Transcript Aaxali antituberkulozuri preparatebi: proeqtebi da

Aaxali antituberkulozuri preparati _ PA 824
ganviTareba da kvlevebi
lika trapaiZe,
“samSabaToba”, 26.01.10
rezistentuli tuberkulozis mkurnaloba Sors aris srulyofilebisagan
msoflios wamyvan farmakologiur kompaniebSi axali preparatebis Sesaqmnelad
mimdinare muSaobis ZiriTadi mimarTulebebia:
axali, efeqturi TB preparatis Seqmna;
 rezistentuli tuberkulozis mkurnalobis vadebis Semcireba;

preparatebis umravlesoba jerjerobiT kvlevis fazaSia.
PA-824: uaxlesi antibaqteriuli preparatebis
jgufi; nitroimidazoli:
 aqvs baqteriociduli da masterizebeli moqmedeba;

efeqturia rogorc sensitiuri, ise rezistentuli TB-s
samkurnalod;

SeiZleba ARV TerapiasTan kombinaciaSi
gamoyeneba;
2005 wlidan CarTulia klinikuri kvlevebis I
stadiaSi.

 nitroimidazolebis
antituberkulozuri aqtioba pirvelad aRwerili
iqna 1993 wels, Tumca Semdgomi ganviTareba ver hpova,
radgan naerTebi mutagenuri aRmoCnda. SemdgomSi
gafarToebuli kvlevebis Sedegad miRebul iqna PA-824
 ar
arsebobs mtkicebuleba genotoqsiuri kompleqsebiT standartul
gamokvlevebSi PA-824-s mutaciis Sesaxeb;
 ar SeiniSneba mniSvnelovani urTierTqmedeba citoqromul P450-Tan;
 ar SeiniSneba aqtivoba gram-dadebiTi da gram-uaryofiTi baqteriebis
farTo speqtris winaaRmdeg.
PA-824-ze kvlevebi mimdinareobs 2002 wlidan
 TB alliance-is farglebSi;
 kaliforniis bioteqnologiur kompaniaSi (Chiron
Corporation);
 aSS alergiisa da infeqciur daavadebaTa erovnuli centris da
 Research
Triangle Institute monawileobiT. P

sawyisi monacemebis mixedviT, PA-824 efeqturia rogorc
sensitiuri, ise rezistentuli Stamebis winaaRmdeg in vitro (yvela
izolatSi); P
 preklinikurma
gamocdam aCvena, rom cxovelebSi preparati
efeqturia rogorc arsebul preparatebTan SedarebiT, aseve maTTan
kombinaciaSi;
 gansazRvrul iqna naerTis usafrTxoebisa da farmakokinetikis modeli
misi klinikur gamocdaSi CarTvis SesaZleblobis Sefasebis mizniT.
9 dRis ganmavlobaSi Per.os miRebis Semdeg PA-824
efeqturi iyo 50, 100 da 300 mg/kg wonaze. naerTis suspenzia
momzadda ciklodeqstrin- lecitinze. misi aqtioba Sedarda H, R,
Mfx-Tan. PA-824 100 mg/kg doziT iseTive aqtiuri iyo, rogorc
Mfx 100 mg/kg da H 25 mg/kg, da bevrad ufro aqtiuri, vidre
R 20 mg/kg.
 TagvebSi
xangrZlivad (6 Tvis ganmavlobaSi) miRebisas, eqsperimentebSi, sadac PA-824
gamoiyenes H nacvlad ( 2RPA-824Z+ 4RPA-824, an 6 RPA824), 19 Tagvidan relafsi ganviTarda 2-Si, maSin roca standartuli reJimis
(2RHZ+4RH) dros 46 Tagvidan arcerTSi ar ganviTarda relafsi.
 raime mniSvnelovani gansxvaveba PA-824- sa da sxva preparatebiT
monoTerapias Soris (H- 25 mg/kg, R- 10 mg/kg, Gfx- 100 mg/kg da Mfx100 mg/kg) nanaxi ar iqna.


PA-824-ma aCvena mZlavri viwro speqtris aqtioba mgb-s winaaRmdeg;
 ar axasiaTebs jvaredini rezistentoba sxva tubsawinaaRmdego preparatebTan;
 TagvebSi minimaluri efeqturi doza iyo 12, 5 mg/kg dReSi, minimaluri
baqtericiduli doza monoTerapiis dros- 100 mg/kg;

intensiur fazaSi iseTive efeqturi iyo TagvebSi, rogorc H adamianebSi, HTan kombinaciaSi PA-824-ma moaxdina izoniazid-rezistentuli mutaciis
prevencia;

PA-824-ma aCvena aqtioba iseT SemTxvevebSi, roca 2- Tviani intensiuri
fazis (H, R, Z) Semdeg rCeboda bacilagamoyofa.
preklinikuri kvlevebis dasrulebis Semdeg 2005 wels preparati gadavida
klinikuri kvlevebis I stadiaSi, sadac janmrTel voluntarebSi erTjeradi da
jeradi doziT micemisas Sefasebul iqna PA-824-is
 usafrTxoeba;
 tolerabiluroba;
 farmakokinetika;
 ADME
(absorbcia, distribucia, metabolizmi da eqskrecia).
dReisaTvis Sesrulebulia I stadiis 6 faza, rac gulisxmobs:
 randomizebul erTjeradi mzardi doziT kvlevas janmrTel mamakac
voluntarebSi;
 randomizebul mravaljeradi mzardi doziT kvlevas orive sqesis voluntarebSi;
 erTjeradi doziT gamokvlevas normaluri kvebisa da SimSilis pirobebSi;

