The pharmacokinetics of subcutaneously injected bimosiamose disodium in healthy male volunteers

BIOPHARMACEUTICS & DRUG DISPOSITIONBiopharm. Drug Dispos. 28: 475–484 (2007)

Published online in Wiley InterScience

(www.interscience.wiley.com) DOI: 10.1002/bdd.574

The Pharmacokinetics of Subcutaneously InjectedBimosiamose Disodium in Healthy Male Volunteers

Michael Meyera,*, Diana Beyera, Karin Vollhardta, Christiane Woischwilla, Bernd Jilmab and Gerhard Wolffa

a Revotar Biopharmaceuticals AG, Neuendorfstr. 24a, D-16761 Hennigsdorf, Germanyb Department of Clinical Pharmacology, Medical University of Vienna, Waehringerguertel 18-20, A-1090 Wien, Austria

ABSTRACT: Bimosiamose is a novel synthetic pan-selectin antagonist developed for the treatmentof acute and chronic inflammatory disorders. Therefore the pharmacokinetics of Bimosiamosedisodium were studied in healthy male volunteers after single and multiple subcutaneousinjections. A randomized, double-blind, placebo-controlled dose escalation trial was carried out.The subjects received subcutaneous injections of placebo or 100, 200 or 300 mg Bimosiamosedisodium into the abdomen. Plasma and urine concentrations of Bimosiamose were determined.The maximum plasma concentration was 2.17� 0.70 mg/ml and the AUC0-1 11.1� 2.9 hmg/mlafter the highest dose on day 1 (mean� SD). For the apparent clearance CL/f 28.7� 7.3 l/h and theterminal half life t1/2 3.7� 0.6 h were calculated. The mean residence time MRT1 of 5.5 to 6.3 h fors.c. injection exceeded that after i.v. infusion due to an extended absorption time. For multipledosing, constant pre-dose concentrations of about 20 ng/ml may be reached after two subsequentdoses of 200 or 300 mg Bimosiamose disodium once daily. Almost 15% of the administered drugwas excreted unchanged in urine. Moreover, Bimosiamose was well tolerated. Copyright # 2007John Wiley & Sons, Ltd.

Key words: selectin; Bimosiamose; pharmacokinetics; inflammation

Introduction

The pan-selectin antagonist Bimosiamose [1] isthe most advanced synthetic selectin antagonistin clinical development [2]. It targets the selectinfamily of cell adhesion molecules which consistsof three structurally related calcium-dependentcarbohydrate binding proteins, E-, P- and L-selectin. The selectins mediate the initial rollingor ‘tethering’ of leukocytes on the vascularendothelium following inflammation or injuryin most mammalian vascular systems. As theprocess of leukocyte rolling is generally consid-ered to be the primary event in the inflammatory

response, selectins constitute a target for ther-apeutic intervention in the modulation of inflam-mation [3–8].

The disodium salt of Bimosiamose has beenshown to be effective in human proof-of-conceptstudies in asthma after inhalation and in psor-iasis after subcutaneous (s.c.) injection [9,10].Further, Bimosiamose has been used as atemplate for ligand-based design of novel selec-tin antagonists [11].

The tolerability and pharmacokinetics of Bi-mosiamose disodium after intravenous (i.v.)administration to healthy males and after inhala-tion have been described recently showing a highplasma concentration of Bimosiamose only dur-ing a short time after i.v. infusion [12,13].However, for the treatment of moderate to severeconditions of chronic diseases such as psoriasis,

*Correspondence to: Revotar Biopharmaceuticals AG, Neuen-dorfstr. 24a, D-16761 Hennigsdorf, Germany. E-mail: [email protected]

Received 23 February 2007Revised 23 May 2007

Accepted 12 June 2007Copyright # 2007 John Wiley & Sons, Ltd.

a longer residence time and smaller fluctuationsof the plasma concentration without high peaksare desirable. As the oral bioavailability is low,s.c. injection may be a way to circumvent theselimitations.

