pharmacokinetics, metabolism and excretion of intravenous [l4c]-palonosetron in healthy human...

Received 6 February 2004Revised 8 April 2004

Accepted 8 April 2004Copyright # 2004 John Wiley & Sons, Ltd.

BIOPHARMACEUTICS & DRUG DISPOSITIONBiopharm. Drug Dispos. 25: 329–337 (2004)

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/bdd.410

Pharmacokinetics, Metabolism and Excretion of Intravenous[l4C]-Palonosetron in Healthy Human Volunteers

Randall Stoltza, Simona Parisib, Ajit Shahc and Alberto Macciocchib,*aGFI Pharmaceutical Services, Evansville, Indiana, USAbHelsinn Healthcare SA, Lugano, SwitzerlandcMGI Pharma, Inc. Bloomington, Minnesota, USA

ABSTRACT: Palonosetron (Aloxı́(R), Onı́cı́t(R)) is a potent, single stereoisomeric 5-HT3 receptorantagonist developed to prevent chemotherapy-induced nausea and vomiting. The pharmacoki-netics and metabolic disposition of a single intravenous [14C]-palonosetron (10 mg/kg, 0.8 mCi/kg)bolus dose were evaluated in six healthy volunteers (three males, three females) using serial blood,plasma, urine and fecal samples obtained over 10 days. The safety, tolerability and cardiac effectswere assessed. Radiolabeled metabolic characterization revealed that unchanged palonosetronaccounted for 71.9% of the total radioactivity in plasma over 96 h, with an extensive distributionvolume (8.34 l/kg) and mean plasma elimination half-life of 37 h. Approximately 83% of the dosewas recovered in urine (�40% as unchanged drug, with 50% metabolized; M9 and M4 were themajor metabolites) and 3.4% in feces. Hydrolysis of urine samples suggests that the metabolites arenot b-glucuronide or sulfate conjugates of the parent drug or metabolites. The blood to plasmaconcentration ratio of the total radioactivity was 1.2, on average, indicating little selectivepartitioning in erythrocytes. Palonosetron was generally well tolerated; headache was the mostfrequently reported adverse event. Electrocardiograms and 72 h Holter monitoring revealed noclinically significant changes. Palonosetron circulates in plasma mainly as the parent drug. Renalelimination is the primary excretion route, with parent drug and metabolites M9 and M4accounting for the majority of palonosetron disposition. These results indicate that both renal andhepatic routes are involved in the elimination of palonosetron from the body. Copyright # 2004John Wiley & Sons, Ltd.

Key words: palonosetron; metabolism; excretion; pharmacokinetics; chemotherapy-inducednausea and vomiting

Introduction

Nausea and vomiting are common occurrenceswith many cancer chemotherapy regimens, parti-cularly cisplatin-based therapies [1–3]. Selectiveserotonin-3 (5-HT3) receptor antagonists given aloneor in combination with other antiemetic therapiesare the most efficacious and recommended treat-

ments; however, none are completely effective inpreventing acute (424 h after chemotherapy) anddelayed (>24 h after chemotherapy) chemotherapy-induced nausea and vomiting [1,4].

Palonosetron (Aloxı́(R), Onı́cı́t(R)) is shown tobe effective in in vivo models of chemotherapy-induced emesis [5]. Compared with other agents,palonosetron has a longer elimination half-lifeand has the strongest binding affinity for 5-HT3

receptors [6–9], which may contribute to theprolonged antiemetic effect observed in clinicalstudies [10–12].

*Correspondence to: Alberto Macciocchi, MD Helsinn HealthcareSA, PO Box 357, 6915 Pambio-Noranco (Lugano), Switzerland.E-mail: [email protected]

Two dose-ranging studies in US and Japanesevolunteers who were administered a singleintravenous (i.v.) dose of palonosetron (range:0.3–90 mg/kg) showed that systemic exposure[AUC (area under the plasma concentration-versus-time curve) and Cmax (maximal plasmaconcentration)] for palonosetron and its N-oxidemetabolite (M9) increased with increasing dose[9]. The mean total body clearance, plasmaelimination half-life and apparent volume ofdistribution was in the range 1.1–3.9 ml/min/kg, 34–54 h and 3.9–12.6 l/kg in 80 US volunteersand 2.6–3.5 ml/min/kg, 31–37 h, and 7.0–9.9 l/kgin 32 Japanese volunteers [9]. The objective of thisstudy was to determine the pharmacokinetics,metabolism and excretion routes of palonosetronafter administration of a single i.v. dose of [14C]-palonosetron to healthy human subjects.

