semisynthetic taxane chemically simi
`than with paclitaxel 29 This could be
`lar to paclitaxel
`because unlike paclitaxel docetaxel
`is formulated
`80 ie polyoxyethylenesorbitan monooletate
`Tween
`again rendering CrEL as the likely cause of the clinical
`The neurotoxic properties
`observations of neuropathy
`of CrEL are most likely induced by residual unsaturated
`fatty acids possibly due to the appearance of peroxida
`tion products 30 Therefore it
`the
`is suggested that
`ethoxylated derivatives of castor oil account
`for most of
`the neuronal damage observed 31
`
`intestinal
`
`in
`
`32 Lipoprotein patterns and hyperlipidaemia
`
`Lipoprotein alterations accompanying the adminis
`formulated with CrEL were
`tration of miconazole
`reported as early as 1977 by Bagnarello and colleagues
`19 Later CrEL was found to alter the buoyant density
`of high density lipoproteins HDL 20 and shift
`the
`electrophoretic and density gradient HDL to low den
`sity lipoproteins LDLs 2123 These authors showed
`that paclitaxel had a strong affinity for the serum lipo
`protein dissociation products potentially affecting the
`biodistribution and clearance of the drug High con
`centrations of CrEL may also cause hyperlipidaemia
`possibly resulting in Roulaux formation of erythrocytes
`
`34 Reversal of Pglycoprotein activity
`
`In the early 1990s
`several
`groups independently
`that CrEL was able in vitro to modulate the
`observed
`activity of Pglycoprotein a drug transporting mem
`brane protein that is elevated in tumour cells having a
`multidrug resistance phenotype 3235 More recently
`similar phenomena have also been described for various
`80 36
`including Tween
`other nonionic surfactants
`Solutol HS 15 37 and Triton X100 38 Surprisingly
`has never been success
`however multidrug resistance
`fully modified in vivo
`by any nonionic surfactant
`including CrEL 3941 A possible explanation for this
`lack of in vivo efficacy is the extremely low volume of
`distribution of CrEL approximately
`to the
`
`equal
`
`

`

`H Gelderblom et al European Journal of Cancer 37 2001 15901598
`
`1593
`
`graphy Because of the high costs and time consuming
`nature of both assays a new method based on a selec
`tive binding of CrEL to the Coomassie brilliant blue G
`250 dye in protein free extracts was developed 5354
`Most recently an electrochemical detection method was
`developed 55 Largescale
`studies
`pharmacokinetic
`have only recently been possible with the development
`of these newer methods
`
`42 CrEL Disposition
`
`Clinical pharmacokinetic studies with CrEL following
`3h paclitaxel
`indicate a dose independent
`infusions
`behaviour with
`halflife
`of
`terminal disposition
`a
`approximately 80 h with a large range depending on the
`method used for measurement 5657 Interestingly
`with prolongation of the duration of infusion from 1 to
`3 and to 24 h the CrEL clearance
`from
`increased
`160 to 300 to 400 mlhm2 respectively
`approximately
`14 Fig 2 It
`that CrEL shows a linear
`thus appears
`and dose independent but schedule dependent phar
`macokinetic behaviour
`possibly related to the satura
`tion of serum esterase mediated metabolic degradation
`leads to an increase in sys
`This schedule
`dependency
`temic exposure and thus an increase in the possible
`CrELrelated biological side effects with a shortening
`of the infusion duration An example of this phenom
`enon is the higher risk of allergic reactions in the 1h
`versus 3h or 24h infusions of paclitaxel
`As mentioned earlier the volume of distribution of
`CrEL is extremely low implying that
`the tissue and
`tumour delivery of CrEL is probably insignificant This
`is in line with observations that CrEL levels in normal
`in mice 58
`and tumour tissue were not detectable
`Not much is known about
`the elimination routes of
`CrEL CrEL may be largely degraded
`in the blood
`serum carboxylesteraseinduced
`compartment
`by
`degradation similar to that described for Tween 80 59
`causing a gradual
`
`release of the ricinoleic acid residues