Further it is intended to use Bimosiamosedisodium also for the treatment of psoriasis bys.c. injection into uninvolved skin. Therefore itwas the primary aim of this study to determinereliable pharmacokinetic data after single andmultiple s.c. doses in healthy subjects. Thesecondary objective was to assess the safety andtolerability of Bimosiamose disodium after s.c.injection in healthy male subjects.

Materials and Methods

Trial medication

A sterile, transparent colorless to light beigesolution of Bimosiamose disodium was used fors.c. injection into the abdomen. The low solubilityof Bimosiamose in water has required thepresence of the disodium salt form. The adminis-tered formulation contained 100 mg/ml Bimosia-mose disodium in a citrate buffer system. A 0.9%sodium chloride solution with citrate buffer wasused as placebo.

Study design

The study was carried out according to theDeclaration of Helsinki, revised version ofWashington, 2002, and in accordance with locallaw and the requirements of Good ClinicalPractice. Each subject was informed of the natureand risk associated with the study and agreed inwriting to participate before entry into the study.Protocols were reviewed and approved by theindependent Ethics Review Committee of theLandesarztekammer Brandenburg.

The study was designed as a randomized,placebo-controlled, double-blind dose escalationtrial in 24 healthy male subjects. In each treat-ment group, eight subjects were included withsix subjects receiving the active drug and tworeceiving placebo. The study included a screen-ing phase of up to 20 days, an experimentalphase consisting of 10 days, with dosing on days

1 and 3–7 for each dosing group, and a follow-upexamination 7–9 days after the last dosing. Ineach dosing group, the subjects stayed in thestudy unit from the morning of the day beforethe first dose until 48 h after the final dose.

On the pharmacokinetic days (days 1 and 7),no breakfast was given. A standardized lunchwas served 4 h after dosing. Standardized snackand dinner on pharmacokinetic days and mealson all other days were given at customary times.During days 1 and 2, subjects should not drinkmore than 1.5–2 l non-sparkling water per day.Before proceeding to the next dose step, safetydata of the previous dose and the pharmacoki-netic data were reviewed. None of the subjectswas allowed to enter the study twice.

Inclusion and exclusion criteria

Subjects meeting all of the following criteria wereconsidered for enrolment to the study: Healthymale subjects; aged between 18 and 45 years; BMI18–27 kg/m2; normal findings in the medicalhistory, physical examination, laboratory values,urinalysis, 12-lead ECG, blood pressure andpulse rate; negative alcohol urine test and drugscreen; signed informed consent.

Subjects presenting any of the following wereexcluded from the study: history of significantallergic diseases; any condition requiring theregular use of any medication; exposure to anymedication 14 days prior to allocation (exceptparacetamol); exposure to prescription medica-tions or to drugs known to interfere with themetabolism of drugs within 30 days prior toallocation; participation in another study withany investigational drug in the 3 months preced-ing the study; treatment in the previous 3 monthswith any drug known to have a well definedpotential for toxicity to a major organ; symptomsof a clinically significant illness in the 3 monthsbefore the study; blood or plasma donation ofmore than 500 ml during the previous monthbefore allocation and more than 50 ml in the 2weeks before allocation; smoking during theprevious 3 months; positive test for HIV1/2 orhepatitis B or C; current evidence of alcohol ordrug abuse or history of drug abuse within 1 yearof allocation; intolerance to the proposed fastingand study diet or possible lack of compliance;

M. MEYER ET AL.476

Copyright # 2007 John Wiley & Sons, Ltd. Biopharm. Drug Dispos. 28: 475–484 (2007)DOI: 10.1002/bdd

mental condition rendering the subject incapableto understand the scope and possible conse-quences of the study; unlikely to comply with theclinical study protocol; staff or relative thereofdirectly involved in the conduct of the study.