Materials and Methods

Study design

Six subjects (three males and three females) wereenrolled in this open-label study and received asingle i.v. injection of [14C]-palonosetron (10 mg/kg containing 0.8 mCi/kg). The specific activitywas approximately 80 mCi/mg. The study proto-col was reviewed and approved by the appro-priate Institutional Review Board of theparticipating institution, and the study wasperformed in accordance with good clinicalpractice guidelines. All subjects provided writteninformed consent prior to participation.

Subjects

Subjects were between 21 and 44 years of age andwithin 15% of the average weight for theirgender, age and height. To rule out clinicallysignificant abnormalities, the subjects underwenta medical history and physical examination; 12-lead electrocardiogram (ECG); routine laboratorytesting, including hematology, blood chemistriesand liver function tests, within 3 weeks prior todosing; and two 24 h Holter examinations within1 month of study initiation. Subjects wererequired to have a negative drug screening testand to have negative tests for hepatitis B surface

antigen, hepatitis C antibody and human im-munodeficiency virus. Subjects were excludedfor the following: a history of clinically signifi-cant cardiovascular, renal, hepatic or neurologic(seizure disorder) disease; childbearing potential;a history of tobacco, drug, or alcohol abuse; usein the 2 weeks prior to or during the study ofhypnotics, sedatives, antihistamines, or otherdrugs or foods known to induce or inhibitoxidative metabolism; unwillingness to abstainfrom alcohol for 48 h before dosing through thefinal blood draw; required use of nonstudymedication (except for long-term hormone repla-cement therapy); use of over-the-counter medica-tions or vitamins; current participation orparticipation in the preceding 30 days in anyother drug or radiolabeled compound study; or ahistory of receiving any therapeutic or diagnosticradionuclide within 6 months of study participa-tion.

Study drug

[14C]-palonosetron HCl (Figure 1) solution wasprovided in preservative-free 5 ml glass vialscontaining 1.2 ml of [14C]-palonosetron at aconcentration of 1.0 mg/ml (quantitated as thefree base) with sodium chloride and sodiumphosphate in water for injection adjusted to a pHof 7.4. Study doses were prepared based on thesubject’s weight rounded to the nearest kilogramon the day of dosing and were administered byi.v. over 30 s.

Figure 1. Chemical structure of palonosetron

Copyright # 2004 John Wiley & Sons, Ltd. Biopharm. Drug Dispos. 25: 329–337 (2004)

R. STOLTZ ET AL.330

Sample collection

Blood samples (15 ml each) were collected fromthe opposite arm into which the dose wasadministered by direct venipuncture or indwel-ling catheter into a heparinized vacuum contain-er 30 min before dosing and at 5, 15 and 30 minand 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120 and 144 hafter dosing. A portion (1 ml) of each bloodsample was immediately transferred to a poly-propylene tube for analysis of total radioactivityin whole blood. Plasma was separated from theremaining whole blood by centrifugation at3000 rpm for 10 min, and then transferred topolypropylene tubes.

Urine samples were collected immediatelybefore dosing and over the following intervals:every 4 h up to hour 12, once between 12 and 24 hpostdose, then every 24 h up to hour 240. Totalurine volumes were recorded after each collec-tion. A baseline stool sample was collectedwithin the 24 h before dosing, and complete24 h fecal collections were made daily for 10days. Blood, plasma, urine and fecal specimenswere stored at �208C until analysed.

Determination of radioactivity

The total radioactivity in blood, plasma, urineand fecal samples was determined using liquidscintillation counting. Briefly, duplicate aliquotsof whole blood (100 ml) were dried on papercones and assayed for total radioactivity bycombustion analysis with a sample oxidizer.The 14CO2 product was trapped in scintillationfluid and assayed by liquid scintillation counting.Duplicate aliquots of plasma (200 ml) or filteredurine (250 ml) were analysed by liquid scintilla-tion counting. Homogenized fecal samples(�100 mg) were dried on paper cones andassayed for total radioactivity by combustionanalysis with a sample oxidizer. The 14CO2

produced was trapped in scintillation fluid andassayed by liquid scintillation spectrometry.Radioactivity counts were collected and cor-rected for quench, background and specificactivity.

