C. AIMONI

D. PASSALI

G. DERRICO

M.I. CASSETTA

MOTTA G

S. ESPOSITO

S. FALLANI

S. NOVIELLO

S. PILUCCHI

T. MAZZEI AND A. NOVELLI

M. I. CASSETTA

MOTTA, Gaetano

Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli"

Journal of Antimicrobial Chemotherapy (2006) 57, 789–792doi:10.1093/jac/dkl050Advance Access publication 27 February 2006Concentration of moxifloxacin in plasma and tonsillar tissue aftermultiple administration in adult patientsSilvano Esposito1*, Silvana Noviello1, Gioacchino D’Errico2, Gaetano Motta2,Desiderio Passali3, Claudia Aimoni4, Stefano Pilucchi4, Stefania Fallani5,Maria Iris Cassetta5, Teresita Mazzei5 and Andrea Novelli51Dipartimento di Malattie Infettive, Seconda Università di Napoli, Italy; 2Dipartimento di Otorinolaringoiatria,Seconda Università di Napoli, Italy; 3Clinica Otorinolaringoiatrica, Università degli Studi di Siena, Italy;4Dipartimento di Discipline Medico Chirurgiche della Comunicazione e del Comportamento, Sez. ORL,Università degli Studi di Ferrara, Italy; 5Istituto di Farmacologia Preclinica e Clinica,Università di Firenze, ItalyReceived 2 March 2005; returned 20 May 2005; revised 9 September 2005; accepted 7 February 2006Objectives:Theantibacterial spectrumofmoxifloxacin includesall themajor respiratorypathogens,and itspharmacokinetics demonstrate high peak concentrations in plasma as well as at respiratory sites.Nevertheless, tonsillar tissue concentrations have never been investigated. In this study we determinedthe moxifloxacin concentrations in plasma and tonsillar tissue after the administration of three doses ofmoxifloxacin 400 mg to adult patients with chronic or recurrent tonsillitis undergoing tonsillectomy.Methods: This was an uncontrolled, open-label, randomized, parallel group study including 35 patientsassigned randomly to five groups of 7 patients each, depending on the time between the last dose ofmoxifloxacin and plasma and tissue sampling. Moxifloxacin was given orally once daily for 3 days; itsconcentrationsweremeasuredusingavalidatedHPLCassayandfluorescencedetection.Eachsamplewasanalysed twice and the mean value obtained used for the statistical analysis. Pharmacokinetic data wereanalysedbypresentingdescriptivestatisticsofmoxifloxacinconcentrations inplasmaand tonsillar tissue.Results:Cmaxoccurredat 3h in tonsillar tissue (mean8.96mg/L) and inplasma (mean3.20mg/L), the tissue/plasma concentration ratios (mean values) being constantly >2, ranging between 2.37 (after 2 h) and 2.93(after 24 h), which indicates a prolonged maintenance of moxifloxacin concentration in tonsillar tissuecompared with plasma. Variability among patients was present at 6 h, with the tonsillar tissue/plasmaconcentration ratio ranging between 0.8 and 3.4.Conclusions:Moxifloxacinachievesagoodpenetration in tonsillar tissue,whichcompares favourablywiththat reported forother fluoroquinolones.ThemoxifloxacinconcentrationsweobservedexceedtheMICsforthe usual respiratory tract pathogens.Keywords: pharmacokinetics, fluoroquinolones, otorhinolaryngologyIntroductionThe primary objective of this study was to assess moxifloxacinconcentrations in tonsillar tissue in comparison with thosein plasma up to 24 h after three oral doses of 400 mg toadult patients with chronic or recurrent tonsillitis undergoingtonsillectomy.Patients and methodsThis was an uncontrolled, open-label, randomized, parallel groupmulticentre study. The study protocol and the informed consentform were approved by an appropriate ethics committee.A total of 35 patients undergoing tonsillectomy, meeting theinclusion/exclusion criteria, were randomly assigned to five groups.............................................................................................................................................................................................................................................................................................................................................................................................................................