Blood and urine sampling

For the baseline level, control blood was sampledfrom all subjects before the first treatment onstudy day 1. Blood sampling on days 1–3: pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 30,36 and 48 h post-dose, on days 5 and 6: pre-dose(trough values) and on days 7–9: pre-dose and0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 30, 36 and48 h post-dose. All blood samples were collectedin heparinized tubes. After centrifugation plasmaaliquots were made and stored at �808C.

Urine collection was done on days 1 and 7 asfollows: pre-dose, 0-4, 4-8, 8–12 h and 12–24 hcollection periods. From each urine collectioninterval, a sample of 20 ml was taken and dividedinto two aliquots. Urine samples were frozenat �808.

Analytical Methods

Liquid chromatography electrospray mass spec-trometry analysis

A validated LC-ESI-MSMS assay was used todetermine the concentrations of Bimosiamose inhuman plasma samples. Analyses were per-formed using a Finnigan LCQ Advantage massspectrometer interfaced with a Finnigan Sur-veyor HPLC system. Samples were loaded onto aMercury MS, Synergy HydroRP, 20� 2 mm, 2 mm,80 A column (Phenomenex), preceded by asecurity guard. Chromatography was performedat 258C using a gradient system composed of0.1% formic acid (mobile phase A) and acetoni-trile with 0.1% formic acid (mobile phase B) at aflow rate of 250 ml/min. The injection volumewas 25 ml. Negative ionization was performedwith a capillary temperature at 3008C. Normal-ized collision energy for the analyte Bimosiamoseand the internal standard [20-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-bi-phenyl-3-yloxy]-acetic acid was 52%. The spray

voltage was 4.5 kV. The molecular ions weremeasured by selected ion monitoring (SIM) at m/z 861.5! 449.5 for Bimosiamose and m/z405.0! 243.1 for the internal standard.

Linearity of the plasma assay was determinedby spiking samples of human plasma withknown amounts of Bimosiamose and a fixedamount of internal standard. 300 ml methanolcontaining the fixed amount of internal standardwas added to each sample following vortexingand centrifugation at 16 060� g and 48C for10 min. The supernatants were removed andanalysed. A calibration line was constructed ofthe Bimosiamose: internal standard responseratio plotted against the nominal plasma sampleconcentration of Bimosiamose.

For analysis of urine samples, linearity wasdetermined by analysis of standard solutions(H2O/methanol 1:1, v/v) with known amountsof Bimosiamose and a fixed amount of internalstandard. A calibration line was constructed ofthe Bimosiamose: internal standard responseratio plotted against the nominal sample con-centration of Bimosiamose.

Linear least square regression was performedin both cases using a weighting factor of 1/x.Values of slope and y-intercept were used tocalculate the Bimosiamose concentration in studyplasma or urine samples.

For human plasma, the improved limit ofquantification (LOQ) was 2.5 ng/ml. The assaywas validated over the range of 2.5–1250 ng/ml.Accuracy and precision for the LOQ were 117.4%and 18.0%. The limit of detection (LOD) was0.625 ng/ml (the lowest analysed sample) [13].For human urine, the improved LOQ was 2.5 ng/ml. The assay was validated over the range of2.25–2250 ng/ml.

Plasma samples

The principle of the analytical procedure is theextraction of Bimosiamose from plasma samplesby the addition of methanol followed by vortex-ing and centrifugation. To 50 ml of each plasmasample 150 ml MeOH containing 133.3 mg/mlinternal standard was added. Samples werevortex mixed for precipitation of proteins andcentrifuged at 16 060� g at 48C for 10 min. Thenthe supernatants were analysed by LC/MSMS.

PHARMACOKINETICS OF BIMOSIAMOSE DISODIUM 477


Urine samples

The principle of the analytical procedure isextraction and purification of Bimosiamose fromhuman urine by solid phase extraction. To 550 mlof each human urine sample 550 ml of 4% formicacid was added and the samples were vortexed.Samples were purified with Oasis1 HLB 1 cc(10 mg) 96-well extraction plates from WatersGmbH, solid phase extraction was performedas follows: Condition: 1 ml MeOH; equilibration:1 ml H2O; loading: 1 ml acidified sample;washing: 1 ml 50% MeOH; elute: 500 mlMeOH containing 0.2% formic acid. After solidphase extraction the solvents were flushed usinga vacuum manifold from Millipore GmbH.Eluates were collected in 96-deep-well plates.To 100 ml of eluate, 80 ml H2O and 20 ml internalstandard (1 mg/ml) were added before LC/MSMS analysis. Samples were analysed intriplicates.

