Intravitreal, retinal, and central nervous system foscarnet concentrations after rapid intravenous administration to rabbits

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 0066-4804/00/$04.00⫹0Ma . 2000, p. 756–759 Vol. 44, No. 3 Copy igh © 2000, Ame ican Socie y o Mic obiology. All Righ s Rese ed. In a i eal, Re inal, and Cen al Ne ous Sys em Fosca ne Concen a ions a e Rapid In a enous Adminis a ion o Rabbi s LUIS F. LO ´PEZ-CORTE ´S, 1 * R. RUIZ-VALDERAS, 1 M. J. LUCERO-MUN ˜OZ, 2 E. CORDERO, 1 M. T. PASTOR-RAMOS, 3 AND J. MARQUEZ 4 In ec ious Diseases Se ice, 1 Depa men o Oph halmology, 3 and Depa men o Neu osu ge y, 4 Hospi al Uni e si a io Vi gen del Rocı´o, and Pha macy and Pha maceu ical Technology, Facul y o Pha macy, Uni e si y o Se ille, 2 Se ille, Spain Recei ed 22 Ma ch 1999/Re u ned o modi ica ion 16 Oc obe 1999/Accep ed 29 No embe 1999 Re inal, i eous humo , b ain, and ce eb ospinal luid (CSF) osca ne le els we e measu ed by high- pe o mance liquid ch oma og aphy a e adminis a ion o an in a enous dose o 120 mg/kg o body weigh o 32 pigmen ed abbi s. A pha macokine ic analysis was done using a wo-compa men model. The pene a- ion a ios, de ined as a ios o e inal, i eous humo , b ain, and CSF a eas unde he concen a ion- ime cu e om 0 o 2 h we e 110% ⴞ1%, 12.3% ⴞ0.7%, 118% ⴞ1%, and 20.2% ⴞ2.2%, espec i ely. These esul s sugges a good pene a ion o osca ne in o he e inal and b ain issues, eaching highe concen a ions han hose es ima ed om i eous humo and CSF le els. Fosca ne is a d ug used ex ensi ely in he ea men o e ini is and neu ological condi ions caused by cy omegalo i- us (CMV) in pa ien s wi h AIDS, and he e a e da a suppo - ing he use o osca ne wi h aciclo i o ganciclo i in he ea men o e ini is caused by o he he pes i uses (4, 15, 19). I has been sugges ed ha in a enous ganciclo i o osca ne main enance he apy o CMV e ini is may esul in sub he a- peu ic in aocula concen a ions, a ac o implica ed in he p og ession o his disease (1). Howe e , he e a e ew da a on concen a ions o osca ne in issue, and he le els in e ina o b ain ha e no been desc ibed o ei he humans o expe i- men al models. The in aocula pene a ion o osca ne has been assessed only in i eal samples om a ew pa ien s wi h CMV e ini is (1). Likewise, he pene a ion o osca ne in o he cen al ne ous sys em has been e alua ed only om single de e mina ions in ce eb ospinal luid (CSF) and single a ios o concen a ions in CSF o concen a ions in plasma in sam- ples ob ained a a iable and a bi a y in e als om pa ien s wi h nonuni o m dosages. Consequen ly, he esul s ha e been e y a iable, 13 o 340% o he simul aneous concen a ion in plasma (11, 21–23). Mo eo e , o assume ha e inal and b ain osca ne le els a e simila o hose measu ed in i eous hu- mo and CSF may be e oneous. Due o he di icul ies in ob aining issue samples om humans, we used a abbi model o e alua ing he e inal and b ain pene a ion o osca ne a e i s in a enous adminis a ion. The a ios o he a eas unde he concen a ion- ime cu e (AUCs) o issues and CSF o he AUCs o se um we e used o ob ain mo e accu a e esul s (16). We ha e also de e mined whe he he concen a- ions de ec ed in e ina and b ain a e simila o hose in i e- ous humo and CSF. In humans, no signi ican di e ences we e obse ed in plasma concen a ions be ween single- and mul i- ple-dose adminis a ion (25); he e o e, he s udy was designed o ob ain samples a e a single dose o he d ug. S udy design, d ug adminis a ion, and sampling. Thi y- wo heal hy, pigmen ed abbi s wi h a mean