qanastek/EMEA-V3 huggingface dataset:
235 adult patients with accelerated phase disease were enrolled.
235 pazjent bil- marda fil- fażi aċċelerata ġew reklutati.
The first 77 patients were started at 400 mg, the protocol was subsequently amended to allow higher dosing and the remaining 158 patients were started at 600 mg.
L- ewwel 77 pazjent inbdew fuq doża ta ’ 400 mg, u aktar tard il- protokoll kien irranġat sabiex ikun permess li jintuzaw dożi ogħla u fil- fatt il- 158 il- pazjent li kien għad fadal inbdew b’ doża ta ’ 600 mg.
The primary efficacy variable was the rate of haematological response, reported as either complete haematological response, no evidence of leukaemia (i. e. clearance of blasts from the marrow and the blood, but without a full peripheral blood recovery as for complete responses), or return to chronic phase CML.
Il- varjant ewlieni ta ’ l- effikaċja kien ir- rata ta ’ rispons ematoloġiku, li ġie rapportat jew bħala rispons ematoloġiku komplet, jew l- ebda evidenza ta ’ lewkimja (jiġifieri l- clearance tal- blasts mill- mudullun u mid- demm, imma mingħajr mad- demm fil- periferiji jkun reġa ’ ġie f’ tiegħu bħalma jiġri fil- każ ta ’ rispons komplet), jew ir- ritorn għal CML fil- fażi kronika.
A confirmed haematological response was achieved in 71.5% of patients (Table 4).
Konferma ta ’ rispons emataloġiku ntlaħqet f’ 71. 5% tal- pazjenti (Tabella 4).
Importantly, 27.7% of patients also achieved a major cytogenetic response, which was complete in 20.4% (confirmed 16%) of patients.
Fatt importanti huwa li 27. 7% tal- pazjenti kellhom ukoll reazzjoni ċitoġenetika maġġuri, li kienet kompleta fi 20. 4% (ikkonfermata fi 16%) tal- pazjenti.
For the patients treated at 600 mg, the current estimates for median progression-free-survival and overall survival were 22.9 and 42.5 months, respectively.
F’ dawk il - pazjenti li ġew ikkurati b ’ 600 mg, l- istimi attwali għall- medjan ta ’ sopravivenza ħielsa minn avvanz u sopravivenza globali kienu 22. 9 u 42. 5 xhur, rispettivament.
260 patients with myeloid blast crisis were enrolled.
Majelojd blast crisis 260 pazjent b’ majelojd blast crisis kienu reklutati.
95 (37%) had received prior chemotherapy for treatment of either accelerated phase or blast crisis (“ pretreated patients”) whereas 165 (63%) had not (“ untreated patients”).
95 (37%) minnhom kienu diġà ħadu kemoterapija għall- kura tal- fażi aċċelerata jew tal- blast crisis (“ pazjenti li kienu kurati minn qabel ”) filwaqt li 165 (63%) ma ’ kienux għamlu hekk (“ pazjenti mhux ikkurati minn qabel ”).
The first 37 patients were started at 400 mg, the protocol was subsequently amended to allow higher dosing and the remaining 223 patients were started at 600 mg.
L- ewwel 37 pazjent nbdew fuq doża ta ’ 400 mg, u l- protokoll aktar tard tranġa sabiex kienu permessi dożi ogħla biex il- 223 pazjent li kien baqa ’ inbdew fuq doża ta ’ 600 mg.
The primary efficacy variable was the rate of haematological response, reported as either complete haematological response, no evidence of leukaemia, or return to chronic phase CML using the same criteria as for the study in accelerated phase.
Il- varjant ewlieni ta ’ l- effikaċa kien ir- rata ta ’ rispons ematoloġiku, li ġie rapportat bħala, jew rispons ematoloġiku komplet, jew l- ebda evidenza ta ’ lewkimja, jew ir- ritorn għal CML fil- fażi kronika, bl - użu ta ’ l- istess kriterji li ntużaw fl- istudju fuq il- fażi l- aċċelerata.
The rate of
F’ dan l- istudju, 31% tal- pazjenti kellhom reazzjoni ematoloġika (36% f’ pazjenti mhux ikkurati minn qabel u 22% f’ pazjenti li kienu kurati minn qabel).
16 response was also higher in the patients treated at 600 mg (33%) as compared to the patients treated at 400 mg (16%, p=0.0220).