*Correspondence address. Clinica Malattie Infettive, Ospedale Gesù e Maria, Seconda Università degli Studi di Napoli, Via D. Cotugno 1,80135 Napoli, Italy. Tel: +39-081-5666218; Fax: +39-081-5666203; E-mail: silvanoesposito@libero.it.............................................................................................................................................................................................................................................................................................................................................................................................................................789 The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.For Permissions, please e-mail: journals.permissions@oxfordjournals.org at BIBLIOTECA CENTRALIZZATA S. ANDREA DELLE DAME on December 2, 2016http://jac.oxfordjournals.org/Downloaded from (7 patients in each group), depending on the time between the lastdose of moxifloxacin and the time of tissue sampling: group A, 2 h –30 min; group B, 3 h – 30 min; group C, 6 – 1 h; group D, 12 – 2 h;group E, 24 – 3 h. The inclusion criteria were as follows: patients ofboth sexes between 18 and 65 years of age, body weight 40–85 kg,and patients willing and able to provide their informed consent. Theexclusion criteria were as follows: hypersensitivity to quinolonederivatives, pregnancy or lactation, history of tendinopathy associ-ated with fluoroquinolone therapy, syndromes of QTc prolongation,renal or hepatic impairment, concomitant therapy with antacids andsucralfate, and history of convulsions.Eligible patients were randomized to one of the groups (2, 3, 6, 12and 24 h) and instructed to take the study drug prior to surgery at atime dependent on the group to which they were assigned.Moxifloxacin 400 mg was administered orally, as perioperativeprophylaxis, once daily for 3 days, at the same time each day, withwater, before or with food. The real time of initiation of treatmentdepended on the study group to which the patient was assigned.Moxifloxacin was supplied by Bayer S.p.A. as 400 mg film-coated tablets, packaged in bottles labelled with the study number,batch number, expiry date and a statement indicating that it was aninvestigational drug.Patients were randomized according to a predefined block ran-domization list generated at Bayer Vital (Germany).For the samples, 5 mL of venous blood was collected in 5 mLammonium lithium tubes, cooled (4C) and centrifuged for 5 min at5000 g within 2 h from collection. Plasma was pipetted into appro-priately labelled polypropylene sample tubes and stored at –80Cuntil the time of the HPLC analysis, which was performed within2 months.Tonsillar tissue samples, removed during surgery from one tonsil,were rinsed with sterile saline solution and frozen in sealed stopperedglass tubes at –80C until the time of the analysis, which was per-formed within 2 months.The plasma and tonsillar tissue concentrations of moxifloxacinwere determined using a validated HPLC assay and fluorescencedetection.1–3After addition of 10 mL of internal standard (ofloxacin) to 0.25 mLof plasma, 0.25 mL of acetonitrile was added. Plasma proteins wereprecipitated by shaking in an ultrasonic bath (Eurosonic 22), fol-lowed by centrifugation for 10 min at 1500 g (Labofuge 6000,Hereus Christ). The supernatant was then filtered on filter paper,diluted 3-fold with 0.067 M disodium hydrogen phosphate buffer(pH 7.5) and injected onto the column (50 mL). Every sample wasextracted and tested twice. A 15% difference between the two ana-lyses of each sample was regarded as the threshold for repeating theanalysis of the same sample.Tissue specimens were weighed, diluted in sterile normal saline(1:1, w/v), homogenized at 4C (Polytron PT 10-35 Homogenizer,Kinematica, Lucerne, Switzerland) and centrifuged at 1200 g for10 min, and the supernatant was stored at –80C until the HPLCanalysis. The supernatant was then processed in the same manner asplasma samples.3,4The calibration curve was plotted by spiking blank plasma intoaqueous phosphate buffer (pH 7.5) with nine different concentrationsin the range 5–1500 mg/L.Quality control (QC) samples were prepared at three concentra-tions, covering the whole range expected for the unknown samples.QC samples were stored together with samples of the respectivestudy at –80C. Two replicates of each QC sample were analysedtogether with calibration and unknown samples in the same analyt-ical sequence. Calibration samples were freshly prepared prior toeach sequence.An HPLC model 2700 instrument (Bio-Rad) equipped with afluorescence detector Series 200 FL Detector (Perkin Elmer) wasused. The