Pharmacokinetic Data Analysis

All pharmacokinetic data were evaluatedusing noncompartmental models as implemen-ted in WinNonlin version 5.01 [14]. The plasmaconcentrations were analysed using an extravas-cular model for single doses and for steadystate (WinNonlin model 200), the urine concen-trations of Bimosiamose were analysed using amodel for extravascular administration (Win-Nonlin model 210). For the analysis of urinedata, concentrations of Bimosiamose below the

limit of quantification were set to LOQ/2. Alldata are presented as mean � standard devia-tion (SD).

Results

Subjects

Twenty-four Caucasian male volunteers wereenrolled in the study in which six subjects wererandomized for each dosing group of 100, 200 and300 mg Bimosiamose disodium and two subjectsreceived placebo, corresponding to the particulardosing group, respectively. The mean age (� SD)per dose group ranged from 33 (� 8) years(100 mg Bimosiamose disodium) to 39 (� 5) years(placebo). The mean height per dose group rangedfrom 178 (� 9) cm (placebo) to 182 (� 6) cm(300 mg Bimosiamose disodium). The meanweight ranged from 75 (� 8) kg (100 mg Bimo-siamose disodium) to 80 (� 10) kg (placebo).

Tolerability

All enrolled subjects completed the study. Therewere no serious adverse events among partici-pants in the trial. One half of the subjects showedadverse events after placebo treatment, 66.7%after treatment with 100 mg and 33.3% aftertreatment with 200 mg Bimosiamose disodium.No adverse event occurred in the group treatedwith the highest dose of 300 mg Bimosiamosedisodium. All adverse events were of mild(placebo: n ¼ 3, 100 mg Bimosiamose disodium:n ¼ 5, 200 and 300 mg Bimosiamose disodium:

Table 1. Summary of adverse events

Subject ID Dose (mg) Intensity Causality Adverse event

100 100 Mild Unlikely Flatulence102 Placeboa Mild Possible Headache103 100 Mild Unlikely Flatulence103 100 Mild Not related Hemorrhage at injection site104 100 Mild Not related Skin irritation at electrode sites105 Placeboa Mild Unlikely Flatulence106 100 Mild Unlikely Flatulence204 200 Moderate Not related Headache205 200 Moderate Not related Post injection collapse208 Placebob Mild Unlikely Common cold

a In 100 mg group.b In 200 mg group.

M. MEYER ET AL.478


n ¼ 0) or moderate intensity (placebo: n ¼ 0,200 mg Bimosiamose disodium: n ¼ 2, 100 and300 mg Bimosiamose disodium: n ¼ 0). The re-lationship between the adverse events andBimosiamose disodium was considered as un-likely or not related. All adverse events aresummarized in Table 1. The adverse events for

placebo administration occurred in those subjectsassigned to the 100 mg dosing groups.

Plasma pharmacokinetics

Mean plasma concentration profiles of Bimosia-mose are shown in Figure 1. Plasma concentrations

Figure 1. Mean plasma concentrations on day 1 and 7. Standard deviations are indicated by error bars



of Bimosiamose above LOQ were found for alldosing groups 0.5 h post dosing, i.e. in the firstsample that was taken. The last plasma concen-tration above LOQ was found between 16.7 and29.0 h post-dose (mean values) for day 1 and day7, respectively. A broad range for the time toreach the maximum plasma concentration wasfound within each dosing group. The time tmax toreach the maximum plasma concentration ran-ged from 0.8 to 1.4 h. The maximum plasmaconcentrations increased with increasing doses.A doubling of the dose from 100 to 200 mg led toapproximately double plasma concentrations,but the triple dose of 300 mg led only to anincrease of the plasma concentration by a factorof about 2.3 (Figure 2).