Liquid chromatography

Assay of extracts from plasma and urine wasbased on tandem-partition and cation-exchangeliquid chromatography using two mobile phases(0.07m ammonium acetate adjusted to pH 4.5with trifluoroacetic acid and acetonitrile). A BDSHypersil C8 column (Keystone Scientific,4.6� 250 mm, 5 mm) and a SCX column (What-man, 4.6� 100 mm, 5 mm) were used with a three-segment elution sequence consisting of 13%acetonitrile from 0–15 min, 13–30% acetonitrilefrom 15–30 min, then an isocratic segment of 30%acetonitrile until 45 min. For the urine samples,palonosetron and its metabolites were measuredusing high-pressure liquid chromatography witha continuous-flow radiochemical detection meth-od. The assignment of structure to an individualradioactive peak was determined by co-elutionwith either an authentic standard or a previouslyisolated metabolite from animal studies.

Assays of palonosetron and metabolites in plasmaand urine

Aliquots of plasma (2 ml) or filtered urine (1 ml)were mixed with 0.01m of sodium triphosphatesolution and small amounts of sodium hydroxidesufficient to adjust the solution to a pH of 10. Thesamples were applied to methanol-activated andbuffered (0.01m sodium triphosphate) C18 solid-phase extraction columns (500 mg). The columnswere washed with water and then eluted with0.3% trifluoroacetic acid in methanol. The eluantswere concentrated to dry residues and dissolvedin 250 ml of 0.07m ammonium acetate adjusted topH 4.5 with trifluoroacetic acid and acetonitrile(87/13% v/v), and aliquots of this extract wereassayed by liquid scintillation counting to assesstotal radioactivity recovery. For plasma, quanti-fication of palonosetron and metabolites wasperformed by postcolumn fractionation of thecolumn effluent and liquid scintillation countingusing 175 ml aliquots. Fractions (30 s each) werecollected into scintillation vials and counted.

Treatment of urine extracts with b-glucuronidaseand sulfatase

To determine conjugate formation, pooled urinesamples from each subject (taken from 10–24 h


METABOLIC DEPOSITION OF PALONOSETRON 331

postdose) were subjected to enzyme hydrolysis.Glucuronide and/or sulfate conjugates of palono-setron were detected via urine extracts incubatedwith either bovine b-glucuronidase or Aerobacteraerogenes sulfatase and precipitated with trichlor-oacetic acid. The supernatants were then analysedby liquid chromatography, as previously de-scribed. Mass spectrometry was used to identifyunknown metabolites found in plasma and urine.

Pharmacokinetic and metabolic dispositionanalyses

Pharmacokinetic parameters were calculated bynoncompartmental methods. Plasma and urineconcentrations below the limit of quantificationwere treated as zero in all calculations. Concen-trations of total radioactivity in all blood, plasma,urine and fecal samples were determined. Forparent drug and metabolite M9, the meanmaximal concentration of total radioactivity(Cmax) and the time to reach mean maximalconcentration of total radioactivity ðTmaxÞ wererecorded from individual subject concentration-time curves. The terminal elimination rate con-stant ðbÞ was determined from the slope of theterminal portion of the log-concentration versustime curve by linear least squares regressionanalysis of the plasma concentration-time pro-files. Terminal elimination half-life ðt1=2Þ wascalculated as (ln 2)/b. Area under the concentra-tion-versus-time curve from time 0 to the lastquantifiable concentration at time t (AUC0�last)was calculated using the linear trapezoidalmethod. AUC0�1 was computed as the sum ofAUC0�last and the extrapolated area from the lastquantifiable time point to infinity using Clast=b,where Clast is the last quantifiable concentration.For palonosetron, the total body clearance (CLT)was calculated as dose/AUC0�1. Renal clearanceðCLrÞ was calculated as Ae0�1=AUC0�1/bodyweight, where Ae is the amount of drug excretedin the urine up to 1 after the dose and AUC0�1

is the area under the concentration-time curvefrom time 0 to 1 postdose. The apparent volumeof distribution ðVdÞ was calculated as CLT=b.