Ir- rata tar- rispons kienet ukoll ogħla fil- pazjenti li ħadu doża ta ’ 600 mg (33%) meta mqabbla mal- pazjenti li kienu ħadu doża ta ’ 400 mg (16%, p=0. 0220).
The current estimate of the median survival of the previously untreated and treated patients was 7.7 and 4.7 months, respectively.
L- istima kurrenti tas - sopravivenza medjana f’ dawk li ma kienux ħadu trattament minn qabel u f’ dawk li kienu ħaduh kienet ta ’ 7. 7 u 4. 7 xhur, rispettivament.
Lymphoid blast crisis: a limited number of patients were enrolled in phase I studies (n=10).
Limfojd blast crisis: numru limitat ta ’ pazjenti kienu reklutati fi studji ta ’ fażi I (n=10).
The rate of haematological response was 70% with a duration of 2– 3 months.
Ir- rata ta ’ rispons ematoloġiku kienet ta ’ 70% b’ tul ta ’ żmien ta ’ minn 2- 3 xhur.
Response in adult CML studies
Rispons f’ adult bl- istudji CML
Study 0110
Studju 0110
Study 0109
Studju 0109
Study 0102
Studju 0102
Chronic phase, IFN failure (n=532)
Dejta ta ’ 37 xahar Fażi Kronika, meta IFN ma ħadimx (n=532)
Accelerated phase (n=235)
Dejta ta ’ 40. 5 xahar Fażi aċċelerata (n=235)
Myeloid blast crisis (n=260)
Dejta ta ’ 38 xahar Majelojd blast crisis (n=260)
% of patients (CI95%) 1 Haematological response Complete haematological response (CHR)
% tal- pazjenti (CI95%) 17 Rispons ematoloġiku1 Rispons ematoloġiku komplet (CHR)
95% (92.3– 96.3) 95%
95% (92. 3- 96. 3) 95%
71% (65.3– 77.2) 42%
71% (65. 3- 77. 2) 42%
31% (25.2– 36.8) 8%
31% (25. 2- 36. 8) 8%
No evidence of leukaemia (NEL)
L- ebda evidenza ta ’ lewkimja (NEL)
Not applicable
Ma jgħoddx
Return to chronic phase (RTC) 2
Ritorn għall- fażi l- kronika (RTC)
Major cytogenetic response Complete
Rispons ċitoġenetiku maġġuri2 Komplet 3
65% (61.2– 69.5) 53%
65% (61. 2- 69. 5) 53%
28% (22.0– 33.9) 20%
28% (22. 0- 33. 9) 20%
15% (11.2– 20.4) 7%
15% (11. 2- 20. 4) 7%
(Confirmed3) [95% CI] Partial
(Konfermati) [95% CI] Parzjali
(43%) [38.6– 47.2] (16%) [11.3– 21.0] 12% 7%
(16%) [11. 3- 21. 0] 7%
[0.6– 4.4] 8%
[0. 6- 4. 4] 8%
Haematological response criteria (all responses to be confirmed after ≥ 4 weeks):
Kriterji ta ’ rispons ematoloġiku (ir- risponsijiet kollha jridu jkun ikkonfermati wara ≥ 4 ġimgħat):
Study 0110 [WBC < 10 x 109/ l, platelets < 450 x 109/ l, myelocyte+metamyelocyte < 5% in blood, no blasts and promyelocytes in blood, basophils < 20%, no extramedullary involvement] and in studies 0102 and 0109 [ANC ≥ 1.5 x 109/ l, platelets ≥ 100 x 109/ l, no blood blasts, BM blasts < 5% and no extramedullary disease] NEL Same criteria as for CHR but ANC ≥ 1 x 109/ l and platelets ≥ 20 x 109/ l (0102 and 0109 only) RTC < 15% blasts BM and PB, < 30% blasts+promyelocytes in BM and PB, < 20% basophils in PB, no extramedullary disease other than spleen and liver (only for 0102 and 0109).
Studju 0110 [WBC < 10 x 109/ l, plejtlets < 450 x109/ l, majeloċita+metamajeloċita < 5% fid - demm, l- ebda blasts u promajeloċiti fid- demm, bażofils < 20%, l- ebda involviment ̀’ l barra mill- mudullun] u fi studji 0102 u 0109 [ANC ≥ 1. 5 x 109/ l, plejtlets ≥ 100 x109/ l, l- ebda blasts fid- demm, blasts fil- mudullun < 5% u l- ebda mard barra l- mudullun] NEL L- istess kriterji bħal ta ’ CHR imma ANC ≥ 1 x 109/ l u plejtlets ≥ 20 x 109/ l (0102 u 0109 biss) RTC < 15% blasts fil- mudullun u fid- demm fil- periferiji, < 30% blasts+promajeloċiti fil- mudullun u fid- demm fil- periferiji, < 20% bażofils fid- demm fil- periferiji, l- ebda involviment ’ l barra mill- mudullun ħlief għall- involviment tal- milsa u tal- fwied (għal 0102 u 0109 biss).