`
`P=003
`
`750
`
`600
`
`450
`
`300
`
`150
`
`0
`
`LIhm2
`
`CrELC
`
`3
`
`24
`
`Duration of infusion h
`113 rnim2 nom 146 milm2 ERN 188 milm2
`Fig 2 Schedule dependency for CrEL clearance CL as a function of
`the duration of infusion in cancer patients treated with paclitaxel at
`dose of 135 CrEL 113 mlm2 175 CrEL 146 mlm2 and 225
`CrEL 188 mlm2 mgm2 14
`
`volume of the blood compartment suggesting that con
`centrations necessary
`reversal of multidrug
`to affect
`resistance in vitro are probably not attained in vivo in
`solid tumours 42 Recent pharmacokinetic
`experi
`ments conducted
`in mdrla Pglycoprotein knockout
`mice support
`this lack of efficacy despite high peak
`plasma levels of CrEL 28 In contrast
`to treatment
`in
`selectivity of CrEL
`solid tumours the pharmacokinetic
`for the central bloodbone marrow compartment can be
`an advantage
`in the treatment of haematological malig
`nancies in which the expression of Pglycoprotein is
`known to be a principal
`factor contributing to resistance
`to chemotherapy 43
`
`35 In vitro cytotoxicity
`
`Cytotoxic properties of CrEL in doxorubicinresistant
`human breast cancer
`lines were first
`reported by
`cell
`Fjallskog and colleagues 44 and confirmed in various
`human tumour samples 4546 It was postulated that
`formation of
`free radicals by peroxidation of poly
`unsaturated fatty acids andor a direct perturbing effect
`in the cell membrane causing fluidity
`and leakage are
`possible mechanisms contributing
`to this type of cyto
`toxicity 4749 Using clonogenic
`assays however
`has been demonstrated that CrEL can antagonise
`cytotoxicity of paclitaxel by blocking the cell cycle that
`results in the inhibition of cytokinesis 50 Thus
`although CrEL in itself might have some potential
`to
`the concentrations required to mod
`affect cell survival
`ulate cell growth will also change paclitaxelmediated
`and overall cytotoxicity In addition the pharmacoki
`selectivity of CrEL most
`netic
`any
`precludes
`likely
`vehicle mediated change in solid tumour cell kill
`vivo
`
`it
`
`the
`
`in
`
`4 Pharmacokinetics of CrEL
`
`41 Analytical methods
`
`the contribution
`
`of CrEL to clinically
`In view of
`observed effects and to enable further assessment of the
`impact of its use on paclitaxel pharmacology
`the kinetic
`behaviour of CrEL has been studied extensively in
`recent years For this purpose a variety of analytical
`methods have been developed The first assay developed
`for the measurement of CrEL concentrations in plasma
`was based on the ability of CrEL to modulate daunor
`ubicin efflux in multidrug resistant T cell
`leukaemia
`VLI3100 cells 51 Later a more sensitive and reliable
`method was developed which required only micro
`volumes 20 ial of plasma 52 This method is based on
`the measurement of ricinoleic acid after saponification
`of CrEL followed
`and
`by precolumn derivatisation
`chromato
`highperformance
`
`reversed phase
`
`liquid
`
`

`

`1594
`
`H Gelderblom et al European Journal of Cancer 37 2001 15901598
`
`attached to the triglyceride structure It has been shown
`that hepatobiliary elimination of CrEL is a minor elim
`ination pathway 60 In addition the urinary excretion
`for less than 010 of the adminis
`of CrEL accounted
`tered dose in spite of its relatively hydrophilic nature
`61
`
`43 Effects of CrEL on drug disposition
`
`Various
`
`studies
`
`have shown
`
`that CrEL alters the
`
`pharmacokinetics of many drugs including cyclosporin
`A etoposide doxorubicin a number of photosensitisers
`eg C8KC and paclitaxel
`Initially the effect of CrEL
`on the disposition of paclitaxel was studied in mice that
`received the drug by iv injection at doses of 2 10 and
`20 mgkg in the presence of various amounts of CrEL
`58 Fig 3 The paclitaxel clearance of 24 lhkg at the
`lowest dose level was reduced to 033 and 015 lhkg at
`the 10 and 20 mgkg dose levels It was also shown that
`the area under the concentration time curve AUC of
`is formulated in CrEL com
`is higher when it