Safety

Physical examinations and clinical laboratorytesting}including hematology, serum chemis-

tries, urinalysis and vital signs}were performedat baseline. Assessments were repeated duringthe dosing period and at the end of the study toassess the tolerability of palonosetron. Adverseevents, elicited and observed, were rated as mild,moderate or severe and assessed for seriousnessand the potential relationship to study medica-tion. Cardiac monitoring was performedthroughout the study and consisted of two 12-lead ECG (baseline and at end of study) andHolter monitoring for 72 h after dosing. From theECGs the following parameters were evaluated:overall rhythm, atrial and ventricular rates, PRinterval, QRS width, and uncorrected and cor-rected QT intervals.

Results

Radioactivity recovery

In six human subjects (three males, three females;mean age: 35 years; 83% Caucasian; meanweight: males, 86 kg; females, 64 kg), a single10 mg/kg i.v. dose of [14C]-palonosetron waseliminated predominantly in the urine. Therecovery of radioactive dose equivalents(0–240 h) averaged 83.2%� 6.5% in urine and3.38%� 1.54% in feces, with a mean totalrecovery of drug of 86.6%� 6.9% (Table 1). Therecovery of the dose in urine and feces wasmostly complete within 144 h after dosing. Lessthan 5% of the dose was recovered in urine andfeces after 7 days. The recovery of radioactivity inmale and female subjects was similar.

Pharmacokinetics

The pharmacokinetic parameters for total radio-activity and palonosetron in plasma are summar-ized in Table 2. Plasma concentrations of themajor metabolite, metabolite M9, and the minormetabolites were too low for reliable pharmaco-kinetic parameter estimation. Mean plasma con-centration-time profiles for total radioactivityand palonosetron are shown in Figure 2. Themean Cmax was 3.93 ng-Eq/ml and 3.13 ng/ml fortotal radioactivity and palonosetron, respectively,and were observed at 5 min after injection for allsubjects. The mean total radioactivity AUC0�1


R. STOLTZ ET AL.332

was 89.2 ng-Eq�h/ml and mean palonosetronAUC0�1 was 65.0 ng-Eq�h/ml. Based on theaverage ratio of individual subject AUC valuesfor palonosetron to total radioactivity, palonose-tron represented 71.9% of the total radioactivityin plasma over 96 h. The mean terminal half-life

was 39.4 h and 37.4 h for total radioactivity andpalonosetron, respectively. The mean CLT andapparent Vd for palonosetron were 160 ml/h/kgand 8.34 l/kg, respectively. The mean renalclearance of palonosetron was 66.5 ml/h/kg.Overall, the mean pharmacokinetic parametersfor males and females were similar. The mean(standard deviation) of blood to plasma concen-tration ratios of total radioactivity between 5 minand 24 h postdose was 1.19 (0.10), indicating littleselective partitioning of palonosetron-derivedradioactivity into erythrocytes.

Metabolic profiles

Palonosetron and its three metabolites (M4, M5and M9) were observed in the chromatographicanalysis of plasma extracts. Palonosetron, meta-bolites M9 and M4, and low levels of metaboliteM6 were observed in the pooled urine extracts.Representative chromatograms and retentiontimes for plasma and urine samples containingpalonosetron and its metabolites are shown inFigure 3. The major radioactive components (as apercentage of administered dose) recovered inurine were palonosetron (39.3%), metabolite M9(12.5%) and metabolite M4 (10.9%) (Table 3). Theurinary metabolites of [14C]-palonosetron werenot susceptible to hydrolysis by either b-glucur-onidase or sulfatase, indicating that the metabo-lites were not glucuronide or sulfate conjugatesof the parent drug or metabolites. The timecourse for the appearance of the metabolites inurine (�144 h) was similar to that for totalradioactivity, and urinary metabolic profiles weresimilar between males and females.