BM = bone marrow, PB = peripheral blood 2 Cytogenetic response criteria:
BM = Mudullun, PB = demm fil- periferiji 2 Kriterji għar- risponsijiet ċitoġenetiċi:
A major response combines both complete and partial responses: complete (0% Ph+ metaphases), partial (1– 35%) 3 Complete cytogenetic response confirmed by a second bone marrow cytogenetic evaluation performed at least one month after the initial bone marrow study.
3 Rispons ċitoġenetiku komplet ikkonfermat permezz tat- tieni valutazzjoni ċitoġenetika tal - mudullun magħmula mill- inqas xahar wara l- ewwel studju fuq il- mudullun.
A total of 26 paediatric patients of age < 18 years with either chronic phase CML (n=11) or CML in blast crisis or Ph+ acute leukaemias (n=15) were enrolled in a dose-escalation phase I trial.
B’ kollox 26- il pazjent pedjatriku ta ’ età ta ’ < 18- il sena li jew kellhom CML fil - fażi l- kronika (n=11) jew kellhom CML fi blast crisis jew lewkimji akuti (n=15) b’ Ph+ kienu reklutati fi prova ta ’ fażi I li fiha d- doża kienet tiżdied.
This was a population of heavily pretreated patients, as 46% had received prior BMT and 73% a prior multi-agent chemotherapy.
Din kienet popolazzjoni ta ’ pazjenti li kienu diġà ħadu bosta trattamenti, billi 46% kien diġà kellhom BMT u 73% kienu ħadu kemoterapija li kienet tinkludi ħafna sustanzi, minn qabel.
Patients were treated at doses of Glivec of 260 mg/ m2/ day (n=5), 340 mg/ m2/ day (n=9), 440 mg/ m2/ day (n=7) and 570 mg/ m2/ day (n=5).
Il- pazjenti ġew ikkurati b’ dożi ta ’ Glivec ta ’ 260 mg/ m2/ jum (n=5), 340 mg/ m2/ jum (n=9), 440 mg/ m2/ jum (n=7), u 570 mg/ m2/ jum (n=5).
Out of 9 patients with chronic phase CML and cytogenetic data available, 4 (44%) and 3 (33%) achieved a complete and partial cytogenetic response, respectively, for a rate of MCyR of 77%.
Minn 9 pazjenti b’ CML fil- fażi kronika u mit- tagħrif ċitoġenetiku disponibbli, jirriżulta li 4 (44%) u 3 (33%) kellhom rispons ċitoġenetiku komplet u parzjali, rispettivament, għal rata ta ’ MCyR ta ’ 77%.
A total of 51 paediatric patients with newly diagnosed and untreated CML in chronic phase have been enrolled in an open-label, multicentre, single-arm phase II trial.
Total ta ’ 51 pazjent pedjatriku li kienu għadhom kif ġew dijanjostikati b’ CML fil- fażi kronika u li ma kienux għadhom irċevew kura kienu reklutati fi prova open- label, f’ ħafna ċentri, b’ fergħa waħda tal - fażi II.
Patients were treated with Glivec 340 mg/ m2/ day, with no interruptions in the absence of dose limiting toxicity.
Il- pazjenti kienu kurati b’ Glivec 340 mg/ m2/ jum, mingħajr interuzzjonijiet jekk ma jkunx hemm tossiċita li tillimita d- doża.
Glivec treatment induces a rapid response in newly diagnosed paediatric CML patients with a CHR of 78% after 8 weeks of therapy.
Il- kura bi Glivec twassal għal rispons mgħaġġel f’ pazjenti pedjatriċi li kienu għadhom kif ġew dijanjostikati b’ CML b’ CHR ta ’ 78% wara 8 ġimgħat ta ’ terapija.
The high rate of CHR is accompanied by the development of a complete cytogenetic response (CCyR) of 65% which is comparable to the results observed in adults.