weigh o 3 kg we e used. The s udy was conduc ed acco ding o he Minis- e io de Ag icul u a guidelines. A e animals we e anes he- ized wi h an in amuscula injec ion o xylazine (12 mg/kg o body weigh ) and ke amine (60 mg/kg), a jugula ein was ca he e ized by a su gical p ocedu e and main ained as pe - meable by a 0.9% saline solu ion-lock echnique. The en i e expe imen s we e conduc ed unde su gical anes hesia. Each abbi ecei ed 120 mg o osca ne (As a Pha maceu ical, So¨de a¨lje, Sweden) pe kg, as an in a enous dose o e a 3-min pe iod, since his is a usual dose in humans du ing he main enance ea men o CMV e ini is in pa ien s wi h AIDS. Blood (2 ml) was aken be o e and a 5, 15, 30, 45, 60, 75, 90, and 120 min a e he end o in usion. Re ina, i eous humo , b ain, and CSF samples we e ob ained a 30 and 90 min and 60 and 120 min, so ha each animal yielded issue da a o wo di e en ime poin s, be o e being eu hana ized wi h in a enous pen oba bi al. Vi eous humo was ob ained by cu ing he eyes jus behind he lens (mean olume ob- ained, 638 ⫾184 ␮l); a e wa ds, he e ina was ca e ully dissec ed (mean weigh ob ained, 49.3 ⫾13.5 mg). B ain issue was ob ained h ough a small c aniec omy (mean weigh ob- ained, 596 ⫾169 mg), and CSF was ob ained by punc u e o he cis e na magna (mean olume ob ained, 528 ⫾193 ␮l). A e cen i uga ion, plasma and CSF samples we e s o ed a ⫺80°C un il es ing. Be o e being ozen, i eous humo and e inal and b ain issues we e sonica ed a 0.5 cps o 40 s (50-W sonica o ; Sonics & Ma e ials Inc., Danbu y, Conn.). Fo p ocessing, each sample was ans e ed o a mic opa i- ion ube (Cen icon 30; Amicon Inc., Be e ly, Mass.) and cen i uged a 1,500 ⫻g o 20 min. Assay p ocedu e. Concen a ions o osca ne we e de e - mined acco ding o he modi ied me hod o Pe e sson and No dg en (20), using a high-pe o mance liquid ch oma o- g aph wi h an elec ochemical de ec o (Gilson Medical Elec- onics, Inc., Middle on, Wis.). The analy ical column (125 by 4 mm [inside diame e ]) was a Lichosphe 100 RP-18 wi h 5-␮m pa icles (Me ck, Da ms ad , Ge many). The olume injec ed was 20 ␮l, and he low a e was 0.7 ml/min. Quan i- ica ion was based on measu ing s anda d solu ions o osca - ne (As a Pha maceu ical) in 0.9% (w / ol) NaCl solu ion and hyd ochlo o hiazide as he in e nal s anda d. The de ec ion limi was 10 ␮g/ml. Calib a ion lines we e linea ( xy ⬎0.9000) o e a ange o 10 o 1,200 ␮g/ml. An analysis o a iance was * Co esponding au ho . Mailing add ess: Se icio de En e - medades In ecciosas, Hospi al Uni e si a io Vi gen del Rocı´o, A da. Manuel Siu o , s/n. 41013, Se ille, Spain. Phone: 34-5-4248265. Fax: 34-5-4248184. E-mail: [email p o ec ed]. 756 on July 31, 2017 by USE/BCTA.GEN UNIVERSITARIAh p://aac.asm.o g/Downloaded om ca ied ou o de e mine in e assay [F(1–27) ⫽0.84; P⫽ 0.5343] and in a-assay [F(1–37) ⫽0.72; P⫽0.6692] a iabil- i y; no s a is ically signi ican di e ences we e obse ed be- ween hem. The in a- and in e assay coe icien s o a ia ion we e 1 and 1.7%, espec i ely. Reco e y o osca ne om plasma, e ina, i eous humo , b ain, and CSF, a e adding known concen a ions o osca ne o hem, was 86, 82.7, 79.8, 84, and 94.8%, espec i ely. Pha macokine ic analysis. Compa men al pha macokine ic pa ame e s we e calcula ed om he concen a ion- ime cu e da a (12). The co esponding mac ocons an s we e calcula ed om he biexponen ial equa ion Cs ⫽A 0 e ⫺␣ ⫹B 0 e ⫺␤ , whe e Cs is he concen a ion o he d ug in se um a ime .A 0 and B 0 , and ␣and ␤, a e he in e cep s and exponen s, espec i ely, o