The metabolic pathways of palonosetron inhealthy human subjects are presented in Figure 4.With respect to metabolic characterization, thestructure of metabolite M4 has been fullyestablished. This metabolite is the s-isomer of 6-hydroxy-palonosetron (the position of the hydro-xylation was confirmed by nuclear magneticresonance analysis). Metabolite M5 was co-elutedwith the same metabolite isolated from dogurine. Definitive mass spectrometric and nuclearmagnetic resonance studies established the struc-ture of metabolite M5 as isolated from dog urineto be 6-keto-N-oxo-palonosetron. Metabolite M6was present at very low levels in pooled urine

Table 1. Percentage of radioactivity excreted in urine andfeces after a single 10mg/kg i.v. dose of [14C]-palonosetron

Percent of administered dose(mean� SD) over 0–240 h

Urine Feces Total

Male ðn ¼ 3Þ 80.4� 6.0 2.40� 1.4 82.8� 4.6Female ðn ¼ 3Þ 85.9� 6.8 4.38� 1.0 90.3� 7.5Overall mean ðn ¼ 6Þ 83.2� 6.5 3.38� 1.54 86.6� 6.9

SD, standard deviation.

Table 2. Pharmacokinetic parameters (mean� SD) after asingle 10 mg/kg i.v. dose of [14C]-palonosetron

Parameter Total radioactivity Palonosetron

Cmax (ng/ml)Males 4.84� 0.59 3.94� 0.56Females 3.01� 0.36 2.33� 0.38All 3.93� 1.09 3.13� 0.98

t1/2 (h)Males 33.5� 4.2 28.8� 5.5Females 45.3� 5.9 46.0� 15.9All 39.4� 7.9 37.4� 14.2

AUC0�1(ng-Eq�h/ml)Males 83.5� 9.2 56.6� 9.3Females 94.8� 7.6 73.3� 13.4All 89.2� 9.8 65.0� 13.8

CLT (ml/h/kg)Males NC 180� 32Females NC 140� 29All NC 160� 35

CLr (ml/h/kg)Males NC 76.7� 15.7Females NC 56.2� 16.4All NC 66.5� 18.2

Vd (l/kg)Males NC 7.66� 2.87Females NC 9.02� 2.33All NC 8.34� 2.45

SD, standard deviation; i.v., intravenous; Cmax, maximal plasma

concentration; t1=2, elimination half-life; AUC0�1, area under the

plasma concentration-versus-time curve from 0�1 h; CLT, total body

clearance; NC, not calculated; CLr, renal clearance; Vd, apparent

volume of distribution.



and was characterized by mass spectrometry as aketone of palonosetron. Metabolite M9 was co-eluted with the authentic reference standard;however, because of the thermal instability of N-oxide analysis by this technique, the massresponse was 16 atomic units lower than thetheoretical atomic mass.

Safety

No serious or unexpected adverse events oc-curred during the study. Seventeen adverseevents were reported by five of the six subjects.One subject accounted for 10 of these events dueto interconcurrent illness; these events wereassessed as not related to palonosetron. The mostfrequent adverse event was headache (83.3%,n=5), reported from 3.5 h to 7 days after dosing.Vertigo, abnormal dreams, vasodilation, consti-pation, petechia, infection, lung disorder, contactdermatitis, pain, sweating and lacrimation wereeach reported once; none were assessed as severeor as likely related to palonosetron. No clinicallyimportant changes in data were noted forphysical examinations, vital signs, ECGs orHolter monitoring. Only one subject had clini-cally important laboratory values (elevatedmonocytes, basophils and eosinophils) outside

the reference range during the study afteradministration of palonosetron.

Discussion

After administration of radiolabeled [14C]-palo-nosetron, palonosetron accounted for 72% of thetotal radioactivity in plasma over 96 h, with amean plasma elimination half-life of 37 h. Themean systemic clearance was approximately 12%of hepatic blood flow, consistent with very lowhepatic extraction and elimination of palonose-tron from plasma. Palonosetron had a volume ofdistribution of 8.34 l/kg, indicating extensivetissue distribution. The levels of total radio-activity in erythrocytes were about 1.2 timesthose of plasma, indicating little accumulation inerythrocytes. Palonosetron was essentially themain radioactive component in the plasma,which was consistent with the transient andlow concentrations of circulating metabolites(M9, M4 and M5) detected in plasma.