The dose normalized maximum plasma concen-trations Cmax/D (9.6� 10�3� 3.5� 10�3, 9.4�10�3� 1.3� 10�3 and 7.2� 10�3� 2.3� 10�3l�1)for 100, 200 and 300 mg Bimosiamose disodiumon day 1, were somewhat higher than on day 7(7.4� 10�3� 5.5� 10�3, 6.9� 10�3� 1.8� 10�3

and 5.6� 10�3� 1.6� 10�3 l�1). For the dosenormalized area under the curve AUC0-1/D rathersimilar results were found for day 1 (0.049� 0.009,0.040� 0.006 and 0.037� 0.010 h/l) and day 7(0.037� 0.014, 0.044� 0.009 and 0.036� 0.007 h/l).The standard deviations of Cmax/D and AUC0-1/Dwere quite high when compared with the change of

these pharmacokinetic parameters with respectto the dose or day (Figure 3). This hampered adetailed analysis of the dose dependency. Qua-litatively, Cmax/D tended to decrease somewhatwith dose on both days, the dose dependency ofAUC0-1/D appeared to be less clear.

As the fraction of the dose systemicallyavailable after s.c. administration is unknown,the apparent clearance CL/f was calculatedinstead of the total clearance. On day 1 CL/franged from 20.7 to 28.7 l/h for the differentdoses (Table 2a). For the terminal half life a rangefrom 3.7 to 3.9 h was found, whereas a meanresidence time MRT1 between 5.5 and 5.8 h wasdetermined for day 1. The apparent volume ofdistribution in the terminal phase Vz/f rangedfrom 113 to 152 l.

Multiple dosing leads to minor differencesin pharmacokinetic parameters without signifi-cance in most cases. On day 7, the areasunder the curve and the maximum plasmaconcentrations were somewhat smaller thanon day 1. The theoretical accumulation indexRtheor for multiple s.c. injection once daily didnot exceed the value of 1 significantly. Forthe 200 and 300 mg doses trough concentrationsCtrough above LOQ were found pre-dose onday 5, 6 and 7 after multiple dosing (Table 2a,Figure 4).

Figure 2. Maximum plasma concentration of Bimosiamose after subcutaneous injection. Standard deviations are indicated byerror bars

M. MEYER ET AL.480


Urine pharmacokinetics

Mean values for the pharmacokinetic parametersderived from the urine concentrations are listedin Table 2b. For day 1 the mean values of themaximum urine concentration were 6, 17 and52 mg/ml for the doses of 100, 200 and 300 mgBimosiamose disodium. These concentrationsexceed the LOQ by more than three orders ofmagnitude. Due to the sparse sampling adetermination of the first order rate constantassociated with the terminal urine excretioncurve was not possible. For the lowest dose mostpharmacokinetic parameters were ill determined.

Measurable urine concentrations were found ingeneral in the first sample taken in the timeinterval between 0 and 4 h post-dosing, except forthe lowest dose. Therefore, the confidence inter-val of the lag time, the midpoint prior to the firstnon-zero rate included zero, except for the lowestdose. The time of the last mid point correspond-ing to a measurable urine concentration wasbetween 12.7 and 15.3 h for the highest doses.

In the time span from 0 to 24 h between 13.2%and 14.7% of the drug was excreted unchangedin urine after s.c. injections of 200 and 300 mgdoses of Bimosiamose disodium. The amount ofunchanged drug excreted in the urine and theAUC up to 24 h were used to estimate theapparent renal clearance CLR/f ranging from 3.0to 4.0 l/h.

The maximum excretion rate kR,max rangingfrom 4.0 to 6.0 mg/h was observed between 3.3and 6.7 h post dose.