Ir- rata għolja ta ’ CHR tkun missieħba b’ żvilupp ta ’ rispons ċitoġenetiku komplet (CCyR) ta ’ 65% li jaqbel mar- riżultati miksuba fl- adulti.
The
Minbarra hekk, rispons ċitoġenetiku parzjali (PCyR) kien evidenti f’ 16% għal MCyR ta ’ 81%.
17 majority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 5.6 months.
Il- maġġoranza tal- pazjenti li kisbu CCyR żviluppaw is- CCyR bejn it- 3 u l- 10 xahar b’ ħin medjan għar- rispons bażat fuq l- istima Kaplan- Meier ta ’ 5. 6 xhur.
Clinical studies in Ph+ ALL Newly diagnosed Ph+ ALL:
Provi kliniċi f’ Ph+ ALL Ph+ ALL li jkunu għadhom kif ġew dijanjostikati:
50%; p=0.0001).
Fi studju kontrollat (ADE10) ta ’ imatinib versus induzzjoni b’ kimoterapija f’ 55 pazjent li kienu għadhom kif ġew dijanjostikati ta ’ etajiet minn 55 sena ‘ l fuq. imatinib użat waħdu wassal għal rispons ematoloġiku komplet b’ rata ogħla minn kimoterapija (96. 3% vs 50%; p=0. 001).
When salvage therapy with imatinib was administered in patients who did not respond or who responded poorly to chemotherapy, it resulted in 9 patients (81.8%) out of 11 achieving a complete haematological response.
Meta terapija ta ’ sokkors b’ imatinib ingħatat f’ pazjenti li ma wrewx rispons jew li urew rispons fqir għall- kimoterapija, irriżulta li 9 pazjenti (81. 8%) minn 11 kisbu rispons ematoloġiku komplet.
This clinical effect was associated with a higher reduction in bcr- abl transcripts in the imatinib-treated patients than in the chemotherapy arm after 2 weeks of therapy (p=0.02).
Il -
All patients received imatinib and consolidation chemotherapy (see Table 5) after induction and the levels of bcr-abl transcripts were identical in the two arms at 8 weeks.
18 pazjenti kollha rċevew imatinib u terapija konsolidata (ara Tabella 5) wara induzzjoni u l- livelli ta ’ bcr- abl transcripts kienu identiċi fiż- żewġ friegħi mat- 8 ġimgħa.
As expected on the basis of the study design, no difference was observed in remission duration, disease-free survival or overall survival, although patients with complete molecular response and remaining in minimal residual disease had a better outcome in terms of both remission duration (p=0.01) and disease-free survival (p=0.02).
Kif mistenni mill- mod kif ġie diżenjat dan l- istudju, ma kienx hemm differenzi fit- tul taż- żmien ta ’ remissjoni, sopravivenza ħielsa mill - marda jew sopravivenza globali, għalkemm il- pazjenti b’ rispons molekulari komplet u li baqgħu bir - residwu minimu tal- marda kellhom konsegwenzi aħjar kemm mil- lat taż- żmien ta ’ remissjoni (p=0. 01) u s- sopravivenza ħielsa mill- marda (p=0. 02).
The results observed in a population of 211 newly diagnosed Ph+ ALL patients in four uncontrolled clinical studies (AAU02, ADE04, AJP01 and AUS01) are consistent with the results described above.
Ir- riżultati li kienu osservati f’ popolazzjoni ta ’ 211 pazjenti li kienu għadhom kif ġew dijanjostikati Ph+ ALL f’ erba ’ studji kliniċi mingħajr kontroll (AAU02, ADE04, AJP01 u AUS01) huma konsistenti mar- risżultati deskritti hawn fuq.
Imatinib in combination with chemotherapy induction (see Table 5) resulted in a complete haematological response rate of 93% (147 out of 158 evaluable patients) and in a major cytogenetic response rate of 90% (19 out of 21 evaluable patients).
Imatinib kombinat ma ’ induzzjoni b’ kemoterapija (ara Tabella 5) wassal għal rata ta ’ rispons ematoloġiku komplet ta ’ 93% (147 minn 158 pazjenti li setgħu jkunu evalwati) u f’ rata ta ’ rispons citoġenetika maġġuri ta ’ 90% (19 minn 21 pazjenti li setgħu jkunu evalwati).
The complete molecular response rate was 48% (49 out of 102 evaluable patients).
Ir- rata ta ’ rispons molekulari komplet kienet 48% (49 minn 102 pazjenti li setgħu jkunu evalwati).