he wo exponen ial phases. Twen y da a pe ime poin we e used o de e mine he se um pha macokine ic pa ame- e s, which we e calcula ed manually, and 8 o 10 da a o each issue pe ime poin we e used. The AUC om0h oin ini y (AUC 0–⬁ ) was calcula ed up o he ime o he las quan i iable se um concen a ion using he apezoidal ule and hen o in ini y using he quo ien o he las measu able concen a ion o he e minal-phase a e cons an , which was calcula ed by he abo e-men ioned cu e i ing. Resul s we e exp essed pe millili e , assuming issue densi ies as 1. The pene a ion a io was de ined as he a io o he AUC 0–2 o issues and CSF o he AUC 0–2 o se um. Resul s. Figu e 1 shows he mean se um and issue concen- a ion- ime cu es a e he in a enous adminis a ion o os- ca ne (120 mg/kg). The da a i ed o a wo-compa men model, he equa ion being Cs ⫽0.49e ⫺10.02 ⫹0.382e ⫺0.636 . The p o ile clea ly shows he wo dis inc phases associa ed wi h a wo-compa men model. The ␣phase is basically he apid dis ibu ion o he d ug (A/␣⬍B/␤), while he ␤phase is basically i s elimina ion, a e eaching he s a iona y equi- lib ium s a e. Fosca ne has a apid disappea ance om se um wi h a mean ␣-phase hal -li e o 0.065 ⫾0.001 h and a ␤-phase hal -li e o 1.09 ⫾0.26 h. Table 1 summa izes he alues o he pha macokine ic pa ame e s o osca ne ob ained wi h his model. High le els o osca ne we e ound in e ina and b ain, wi h AUC 0–2 o 532 ⫾183 and 574 ⫾202 ␮g䡠h/ml, espec i ely. Pene a ion in o bo h he e ina and he b ain was ema kably high, wi h es ima ed pene a ion a ios o 110% ⫾1% and 118% ⫾1%, espec i ely. Lowe le els o osca ne we e ound in i eous humo and CSF, wi h AUC 0–2 o 59.7 ⫾23.0 and 93 ⫾1.8 ␮g䡠h/ml and pene a ion a ios o 12.3% ⫾0.7% and 20.2% ⫾2.2%, espec i ely. Discussion. In his model, he es ima ed dis ibu ion ol- umes sugges ha osca ne is a d ug widely dis ibu ed in di e en o gans, as deduced om he equa ion V ss /V c ⫺1⫽ 0.96 (12), whe e V ss is olume o dis ibu ion a s eady s a e and V c is olume o dis ibu ion in cen al compa men , in spi e o a sho biological hal -li e in bo h ␣and ␤phases. Ou da a show ha osca ne has a good pene a ion in bo h e inal and b ain issues, eaching le els a abo e he 50% inhibi o y concen a ion (120 ␮g/ml; ange, 7.5 o 240) o mos s ains o FIG. 1. Mean (⫾s anda d de ia ion; mic og ams pe millili e ) se um and issue concen a ion- ime cu es a e an in a enous dose o osca ne (120 mg/kg). VOL. 44, 2000 NOTES 757 on July 31, 2017 by USE/BCTA.GEN UNIVERSITARIAh p://aac.asm.o g/Downloaded om human CMV (7). Fosca ne is a e y small and highly nega- i ely cha ged molecule, wi h a p o ein binding le el o 15% and wi h an o ganic/wa e pa i ion coe icien o 0.426 (3). These physicochemical p ope ies would acili a e i s di usion h ough he blood-b ain and blood- e inal ba ie s (17). These high a ios may also be due o a slowe elimina ion om e ina and b ain han om se um, so ha he a io o d ug concen- a ions in hese issues and se um inc eases wi h ime a e in usion, as equen ly occu s wi h o he d ugs (13, 16). How- e e , he concen a ions and AUC 0–2 obse ed in he i eous humo a e much lowe han hose in he e ina. Thus, he e inal concen a ions eached a e he in a enous adminis- a ion o osca ne canno be es ima ed om hose obse ed in he i eous humo . In he same way, le els o osca ne in CSF a e lowe han hose obse ed in b ain. CSF d ug concen a ions a e e- quen ly lowe han hose o he ce eb al ex acellula luid and he b ain issue, o e all when CSF is ob ained om en icles o he cis e na magna (6, 18, 26). Howe e , he