Discussion

Pharmacokinetic parameters were determinedfrom plasma and urine concentrations after s.c.administration of Bimosiamose disodium withdoses of 100, 200 and 300 mg. The time to reachthe maximum plasma concentration after s.c.administration on day 1 (0.8 to 1.3 h) exceededthe corresponding time after single i.v. infusion(0.222 to 0.36 h) of doses from 1 to 30 mg/kg [10].The uncertainty in the estimate of tmax isprobably due to the flat concentration-timeprofile, the lack of tight plasma sampling afters.c. injection and inter-individual variability. Theterminal half life t1/2 after s.c. injection of about3.8 h on day 1 corresponds to the i.v. infusion ofmuch higher doses. After i.v. infusion t1/2

increased with an increasing dose from 2.18 to4.06 h. In particular, the mean residence timeMRT1 of 5.5 to 5.8 h on day 1 was much longerfor s.c. injection than for single i.v. infusion.When the dose increased from 8 to 30 mg/kg,MRT1 increased from 0.53 to 1.81 h for i.v.infusions. These doses are higher than in thepresent s.c. study and therefore a rigorouscomparison of MRT1 is not possible. Never-theless, a crude estimate of the mean absorption

Figure 3. Dose normalized maximum plasma concentrations(top) and areas under the curve (bottom). Standard deviationsare indicated by error bars



time (MAT) of 5 h for s.c. injection appears to bereasonable.

Almost 15% of the s.c. injected drug wasexcreted unchanged in the urine (fe/f) at a

maximum rate of 4 to 6 mg/h found between3.3 and 6.7 h post-dosing. The apparent renalclearance CLR/f of 3.0 to 4.0 l/h is smaller thanthe apparent plasma clearance CL/f ranging from

Table 2. Summary of pharmacokinetic parameters for single and multiple subcutaneous dosing of Bimosiamose disodium.Parameters derived from (a) Bimosiamose plasma concentrations and (b) Bimosiamose urine concentrations

Parameter Day Dose (mg)

100 200 300

(a)AUC0–1 (hmg/ml) 1 4.9� 0.9 9.8� 1.3 11.1� 2.9AUC0–24 (hmg/ml) 1 } 9.6� 1.2 10.9� 2.9AUC0–tz (hmg/ml) 1 5.0� 0.9 9.7� 1.2 11.0� 2.9CL/f (l/h) 1 21.0� 3.9 20.7� 2.6 28.7� 7.3Cmax (mg/ml) 1 0.96� 0.35 1.88� 0.26 2.17� 0.70MRT1 (h) 1 5.5� 1.5 5.8� 1.1 5.8� 1.2t1/2 (h) 1 3.9� 1.3 3.8� 1.0 3.7� 0.6tmax (h) 1 0.9� 1.0 1.3� 0.8 0.8� 0.8tZ (h) 1 21.3� 4.1 28.0� 9.8 27.0� 3.2Vz/f (l) 1 115� 29 113� 29 152� 39AUCt.ss (hmg/ml) 7 3.6� 1.4 8.7� 1.7 10.6� 2.2AUC0–1 (hmg/ml) 7 3.7� 1.4 8.9� 1.9 10.8� 2.2AUC0–tz (hmg/ml) 7 3.5� 1.3 8.8� 1.8 10.7� 2.2CLss/f (l/h) 7 30.7� 10.5 23.8� 4.8 29.4� 6.5Cmax (mg/ml) 7 0.74� 0.55 1.39� 0.37 1.69� 0.48Ctrough (ng/ml) 7 } 18.1� 8.2 24.6� 26.4MRT1 (h) 7 5.6� 1.5 6.0� 1.5 6.3� 1.9Rtheor 7 1.013� 0.010 1.062� 0.115 1.024� 0.025t1/2 (h) 7 3.6� 0.9 5.0� 3.2 4.2� 1.2tmax (h) 7 1.3� 1.4 0.8� 0.5 1.4� 1.5tZ (h) 7 16.7� 3.9 26.7� 7.9 29.0� 5.9Vz/f (l) 7 154� 52 157� 78 181� 69

Dose (mg)