In humans, nearly 80% of the administereddose of palonosetron was recovered in urineover 7 days, and of this total, approximately40% of the dose was recovered as parentpalonosetron. Mean renal clearance was 42%

Figure 2. Plasma concentrations (mean� SD) for total radioactivity and palonosetron after a single 10mg/kg i.v. dose of [14C]-palonosetron


R. STOLTZ ET AL.334

of the mean systemic clearance, indicating amajor contribution of the kidney to the clearanceof palonosetron. About 50% of the administered[14C]-palonosetron was metabolized in humans.The major metabolites in urine were M9 and M4.In vitro studies of incubations of palonosetronwith individual cytochrome P450 enzymesshowed that CYP2D6 is the major enzymeinvolved in the metabolism of palonosetron,

followed by CYP3A and CYP1A2 [17]. Overall,metabolism and disposition were similar inmales and females after i.v. administration.

Because the major metabolites of palonosetron,M4 and M9, have a low affinity for the 5-HT3

receptor and low systemic exposure, they prob-ably do not contribute significantly to thepharmacologic activity of palonosetron. Thiswas confirmed by testing metabolites M4 and

Figure 3. Comparison of representative high-performance liquid chromatography profiles in plasma (a) and urine (b) forpalonosetron and its metabolites after a single 10mg/kg i.v. dose of [14C]-palonosetron



M9 for 5-HT3 receptor antagonism activity in anileal guinea-pig model. Both metabolites wereshown to possess less than 1% of 5-HT3 receptorantagonist activity of the parent compound. Thehuman metabolites of palonosetron have also

been detected in the rat, dog and monkey,although the metabolic profile of palonosetronwas quite different in these species.

Compared with palonosetron, ondansetronundergoes more extensive metabolism (95% forondansetron vs 50% for palonosetron) [13]. Themore rapid metabolism of ondansetron results ina much shorter duration of antiemetic action,with a half-life of approximately 4 h, comparedwith approximately 40 h for palonosetron [13].Both compounds have large volumes of distribu-tion (2.35 l/kg vs 8.35 l/kg for ondansetron andpalonosetron, respectively) and distribute intoerythrocytes. Neither agent is extensively boundto plasma protein (ondansetron �75% bound,palonosetron �62% bound) [13]. Ondansetronand palonosetron are eliminated mainly in urine,with about 5% of ondansetron excreted un-changed compared with approximately 40% ofpalonosetron excreted unchanged.

Table 3. Urinary metabolic excretion (mean� SD) after asingle 10 mg/kg i.v. dose of [14C]-palonosetron

Percent urinary excretion ofdose over 0–144 h

Analyte Males Females All subjectsðn ¼ 3Þ ðn ¼ 3Þ ðn ¼ 6Þ

Total radioactivity 77.8� 5.9 81.1� 6.9 79.5� 6.0Palonosetron 41.8� 14.0 36.8� 5.0 39.3� 1.6Metabolite M9 11.2� 6.5 13.8� 2.1 12.5� 0.5Metabolite M4 10.2� 4.1 11.6� 1.6 10.9� 0.7Other metabolites 14.6� 6.1 18.9� 3.1 16.8� 0.7

SD, standard deviation; i.v., intravenous.

Figure 4. Metabolic pathways of palonosetron in humans. Bold arrows indicate major pathways.


R. STOLTZ ET AL.336

A similar study of the metabolism of single-dose, oral dolasetron ([14C]-dolasetron 300 mg) insix male subjects reported that 60% of the totalradioactivity was recovered in urine and 25% infeces [14]. Metabolites were quantified in urinesamples for up to 36 h postdose. In urine,reduced dolasetron accounted for 17%–54% andhydroxylated metabolites accounted for 9% ofthe administered dose. Most of the remainingurinary radioactivity consisted of conjugatedmetabolites of reduced dolasetron and hydroxy-reduced dolasetron. The glucuronide of reduceddolasetron was the most abundant conjugatein urine; only a small percentage (51%)was identified as the N-oxide of reduced dola-setron [14].

Palonosetron has the longest half-life com-pared with other available 5-HT3 receptorantagonists [9]. Intravenous doses of ondanse-tron, granisetron and hydrodolasetron producedhalf-lives of 4–6 h, 5–8 h and 7 h, respectively [13,15,16]. Because palonosetron has low plasmaprotein binding and is both renally and hepati-cally eliminated, there is a low potential fordrug–drug interactions. Clinical advantages ofpalonosetron may result from stronger bindingaffinity, sustained plasma concentration profiles,and a substantially longer half-life (�40 h)compared with other 5-HT3 antagonists.

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