Disease-free survival (DFS) and overall survival (OS) constantly exceeded 1 year and were superior to historical control (DFS p < 0.001; OS p < 0.0001) in two studies (AJP01 and AUS01).
Sopravivenza ħielsa mill- marda (DFS) u sopravivenza globali (OS) qabżu sena 1 b’ mod fiss u kienu superjuri għall- kontroll storiku (DFS p < 0. 001; OS p < 0. 0001) f’ żewġ studji (AJP01 u AUS01).
Chemotherapy regimen used in combination with imatinib
Reġimen ta ’ kimoterapija kombinata ma ’ imatinib
DEX 10 mg/ m2 oral, days 1-5; CP 200 mg/ m2 i. v., days 3, 4, 5; MTX 12 mg intrathecal, day 1
Studju ADE10 Qabel il- fażi Induzzjoni tar - remissjoni Terapija
DEX 10 mg/ m2 oral, days 6-7, 13-16; VCR 1 mg i. v., days 7, 14; IDA 8 mg/ m2 i. v.
DEX 10 mg/ m2 oralii, jiem 1- 5; CP 200 mg/ m2 i. v., jiem 3, 4, 5; MTX 12 mg intrathecal, jum 1 DEX 10 mg/ m2 orali, jiem 6- 7, 13- 16; VCR 1 mg i. v., jiem 7, 14; IDA 8 mg/ m2 i. v.
(0.5 h), days 7, 8, 14, 15; CP 500 mg/ m2 i. v. (1 h) day 1; Ara- C 60 mg/ m2 i. v., days 22-25, 29-32
(0. 5 h), jiem 7, 8, 14, 15; CP 500 mg/ m2 i. v. (1 h) jum 1; Ara- C 60 mg/ m2 i. v., jiem 22- 25, 29- 32 MTX 500 mg/ m2 i. v.
(24 h), days 1, 15; 6-MP 25 mg/ m2 oral, days 1-20
(24 h), jiem 1, 15; 6- MP 25 mg/ m2 orali, jiem 1- 20
Ara-C 75 mg/ m2 i. v.
t’ aċċertament I, III, V Ara- C 75 mg/ m2 i. v.
(1 h), days 1-5; VM26 60 mg/ m2 i. v.
(1 h), jiem 1- 5; VM26 60 mg/ m2 i. v.
Daunorubicin 30 mg/ m2 i. v., days 1-3, 15-16; VCR 2 mg total dose i. v., days 1, 8, 15, 22; CP 750 mg/ m2 i. v., days 1, 8; prednisone 60 mg/ m2 oral, days 1-7, 15-21; IDA 9 mg/ m2 oral, days 1-28; MTX 15 mg intrathecal, days 1, 8, 15, 22; Ara-C 40 mg intrathecal, days 1, 8, 15, 22; methylprednisolone 40 mg intrathecal, days 1, 8, 15, 22
(1 h), jiem 1- 5 Terapija t’ aċċertament II, IV Studju AAU02 Daunorubicin 30 mg/ m2 i. v., jiem 1- 3, 15- 16; VCR 2 mg doża totali i. v., Terapija jiem 1, 8, 15, 22; CP 750 mg/ m2 i. v., jiem 1, 8; prednisone 60 mg/ m2 t’ aċċertament (de orali, jiem 1- 7, 15- 21; IDA 9 mg/ m2 orali, jiem 1- 28; MTX 15 mg novo Ph+ ALL) intrathecal, jiem 1, 8, 15, 22; Ara- C 40 mg intrathecal, jiem 1, 8, 15, 22; methylprednisolone 40 mg intrathecal, jiem 1, 8, 15, 22 Ara- C 1, 000 mg/ m2/ 12 h i. v. (3 h), jiem 1- 4; mitoxantrone 10 mg/ m2 i. v.
Consolidation (de novo Ph+ ALL) Study ADE04
Aċċertament (de
Ara-C 1,000 mg/ m2/ 12 h i. v. (3 h), days 1-4; mitoxantrone 10 mg/ m2 i. v. days 3-5; MTX 15 mg intrathecal, day 1; methylprednisolone 40 mg intrathecal, day 1
novo Ph+ ALL) Studju ADE04 Qabel il- fażi Terapija ta ’ induzzjoni I Terapija ta ’ induzzjoni II Terapija t’ aċċertament Studju AJP01
DEX 10 mg/ m2 oral, days 1-5; VCR 2 mg i. v., days 6, 13, 20; daunorubicin 45 mg/ m2 i. v., days 6-7, 13-14
jiem 3- 5; MTX 15 mg intrathecal, jum 1; methylprednisolone 40 mg intrathecal, jum 1 DEX 10 mg/ m2 orali, jiem 1- 5; CP 200 mg/ m2 i. v., jiem 3- 5; MTX 15 mg intrathecal, jum 1 DEX 10 mg/ m2 orali, jiem 1- 5; VCR 2 mg i. v., jiem 6, 13, 20; daunorubicin 45 mg/ m2 i. v., jiem 6- 7, 13- 14 CP 1 g/ m2 i. v.