200 300

(b)AURC0–tz (mg) 1 27� 11 39� 21CLR/f (l/h) 1 3.0� 1.2 4.0� 2.1fe/f (%) 1 14.6� 5.4 14.7� 6.6kR.max (mg/h) 1 4.0� 1.3 6.0� 2.3tmid.Z (h) 1 15.3� 4.1 14.7� 5.3tR.max (h) 1 5.3� 3.9 3.3� 2.1AURC0–tz (mg) 7 23� 11 36� 22CLR.ss/f (l/h) 7 3.1�1.4 4.0� 2.5fe/f (%) 7 13.2� 5.4 14.2� 8.2kR.max (mg/h) 7 4.5� 1.8 4.1� 2.0tmid.Z (h) 7 12.7� 4.1 15.3� 4.1tR.max (h) 7 3.3� 2.0 6.7� 4.0

AUC0–1, area under the concentration time curve in the interval from the first dose to infinity; AUC0–tz, area under the concentration time curve in

the interval from the first dose to last observed concentration value above lower limit of quantification; AUCt.ss, area under the concentration time

curve during dosing interval t at steady state; AURC0–tz, area under the urinary excretion rate curve from 0 to the last measurable rate; Cmax,

maximum concentration; Cmin, minimum concentration; CL/f, apparent clearance; CLR/f, apparent renal clearance; f, fraction of dose absorbed; fe/f,fraction of s.c. administered drug excreted into urine; kR.max, maximum renal excretion rate; MRT1, mean residence time extrapolated to infinity;

Rtheor, theoretical accumulation index; tmax, time to maximum plasma concentration; tmid.Z, last midpoint of collection interval with drug

concentration above LOQ; tR.max, midpoint of collection interval associated with maximum excretion rate; tZ, time of last measurable concentration;

t1/2, terminal elimination half life; Vz/f, apparent volume of distribution based on the terminal phase.

M. MEYER ET AL.482


20.7 to 28.7 l/h. These data are consistent with themolecular weight of Bimosiamose (862.93 g/mol)as drugs with a molecular weight below 300 arepredominantly excreted in urine, whereas abiliary excretion is of increasing importance forhigher molecular weights [15]. This suggestion issupported by the observation that Bimosiamoseis subject to only limited metabolic conversion inrats and the excretion of 14C-labelled Bimosia-mose in rat after i.v. infusion suggested thatbiliary elimination appeared to be the main routeof excretion of total radioactivity with about 92%of the dose excreted in faeces and less than 1% inthe urine [16]. Compared with these data, ahigher fraction of Bimosiamose appears to beexcreted in the urine in healthy males than inrats.

Multiple s.c. dosing within the short timerange of 1 week was studied and only minordifferences were found between the parametersdetermined from plasma and urine concentra-tions determined on day 1 and day 7. Multipledosing of Bimosiamose disodium once daily ledto stable trough concentrations after the seconddose of 200 or 300 mg. Nevertheless, extrapola-tion from this study with healthy male volunteersto administration in patients with chronic dis-eases has limitations due to gender, age andmultiple dosing over a long time range.

In summary, a randomized controlled pharma-cokinetic dose escalation trial with sc injectionwas performed in healthy male volunteers usingmultiple doses of 100, 200 and 300 mg Bimosia-mose disodium. The terminal half life rangedfrom 3.6 to 4.96 h, the mean residence time from5.5 to 6.3 h. Almost 15% of the administered drugwas excreted unchanged in the urine. Theconcentration-time profiles indicate minimal ac-cumulation of Bimosiamose after multiple s.c.injections. Trough concentrations of about 20 ng/ml were found for doses of 200 and 300 mgBimosiamose disodium.

Acknowledgements

This project was supported by grants of theMinistry of Economics of the State of Branden-burg and the European Union. Responsibility forthe content of this publication rests upon theauthors.