fluorescence detection was performed at an excitationwavelength of 296 nm and an emission wavelength of 504 nm forall samples. The sampler temperature was kept at 8C. A Nucleosil100 C18 (5 mm particle size, 250 · 4.6 mm I.D.; Alltech, Lokeren,Belgium) capillary column preceded by a guard column (NovaPak C18) was used for separation. The column was set at roomtemperature.The mobile phase consisted of a solution of tetrabutylammoniumhydrogensulphate (Sigma) (pH 3.0) in Milli-Q Plus water (10 g/L)(Millipore) with a gradient from 60% (0 min) to 0% within 7 min(pump A) and tetrabutylammonium hydrogensulphate andacetonitrile (Merck) 50:50 with a gradient from 40% (0 min) to100% within 7 min (pump B) and a flow rate of 1.0 mL/min.Moxifloxacin and the internal standard were eluted at 7 and4 min, respectively.Validation was performed according to the guidelines for devel-opment of bioanalytical assays in human biomatrices.3Pharmacokinetic data were analysed by presenting descriptivestatistics of plasma and tonsillar concentrations. Statistics were arith-metic mean, standard deviation, minimum value, maximum valueand number of measurements.The ratio between tonsillar and plasma concentration was com-puted for each patient and was analysed descriptively.ResultsPatient enrolment was started on 16 November 2001, and the lastvisit was on 9 May 2002. A total of 35 patients were randomizedfrom three centres (7 patients in each group): 33 (94%) completedthe study and 2 (6%) terminated prematurely, one for adverseevent and one for protocol violation.Four more patients were excluded from the per protocol ana-lysis for the following reasons: serum alanine transaminase andaspartate transaminase values outside the range of acceptance forincluding patients in the study (one patient); collection time ofkinetic samples outside the planned window (one patient); andinadequate tonsil sample (two patients). In the end, 29 patientswere included in the per protocol analysis.Demographic and baseline characteristics appeared to be wellbalanced among time groups (Table 1).Results in terms of concentration in plasma and in tonsillartissue and the tissue/plasma concentration ratio are reported inTable 2.All the collection times showed higher mean tissue con-centrations of moxifloxacin than plasma mean concentrations. Themean ratio was on average always >2 (range: 2.37–2.93). A peakin the ratio mean was evident corresponding to the third hour, theestimated peak for both plasma and tissue concentration curves.DiscussionThis was a non-controlled, open-label, randomized, parallel groupmulticentre trial, primarily aimed at assessing the moxifloxacinconcentrations in tonsillar tissue in comparison with those ofplasma up to 24 h after three oral doses of 400 mg, performedin adult patients with chronic or recurrent tonsillitis undergoingtonsillectomy.As far as the tissue/plasma concentration ratio is concerned,the results were fully consistent with data previously obtained inEsposito et al.790 at BIBLIOTECA CENTRALIZZATA S. ANDREA DELLE DAME on December 2, 2016http://jac.oxfordjournals.org/Downloaded from other tissues of the respiratory system.4,5 In particular, tissueconcentrations were on average 2- or 3-fold higher than plasmaconcentrations.The time profile in tissue seemed to be very similar to that inplasma. In particular, the peak concentration in the tissueoccurred at the same time (hour 3) as in the plasma, with aratio of 3 (2.89) in favour of the tissue mean.After hour 3, the ratio seemed to increase, starting linearlyfrom a value similar to that of hour 2, indicating a prolongedmaintenance of moxifloxacin concentrations in the tissue com-pared with the plasma. However, a large variability amongpatients was present at hour 6, where the ratio ranged between0.8 and 3.4. For the other collection times, the ratio was between1.6 and 3.6.The tissue concentration at 24 h was >1 mg/L in all patients.These concentrations, for a period of 12–24 h followingadministration, were more than 10-fold higher than the MIC90values for a wide range of causative microorganisms, includingatypical pathogens.6Thus, moxifloxacin achieves a good penetration in tonsillartissue, which compares favourably with the following tonsil/plasma mean concentration ratios reported for other fluoroquino-lones: 1.5–1.9 for ciprofloxacin, from 1 to 8 