(1 h), days 26, 46; Ara-C 75 mg/ m2 i. v.
(1 h), jiem 26, 46; Ara- C 75 mg/ m2 i. v.
DEX 10 mg/ m2 oral, days 1-5; vindesine 3 mg/ m2 i. v., day 1; MTX 1.5 g/ m2 i. v.
(1 h), jiem 28- 31, 35- 38, 42- 45; 6- MP 60 mg/ m2 orali, jiem 26- 46 DEX 10 mg/ m2 orali, jiem 1- 5; vindesine 3 mg/ m2 i. v., jum 1; MTX 1. 5 g/ m2 i. v.
(24 h), day 1; etoposide 250 mg/ m2 i. v.
(24 h), jum 1; etoposide 250 mg/ m2 i. v.
(1 h) days 4-5; Ara- C 2x 2 g/ m2 i. v.
(1 h) jiem 4- 5; Ara - C 2x 2 g/ m2 i. v.
(3 h, q 12 h), day 5
(3 h, q 12 h), jum 5
CP 1.2 g/ m2 i. v.
ta ’ CP 1. 2 g/ m2 i. v.
(3 h), day 1; daunorubicin 60 mg/ m2 i. v.
(3 h), jum 1; daunorubicin 60 mg/ m2 i. v.
(1 h), days 1-3; vincristine 1.3 mg/ m2 i. v., days 1, 8, 15, 21; prednisolone 60 mg/ m2/ day oral
(1 h), jiem 1- 3; Terapija vincristine 1. 3 mg/ m2 i. v., jiem 1, 8, 15, 21; prednisolone 60 mg/ m2/ jum induzzjoni orali
Consolidation therapy
Terapija
(24 h), day 1, and Ara-C 2 g/ m2 i. v.
Alternar bejn kors ta ’ kimoterapija:
(q 12 h), days 2-3, for 4 cycles
Kimoterapija b’ doża għolja ta ’ MTX
Maintenance Study AUS01
t’ aċċertament Manteniment Studju AUS01 Terapija ta ’ induzzjoni - aċċertament
VCR 1.3 g/ m2 i. v., day 1; prednisolone 60 mg/ m2 oral, days 1-5
(q 12 h), jiem 2- 3, għal 4 ċikli VCR 1. 3 g/ m2 i. v., jum 1; prednisolone 60 mg/ m2 orali, jiem 1- 5 Reġimen iper- CVAD:
(3 h, q 12 h), days 1-3; vincristine 2 mg i. v., days 4, 11; doxorubicine 50 mg/ m2 i. v.
(3 h, q 12 h), jiem 1- 3; vincristine 2 mg i. v., jiem 4, 11; doxorubicine 50 mg/ m2 i. v.
(24 h), day 4; DEX 40 mg/ day on days 1-4 and 11-14, alternated with MTX 1 g/ m2 i. v.
(24 h), jum 4; DEX 40 mg/ jum f’ jiem 1- 4 u 11- 14, alternati b’ MTX 1 g/ m2 i. v.
(24 h), day 1, Ara-C 1 g/ m2 i. v.
(24 h), jum 1, Ara- C 1 g/ m2 i. v.
(2 h, q 12 h), days 2-3 (total of 8 courses)
(2 h, q 12 h), jiem 2- 3 (total ta ’ 8 korsijiet)
Maintenance
Manteniment
VCR 2 mg i. v. monthly for 13 months; prednisolone 200 mg oral, 5 days per month for 13 months
VCR 2 mg i. v. kull xahar għall- 13- il xahar; prednisolone 200 mg orali, 5 jiem kull xahar għall- 13- il xahar
All treatment regimens include administration of steroids for CNS prophylaxis.
Ir- reġimens ta ’ kura kollha jinkludu l- użu ta ’ sterojdi sabiex tevita mard tas- CNS.