PA-824-is radiomoniSnuli 2 erTjeradi doziT kvlevas orive sqesis
voluntarebSi misi ADME Sefasebis mizniT.
niu-iorkSi Catarda kvleva janmrTel kontigentSi
kvlevisaTvis SerCeul iqna:
 orive sqesis 77 piri;
aqedan 58 maTgani iRebda PA-824-s;
 19- placebos.

es 77 piri warmoadgenda sxvadasxva rasobriv jgufs
erTjeradi dozis SemTxvevaSi PA 824-is koncentracia meryeobda:
 0,3+
0,1 g/ml-dan (50 mg dozis jgufi);
 2,9+0,5 g/ml-mde (1500 mg dozis jgufi).
sruli gamoyofa meryeobda:
 7,5+3,9 g.sT/ml-dan (50 mg dozis jgufi);
 101,8+25,3 g.sT/ml-mde (1500 mg dozis jgufi).

gverdiTi movlenebi (guliscemis aCqareba, gulisreva, GRebineba da a.S.)
SeiniSna mxolod placebos jgufSi;

dadasturda, rom PA-824 kargad aitaneba

rogorc erTjerad 100 mg-mde doziT 5 dRis ganmavlobaSi;
aseve erTjerad 600 mg-mde doziT 7 dRis ganmavlobaSi ( Global Alliance

for TB Drug Development, 40 Wall Street, New York, New York
10005,1 and RTI International, 3040 Cornwallis Road, P.O. Box
12194, Research Triangle Park, North Carolina 277092).
 mravaljeradi
dozirebis stadia (CL 102) Sewyvetil iqna kreatininis
momatebis gamo, romelic Seqcevadi aRmoCnda;
 PA-
824-s Sewova orive stadiaSi zomierad swrafad moxda;
 maqsimaluri koncentracia miRweul iqna 4 da 5 saaTSi;
Catarda gamokvleva PA-824 miRebis fonze kreatininis zomieri
momatebis mizezis dasadgenad
 gamokvleul
iqna orive sqesis 45 janmrTeli piri;
miecaT 800 an 1000 mg PA- 824
8 dRis ganmavlobaSi.
 maT



dadasturda, rom kreatininis Seqcevadi momateba ar iyo dakavSirebuli Tirkmlis funqciis
darRvevasTan (Antimicrobial Agents and Chemotherapy. September
2009. p. 3726-3733 Ann M. Ginsberg, Martino W. Laurenzi, Doris
J. Rouse, Karl D. Whitney, and Melvin K. Spigelman).
aRmoCnda, rom PA-824-is moqmedebiT xdeba cilis katabolizmis gazrda, gorglovani
filtraciis daqveiTeba da kreatininis sekreciis Semcireba Tirkmlis proqsimalur milakebSi,
Cveulebriv, konkurentuli inhibirebis gziT.
kreatininis momateba aRmoCnda droebiTi, Seqcevadi da klinikurad umniSvnelo, rogorc,
magaliTad, cimetidinis, trimetoprimis, an pirimetaminis miRebis fonze ganviTarebuli
hiperkreatininemia.
aCvena, rom PA-824 kargad asatani preparatia raime
gansakuTrebuli, dozaze damokidebuli gverdiTi reaqciebis gareSe;
 kvlevebma
wels PA-824 mieniWa samedicino produqtis statusi evropis
samedicino saagentos (EMEA) da amerikis sakvebisa da
wamlebis administraciis (FDA) mier.
 2007
2007 wlis bolos daiwyo pirveli klinikuri gamocda bacilagamomyof pacientebSi
(kvleva Catarda keiptaunSi, samxreT afrikaSi)
pacientebi dayofilni iyvnen 2 jgufad;
PA-824 eZleodaT monoTerapiis saxiT, sxvadasxva dozebiT;
 14 dRis ganmavlobaSi;

PA-824 efeqturi iyo kvlevaSi gamoyenebuli mcire doziTac ki




05.2008 - 07.2009 periodSi PA-824 klinikuri ganviTareba SeCerda, radgan cxovelebSi
nanaxi iqna toqsiurobis monacemebi;
Catarda damatebiTi kvlevebi, ris Semdegac ganaxlda preparatis klinikuri ganviTarebis
programa;
dagegmilia preparatis gamocdis meore etapi Semcirebuli dozebiT. gamocdis programa ukve
daSvebulia, Tumca pacientebis registracia jer ar dawyebula;
momdevno ganviTareba moicavs PA-824-is testirebas sxva antituberkulozur preparatebTan
kombinaciaSi, raTa Sefasdes misi potenciali tuberkulozis mkurnalobis gaumjobesebaSi.
gmadlobT
yuradRebisaTvis