`paclitaxel
`pared with formulation in Tween 80 suggesting
`that
`CrEL is responsible for the non linearity of paclitaxel
`that much higher plasma
`disposition Despite the fact
`levels of paclitaxel are reached when given in the CrEL
`containing formulation the tissue levels of paclitaxel
`were essentially similar with all
`tested preparations
`the profound influence of CrEL is only
`indicating that
`In sub
`taking place in the central blood compartment
`sequent years numerous causes of this apparent non
`linear pharmacokinetic behaviour were proposed It has
`been suggested that CrEL might interfere with Pglyco
`proteinmediated biliary
`secretion
`thereby reducing
`paclitaxel elimination 62 In the isolated perfused rat
`liver CrEL inhibited the hepatic elimination of pacli
`taxel primarily preventing the drug from reaching the
`sites of metabolism and excretion 63 However
`recent
`studies indicate that drug transporting Pglycoproteins
`are not essential per se for normal hepatobiliary secre
`tion of paclitaxel 2864 and that as discussed the dis
`
`to modulate
`
`position of CrEL itself
`limits the potential
`Pglycoprotein activity in vivo 42
`More recently it has been proposed that the effect of
`CrEL on paclitaxel pharmacokinetics is associated with
`encapsulation of the drug within CrEL micelles causing
`concentration dependent changes in cellular partition
`ing and bloodplasma concentration ratios of paclitaxel
`64 Fig 4 It was shown that the affinity of paclitaxel
`order CrEL > plasma > human
`in decreasing
`was
`serum albumin with CrEL present
`above the critical
`
`micellar concentration ie 001 Since this effect
`
`was also observed in the absence of plasma proteins it
`could not have been caused by altered protein binding
`for protein dis
`or by an increased affinity of paclitaxel
`
`sociation products that are produced by the action of
`CrEL on native lipoproteins 22 These findings are
`can be
`consistent with the hypothesis that paclitaxel
`entrapped within micelles composed primarily of poly
`triricinoleate and that
`these micelles
`ethyleneglycerol
`in the systemic
`act as the principal carrier of paclitaxel
`circulation The percentage of total paclitaxel
`trapped in
`micelles increases disproportionately with higher doses
`of CrEL administered
`the nonlinear pharmacokinetics
`The hypothesis that
`is related to time varying CrEL concentra
`of paclitaxel
`recently confirmed
`tions was
`in a group of cancer
`increasing doses of 135 175 and
`patients all
`225 mgm2 65 Again the plasma clearance of pacli
`taxel turned out to be dose dependent with the slowest
`the highest dose level Fig 5 In line with
`clearance at
`the in vitro data the nonlinear disposition of paclitaxel
`in the plasma appeared to be an artifact caused by dose
`related levels of CrEL in blood 65 Therefore the non
`micellar bound or unbound fraction of paclitaxel
`plasma might be a better pharmacokinetic parameter to
`predict toxicity and to guide dosing of paclitaxel since it
`that the unbound fraction of
`is generally acknowledged
`a drug is capable of diffusing across biological barriers
`and interacting with essential structures in tumour tis
`sues 66
`
`receiving
`
`in
`
`fu
`
`Paclitaxel
`
`Cremophor EL
`
`Tween 80
`DMA
`
`100000
`
`10000
`
`1000
`
`100
`
`10
`
`Paclitaxelngml
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`Time h
`
`Fig 3 Effect of the formulation vehicle CrEL Tween
`80 or dime
`thylacetamide DMA on paclitaxel
`in female FVB
`concentration
`mice receiving paclitaxel at a dose of 10 mgkg 58
`
`CrEL nlm1
`
`Fig 4 Effect of the CrEL concentration
`paclitaxel fu in human plasma 56
`
`on the fraction of unbound
`
`

`

`H Gelderblom et al European Journal of Cancer 37 2001 15901598
`
`1595
`
`to the potential benefits obtained from the
`In contrast
`use of CrEL in the case of cisplatin chemotherapy
`combination studies conducted with the combination of
`paclitaxel and doxorubicin have shown that CrEL can