h after oral orintravenous doses of 200–500 mg; 2.02–2.08 for levofloxacin,from 1 to 9 h after single oral doses of 100 or 200 mg; and 1.4 forofloxacin, 2 h after a single administration of an oral 200 mgdose.7,8Taking into account the failure of penicillin to penetrate thetonsillar tissue, the possible internalization of Streptococcuspyogenes in the tonsillar crypts, the increasing macrolide resist-ance among streptococcal strains and the changing epidemiologyof pharyngotonsillitis aetiology, now including Chlamydia pneu-moniae and Mycoplasma pneumoniae, the results of our studyshowing a high tonsillar concentration of moxifloxacin appear, inour opinion, of some interest.9,10Transparency declarationsNone to declare.References1. Stass H, Dalhoff A. Determination of BAY 12-8039, a new 8-methoxyquinolone, in human body fluids by high-performance liquidchromatography with fluorescence detection using on-column focusing.J Chromatogr B Biomed Sci Appl 1997; 702: 163–74.2. Stass H, Dalhoff A, Kubitza D et al. Pharmacokinetics, safety, andtolerability of ascending single doses of moxifloxacin, a new 8-methoxyquinolone, administered to healthy subjects. Antimicrob AgentsChemother 1998; 42: 2060–5.Table 1. Demographic and baseline characteristics (population meeting criteria for per protocol analysis)2 h 3 h 6 h 12 h 24 h TotalSexmale 3 5 3 3 2 16female 2 1 4 2 4 13Age, yearsmean (SD) 25.6 (5.5) 27.2 (5.7) 26.3 (7.5) 25.5 (2.8) 29.4 (14.4) 26.8 (7.9)min–max 20–34 19–34 18–40 21–29 19–58 18–58Weight, kgmean (SD) 66.4 (10.5) 67.8 (13.3) 71.9 (12.3) 66.4 (11.4) 66.5 (10.3) 68.0 (11.1)min–max 55–80 50–88 54–85 56–82 58–82 50–88BMImean (SD) 21.4 (2.2) 23.1 (3.1) 25.9 (5.7) 21.1 (2.7) 23.8 (2.0) 23.3 (3.8)min–max 18.6–23.9 20.8–28.4 20.3–34.5 18.5–24.0 20.8–26.9 18.5–34.5BMI, body mass index.Table 2. Plasma and tonsillar tissue concentrations (mg/L) and tissue/plasma concentration ratio (population meeting criteria for perprotocol analysis)2 h – 30 min 3 h – 30 min 6 – 1 h 12 – 2 h 24 – 3 hPlasma, mg/Lmean (SD) 2.67 (1.26) 3.20 (0.86) 2.49 (1.24) 1.68 (0.20) 0.68 (0.26)min–max 0.4–3.4 2.0–4.3 0.3–3.9 1.4–2.0 0.5–1.2Tissue, mg/Lmean (SD) 6.06 (2.86) 8.96 (1.47) 5.44 (3.16) 4.27 (1.01) 1.97 (0.68)min-max 1.3–8.9 6.4–10.8 0.9–10.8 2.9–5.7 1.4–3.3Ratio tissue:plasmamean (SD) 2.37 (0.36) 2.89 (0.50) 2.41 (0.80) 2.56 (0.56) 2.93 (0.27)min–max 2.0–2.8 2.3–3.6 0.8–3.4 1.6–3.0 2.5–3.3Plasma and tonsil pharmacokinetics of moxifloxacin791 at BIBLIOTECA CENTRALIZZATA S. ANDREA DELLE DAME on December 2, 2016http://jac.oxfordjournals.org/Downloaded from 3. Wirtz M, Kleeff J, Swoboda S et al. Moxifloxacin penetration intohuman gastrointestinal tissues. J Antimicrob Chemother 2004; 5: 875–7.4. Breilh D, Jougon J, Djabarouti S et al. Diffusion of oral and intra-venous 400 mg once-daily moxifloxacin into lung tissue at pharmaco-kinetic steady-state. J Chemother 2003; 15: 558–62.5. Dinis PB,MonteiroMC,MartinsML et al.Sinus tissue concentrationof moxifloxacin after a single oral dose. Ann Otol Rhinol Laryngol 2004;113: 142–6.6. Blondeau JM. A review of the comparative in-vitro activities of 12antimicrobial agents, with a focus on five new ‘respiratory quinolones’.J Antimicrob Chemother 1999; 43 Suppl B: 1–11.7. Falser N, Dalhoff A, Wenta H. Ciprofloxacin concentrations intonsils following single or multiple administrations. Infection 1998; 16Suppl 1: 14–8.8. Fish DN, Chow AT. The clinical pharmacokinetics of levofloxacin.Clin Pharmacokinet 1997; 32, 101–19.9. Neeman R, Keller N, Barzilai A et al. Prevalence of internalisation-associated gene, prtF1, among persisting group-A streptococcus strainsisolated from asymptomatic carriers. Lancet 1998; 352: 1974–7.10. Novielllo S, Ianniello F, Esposito S et al. In vitro susceptibility ofdifferent erythromycin-resistant phenotypes of Streptococcus pyogenesto moxifloxacin and other fluoroquinolones. Infez Med 2000; 1: 34–8.Esposito et al.792 at BIBLIOTECA CENTRALIZZATA S. ANDREA DELLE DAME on December 2, 2016http://jac.oxfordjournals.org/Downloaded from 

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Concentration of moxifloxacin in plasma and tonsillar tissue after multiple administration in adult patients

Concentration of moxifloxacin in plasma and tonsillar tissue after multiple administration in adult patients

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