References

1. Kogan TP, Dupre B, Bui H, et al. Novel synthetic inhibitorsof selectin-mediated cell adhesion: synthesis of 1,6-bis[3-(3-carboxymethylphenyl)-4-(2-alpha-d-mannopyranosyloxy)

Figure 4. Pre-dose plasma concentrations of Bimosiamose after multiple subcutaneous administrations. Standard deviations areindicated by error bars



phenyl] hexane (TBC1269). J Med Chem 1998; 41: 1099–1111. DOI: 10.1021/jm9704917

2. Romano SJ. Selectin antagonists}therapeutic potential inasthma and COPD. Treat Respir Med 2005; 4: 85–94.

3. Kansas GS. Selectins and their ligands: current conceptsand controversies. Blood 1996; 88: 3259–3287.

4. Aydt E, Wolff G. Development of synthetic pan-selectinantagonists: a new treatment strategy for chronic inflam-mation in asthma. Pathobiology 2002; 70: 297–301. DOI:10.1159/000070746

5. Ley K. The role of selectins in inflammation and disease.Trends Mol Med 2003; 9: 263–268. DOI: 10.1016/S1471-4914(03)00071-6

6. Vanderslice P, Biediger RJ, Woodside DG, Berens KL,Holland GW, Dixon RAF. Development of cell adhesionmolecule antagonists as therapeutics for asthma andCOPD. Pulm Pharmacol Ther 2004; 17: 1–10.

7. Bock D, Philipp S, Wolff G. Therapeutic potential ofselectin antagonists in psoriasis. Expert Opin InvestigDrugs 2006; 15: 963–979. DOI: 10.1517/13543784.15.8.963

8. Ley K, Reutershan J. Leucocyte-endothelial interactions inhealth and disease. Handb Exp Pharmacol Pt 2 2006; 176:97–133.

9. Beeh KM, Beier J, Meyer M, Buhl R, Zahlten R, Wolff G.Bimosiamose, an inhaled small-molecule pan-selectinantagonist, attenuates late asthmatic reactions followingallergen challenge in mild asthmatics: a randomized,double-blind, placebo-controlled clinical cross-over-trial.

Pulm Pharmacol Ther 2006; 19: 233–241. DOI: 10.1016/j.pupt.2005.07.004

10. Friedrich M, Bock D, Philipp S, et al. Pan-selectinantagonism improves psoriasis manifestation in miceand man. Arch Dermatol Res 2006; 297: 345–351. DOI:10.1007/s00403-005-0626-0

11. Kranich R, Busemann AS, Bock D, et al. Rational designof novel, potent small molecule pan-selectin anta-gonists. J. Med. Chem. 2007; 50: 1101–1115. DOI: 10.1021/jm060536g

12. Meyer M, Jilma B, Zahlten R, Wolff G. Physiochemicalproperties, safety and pharmacokinetics of Bimosiamosedisodium after intravenous administration. Int J ClinPharmacol Ther 2005; 43: 463–471.

13. Meyer M, Beeh K-M, Beier J, et al. Tolerability andpharmacokinetics of inhaled bimosiamose disodium inhealthy males. Br J Clin Pharmacol 2007; 63: 451–458. DOI:10.1111/j.1365-2125.2006.02775.x

14. WinNonlin version 5.01, Pharsight Corporation, Moun-tain View, California 94040, USA.

15. Gonzalez Lopez F, Martinez Lanao J. Excrecion no renal.In Biofarmacia y Farmacocinetica, Vol. II, Biofarmacia,Domenech Berrozpe J, Martınez Lanao J, Pla Delfina JM(eds). Editorial Sintesis: Madrid, 2000; 577–591.

16. Inveresk Research. The excretion and plasma kinetics of[14C]-TBC1269Z in the rat following intravenous admin-istration. Inveresk Report No 14361. Tranent, EH33 2NE,Scotland, 1996.

M. MEYER ET AL.484


The pharmacokinetics of subcutaneously injected bimosiamose disodium in healthy male volunteers

Documents

Transcript of The pharmacokinetics of subcutaneously injected bimosiamose disodium in healthy male volunteers