`be linked to clinically important kinetic and dynamic
`interactions that greatly impact upon the overall toxi
`city profiles Two independent studies have shown pro
`found decreases in doxorubicin clearance particularly
`when paclitaxel was given prior to the anthracycline
`6275 resulting in substantially worse mucositis and
`toxicity Therefore
`is advised
`to
`haematological
`administer doxorubicin
`in this combination In
`is expected that even minor modifications in
`addition it
`the duration of the infusion or dose may lead to unpre
`dictable pharmacodynamic consequences Similar inter
`actions with CrEL have
`been
`also
`described
`for
`etoposide epirubicin and the irinotecan metabolite SN
`38 76 Clearly the magnitude of
`these interactions
`depend largely on the combination drug involved the
`paclitaxel and CrEL dose administered and the dura
`tion of infusion administration sequence used for the
`combined agents
`
`first
`
`it
`
`5 Conclusions
`
`and future perspectives
`
`that CrEL a
`Recent
`have
`revealed
`investigations
`and
`widely used formulation vehicle is a biologically
`ingredient of various com
`active
`pharmacologically
`mercially available drugs For example when used in
`an
`administrations
`paclitaxel
`exceptionally
`large
`amount of CrEL is inevitably co administered with the
`iv infusions causing important biological events that
`can lead to serious acute hypersensitivity reactions and
`toxicity depending on the dose and dura
`neurological
`tion of infusion In addition the substantial effects of
`
`P<0001
`
`200
`
`150
`
`100
`
`50
`
`scontrol
`
`uptakev
`
`PBL
`
`CDDP
`
`Carbo
`
`Dox
`
`Epi
`
`Fig 6 Influence of CrEL on anticancer drug pharmacodynamics
`Bars indicate the amount of drug accumulated in peripheral blood
`leucocytes PBL expressed as percentage
`relative to a 100 control
`for 2h incubations with cisplatin CDDP carboplatin Carbo
`doxorubicin dox and epirubicin Epi 70 data not shown NS
`non significant
`
`44 Effects of CrEL on anticancer drug
`pharmacodynarnics
`
`interactions
`
`Besides its effect on anticancer drug disposition the
`use of CrEL has also been associated with alterations in
`outcome of a number of drugs
`the pharmacodynamic
`co administered with paclitaxel For example clinical
`combination chemotherapy studies with paclitaxel and
`cisplatin revealed important sequence dependent differ
`in toxicity with less myelotoxicity when the tax
`ences
`ane was given before cisplatin that could not be linked
`6768
`changes
`in pharmacokinetics
`to consistent
`Interestingly no toxicity or pharmacokineticsequence
`interaction was seen in the combination of carboplatin
`and paclitaxel 69 One of the mechanisms underlying
`to be
`important
`these clinically
`appears
`related to a selective inhibition of cisplatin accumula
`tion in peripheral blood and bone marrow cells by
`CrEL without affecting antitumour activity 7072
`Fig 6 In addition it has been demonstrated that
`the level of serum haemato
`CrEL markedly reduced
`poietic inhibitory activity which resulted in a decrease
`in femoral bone marrow cellularity and an upregulation
`of B and T cells as well as a transiently elevated inci
`dence of both primitive and committed haematopoietic
`progenitor cells within several hours after injection 73
`that the unusual
`Taken together
`these findings suggest
`observations noted with cisplatinpaclitaxel
`clinical
`combination
`therapy are due to a myeloprotective
`interaction with cisplatin by CrEL Since CrEL doses of
`up to 30 mlm2 as a 3h infusion can be safely admi
`nistered 74 it
`is anticipated that an improvement
`in
`the therapeutic window for cisplatin could be obtained
`by reformulation of this agent with CrEL This con
`is currently under further investigation data not
`cept
`shown
`
`a A
`
`50
`
`100
`
`15
`
`0
`
`200
`
`250
`
`300
`
`Dose mgm2
`
`40 7
`
`30 1
`
`20 1
`
`10 1
`
`0+
`0
`
`nMh
`
`AUC
`
`Paclitaxel
`
`Fig 5 Effect of dose on paclitaxel plasma circles and whole blood
`curve AUC triangles
`area under