Ara-C: cytosine arabinoside; CP: cyclophosphamide; DEX: dexamethasone; MTX: methotrexate; 6-MP:
Ara- C: cytosine arabinoside; CP: cyclophosphamide; DEX: dexamethasone; MTX: methotrexate; 6- MP:
6-mercaptopurine VM26:
6- mercaptopurine VM26:
Teniposide; VCR: vincristine; IDA: idarubicine; i. v.: intravenous
Teniposide; VCR: vincristine; IDA: idarubicine; i. v.: għal ġol - vini
Relapsed/ refractory Ph+ ALL:
Ph+ ALL li jirkadi/ rifrattorju:
When imatinib was used as single agent in patients with relapsed/ refractory Ph+ ALL, it resulted, in the 53 out of 411 patients evaluable for response, in a haematological response rate of 30% (9% complete) and a major cytogenetic response rate of 23%.
Meta imatinib intuża waħdu f’ pazjenti b ’ Ph+ ALL li jirkadi/ rifrattorju, irriżulta li, fil- 53 mill- 411 pazjent li setgħu jiġu evalwati għar- rispons, f’ rata ta ’ rispons ematoloġiku ta ’ 30% (9% kompleti) u rata ta ’ rispons ċitoġenetiku maġġuri ta ’ 23%.
(Of note, out of the 411 patients, 353 were treated in an expanded access program without primary response data collected.) The median time to progression in the overall population of 411 patients with relapsed/ refractory Ph+ ALL ranged from 2.6 to 3.1 months, and median overall survival in the 401 evaluable patients ranged from 4.9 to 9 months.
Il- ħin medjan għall- avvanz fil- popolazzjoni globali ta ’ 411 pazjent b ’ Ph+ ALL li jirkadi/ rifrattorju kienet bejn 2. 6 u 3. 1 xhur, u s- sopravivenza medja globali fil- 401 pazjent li setgħu jiġu evalwati kienet bejn 4. 9 u 9 xhur.
The data was similar when re-analysed to include only those patients age 55 or older.
Id- dejta kienet simili meta kienet analizzata mill- ġdid sabiex tinkludi biss dawk il- pazjenti ta ’ etajiet minn 55 sena ‘ l fuq.
Clinical studies in MDS/ MPD Experience with Glivec in this indication is very limited and is based on haematological and cytogenetic response rates.
Provi kliniċi f’ MDS/ MPD L- esperjenza bi Glivec għal din l- indikazzjoni hija limitata ħafna u hija bażata fuq rati ta ’ rispons ematoloġiku u ċitoġenetiku.
There are no controlled trials demonstrating a clinical benefit or increased survival.
M’ hemmx provi kliniċi li juru benefiċċju kliniku jew żieda fis - sopravivenza.
One open label, multicentre, phase II clinical trial (study B2225) was conducted testing Glivec in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases.
Prova klinika waħda open label, f’ ħafna ċentri, ta ’ Fażi II (studju B2225) kien imwettaq billi Glivec kien ittestjat f’ popolazzjonijiet diversi ta ’ pazjenti li jsofru minn mard li jheddu l- ħajja assoċjati ma ’ Abl, Kit jew PDGFR proteini tyrosine kinases.
This study included 7 patients with MDS/ MPD who were treated with Glivec 400 mg daily.
Dan l- istudju kien jinkludi 7 pazjenti b’ MDS/ MPD li kienu trattati b’ Glivec 400 mg kuljum.
Three patients presented a complete haematological response (CHR) and one patient experienced a partial haematological response (PHR).
Tlett pazjenti urew rispons ematoloġiku komplet (CHR) u pazjent wieħed kellu rispons ematoloġiku parzjali (PHR).
At the time of the original analysis, three of the four patients with detected PDGFR gene rearrangements developed haematological response (2 CHR and 1 PHR).
Fiż- żmien ta ’ meta saret l - analiżi oriġinali, tlieta mill- erba ’ pazjenti li kellhom tibdil fil- ġene PDGFR żviluppaw rispons ematoloġiku (2 CHR u 1 PHR).
The age of these patients ranged from 20 to 72 years.
L- etajiet ta ’ dawn il- pazjent kienu bejn 20 u 72 sena.
In addition a further 24 patients with MDS/ MPD were reported in 13 publications.
Minbarra hekk, 24 pazjent ieħor b’ MDS/ MPD kienu rappurtati f’ 13- il publikazzjoni.
21 patients were treated with Glivec 400 mg daily, while the other 3 patients received lower doses.