p esence o an AUC in he b ain six old highe han ha in he CSF sugges s ha , a leas in his animal, he e may be a high e lux clea ance o osca ne om CSF. This could be p oduced ia he a ach- noid illi and nona achnoidal CSF d ainage pa hways (c ibi- o m a ea, o bi al a ea, and inne ea ) p esen in he abbi and o he lowe mammals (8, 15). In addi ion, as osca ne is a weak acid (9), he e could be an ac i e e lux om he CSF, as occu s wi h o he weak o ganic acid d ugs (5). Al hough he in a i eal le els o osca ne obse ed in he pa ien s s udied by A e alo e al. (1) we e simila o hose we ha e ound in abbi s, i is di icul o know whe he ou da a a e en i ely applicable o humans since he ew epo ed pha - macokine ic s udies o osca ne in humans ha e been ca ied ou wi h he e ogeneous doses, a es o pe usions, and pha - macokine ic analyses. I would be expec ed ha he concen- a ions o osca ne in hese issues would be simila o o highe han hose obse ed in abbi s, since in humans he V ss o osca ne is highe and he hal -li e is longe han hose in abbi s (2, 24, 26). 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Pha macokine ic pa ame e s o osca ne a e in a enous adminis a ion o 120 mg/kg o abbi s Pa ame e (uni e) a Value (mean ⫾SD) Concn (␮g/ml) 0 h...................................................................................... 872 ⫾120 Maximum in pe iphe al compa men .......................... 343 ⫾92 A 0 ....................................................................................... 490 ⫾45 B 0 ........................................................................................ 382 ⫾75 Phase (h ⫺1 ) ␣.........................................................................................10.02 ⫾0.24 ␤.........................................................................................0.636 ⫾0.12 1/2 (h) ␣.........................................................................................0.065 ⫾0.001 ␤......................................................................................... 1.09 ⫾0.26 ss (h)...................................................................................... 0.37 ⫾0.078 V(ml/kg) V c ........................................................................................137.6 ⫾22 V p .......................................................................................132.4 ⫾14.2 V ss ....................................................................................... 270 ⫾37 CL (ml/kg/min)..................................................................... 2.86 ⫾0.91 k(h ⫺1 ) k 1–2 ..................................................................................... 4.57 ⫾0.01 k 2–1 ..................................................................................... 4.47 ⫾0.12 k el ....................................................................................... 1.34 ⫾0.2 AUC (␮g䡠h/ml) AUC 0–2 .............................................................................. 484 ⫾166 AUC 0–⬁ ............................................................................. 649 ⫾38 a 1/2 , hal -li e; ss , ime in s eady s a e; V c ,V p , and V ss , olume o dis ibu ion in he cen al o pe iphe al compa men o a s eady s a e, espec i ely; CL, clea ance; k, a e cons an ; k el , elimina ion a e cons an . 758 NOTES ANTIMICROB.AGENTS CHEMOTHER. on July 31, 2017 by USE/BCTA.GEN UNIVERSITARIAh p://aac.asm.o g/Downloaded om ce eb ospinal luid in humans wi h unin lamed meninges. 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