`the
`concentration
`in cancer
`patients treated with paclitaxel at three different dose levels 65 Please
`the higher the AUC the slower the clearance of a drug
`
`note that
`
`

`

`1596
`
`H Gelderblom et al European Journal of Cancer 37 2001 15901598
`
`5 Goldspiel BR Guidelines for administration In McGuire WP
`Rowinsky EK eds Paclitaxel
`New York
`in Cancer Treatment
`1995 175186
`Marcel Dekker
`6 Wani MC Taylor HL Wall ME Coggon P McPhail AT Plant
`antitumor agents VI the isolation and structure of Taxol a
`novel antileukemic and antitumor agent from Taxus brevifolia J
`Am Chem Soc 1971 93 23252327
`7 Adams JD Flora KP Goldspiel BR Wilson JW Arbuck SGI
`Taxol
`and current
`a history of pharmaceutical
`development
`concerns J Natl Cancer
`Inst Monogr 1993 15
`
`toxicities
`
`pharmaceutical
`141147
`8 Rowinsky EK Eisenhauer EA Chaudhry V Chaudrhy V
`Arbuck SG Clinical
`encountered with paclitaxel
`Taxol Semin Oncol 1993 20 115
`9 Weiss RB Donehower RC Wiernik PH et al Hypersensitivity
`reactions from Taxol J Clin Oncol 1990 8 12631268
`10 Eisenhauer EA ten Bokkel Huinink WW Swenerton KD et al
`European Canadian randomized trial
`in relapsed
`of paclitaxel
`ovarian cancer high dose versus low dose and long versus short
`infusion J Clin Oncol 1994 12 26542666
`11 Szebeni J Muggia FM Alving CR Complement
`Cremophor EL as a possible contributer
`to
`to hypersensitivity
`Inst 1998 90 300306
`an in vitro study J Natl Cancer
`12 Watkins J Ward AM Appleyard TN Adverse reactions to
`agents Br Med J 1997 2
`
`activation by
`
`paclitaxel
`
`intravenous
`
`anaesthetic
`
`induction
`
`control of
`
`CrEL on the disposition of other co administered drugs
`eg anthracyclines with a narrow therapeutic window
`regimens also can be poten
`in poly chemotherapeutic
`tially hazardous to the patient
`the in vitro
`In contrast
`and in vivo observations of myeloprotective effects rela
`ted to the use of CrEL in combination with some
`agents such as cisplatin might be used to reformulate
`such agents with CrEL in order to achieve an optimisa
`tion of their therapeutic window
`In view of the inherent problems associated with the
`use of CrEL it can be anticipated that
`there may be a
`from using paclitaxel
`formula
`therapeutic advantage
`tions in which CrEL is absent Such new formulation
`should clearly be pursued to allow a better
`approaches
`the systemic CrELmediated toxicity and
`interactions observed with numerous
`pharmacokinetic
`agents given in combination with the taxane Obviously
`formulations should allow the
`alternative paclitaxel
`drug to be delivered at adequate doses and the pre
`paration should be stable for several hours to allow
`handling in the clinical setting Currently a large variety
`of new CrELfree formulation vehicles
`for paclitaxel
`including co solvent
`development
`are in preclinical
`systems Tween 80ethanolPluronic L64 watersoluble
`polymers eg polyethylene glycols emulsions eg
`and
`triacetin liposomes cyclodextrines
`nanocapsules
`microspheres reviewed in Ref 76 Although one of
`these preparations might eventually replace the current
`formulation for the coming years we will
`paclitaxel
`have to cope with the drawbacks of CrEL in the clinical
`is also important to keep in mind that CrEL is
`setting It
`widely used not only by oncologists but also by anaes
`few
`thetists and in transplantation medicine and that
`physicians are aware of the biological and pharmacolo
`gical activity of the compound
`is thus essential
`to
`find other ways to solubilise the drugs formulated in
`CrEL but also in some cases to explore the potential
`is of note
`positive effects of this castor oil derivative It
`the biological effects
`that a proper understanding of all
`of the formulation would presumably have avoided
`the
`major delays in development of paclitaxel as an antic
`the
`ancer agent This underscores
`the importance of
`choice of vehicle in drug development
`in general
`
`It
`
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