21 pazjent kienu kurati b’ Glivec 400 mg kuljum, waqt it- 3 pazjenti l- oħra irċevew dożi aktar baxxi.
In eleven patients PDGFR gene rearrangements was detected, 9 of them achieved a CHR and 1 PHR.
Fi ħdax- il pazjent, tibdil fil- ġene PDGFR kien misjub, 9 minnhom kisbu CHR u 1 PHR.
The age of these patients ranged from 2 to 79 years.
L- etajiet ta ’ dawn il- pazjenti kienu bejn 2 u 79 sena.
In a recent publication updated information from 6 of these 11 patients revealed that all these patients remained in cytogenetic remission (range 32-38 months).
F’ publikazzjoni reċenti tagħrif aġġornat minn 6 minn dawn il- 11 il- pazjent ħabbar li dawn il - pazjenti kollha baqgħu taħt kontroll (medda bejn 32- 38 xahar).
The same publication reported long term follow-up data from 12 MDS/ MPD patients with PDGFR gene rearrangements (5 patients from study B2225).
L- istess publikazzjoni rappurtat dejta fuq żmien twil ta ’ follow- up minn 12 pazjenti b’ MDS/ MPD b’ tibdil fil- ġene PDGFR (5 pazjenti minn studju B2225).
These patients received Glivec for a median of 47 months (range 24 days – 60 months).
Dawn il- pazjenti irċevew Glivec għal medjan ta ’ 47 xahar (medda 24 jum- 60 xahar).
In 6 of these patients follow-up now exceeds 4 years.
F’ 6 minn dawn il- pazjenti, il- follow- up issa jaqbeż l- 4 snin.
Eleven patients achieved rapid CHR; ten had complete resolution of cytogenetic abnormalities and a decrease
Ħdax il- pazjent kisbu CHR malajr, għaxra kellhom fejqan għall- kollox mill- anormalitajiet ċitoġenetiċi u tnaqqis jew tneħħija tat- transcripts ta ’ fużjoni kif imkejjla mill- RT- PCR.
Haematological and cytogenetic responses have been sustained for a median of 49 months (range 19-60) and 47 months (range 16-59), respectively.
Risponsijiet ematoloġiċi u ċitoġenetiċi inżammu għall- medja ta ’ 49 xahar (medda bejn 19 u 60) u 47 xahar (medda 16- 59), rispettivament.
The overall survival is 65 months since diagnosis (range 25-234).
Is- sopravivenza globali hija 65 xahar minn meta saret id- dijanjosi (medda 25- 234).
Glivec administration to patients without the genetic translocation generally results in no improvement.
L- użu ta ’ Glivec f’ pazjenti li ma jkollhomx traslokazzjoni ġeneralment ma tirriżulta fl- ebda titjieb.
Clinical studies in HES/ CEL One open-label, multicentre, phase II clinical trial (study B2225) was conducted testing Glivec in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases.
Provi Kliniċi f’ HES/ CEL Prova klinika waħda open label, f’ ħafna ċentri, ta ’ Fażi II (studju B2225) kien imwettaq billi Glivec kien ittestjat f’ popolazzjonijiet diversi ta ’ pazjenti li jsofru minn mard li jheddu l- ħajja assoċjati ma ’ Abl, Kit jew PDGFR proteini tyrosine kinases.
In this study, 14 patients with HES/ CEL were treated with 100 mg to 1,000 mg of Glivec daily.
Dan l- istudju kien jinkludi 14 pazjenti b’ HES/ CEL li kienu trattati b’ Glivec minn 100 mg sa 1, 000 mg kuljum.
A further 162 patients with HES/ CEL, reported in 35 published case reports and case series received Glivec at doses from 75 mg to 800 mg daily.
162 pazjent ieħor b’ HES/ CEL, rappurtati f’ 35 rapporti ta ’ każijiet u serje ta ’ każijiet li ġew publikati irċevew Glivec b’ dożi bejn 75 mg sa
Cytogenetic abnormalities were evaluated in 117 of the total population of 176 patients.
Anormalitajiet ċitoġenetiċi kienu evalwati f’ 117 mill- popolazzjoni kollha ta ’ 176 pazjent.
In 61 of these 117 patients FIP1L1-PDGFRα fusion kinase was identified.
F’ 61 minn dawn il- 117 pazjent FIP1L1- PDGFRα fusion kinase kien identifikat.
An additional four HES patients were found to be FIP1L1-PDGFRα - positive in other 3 published reports.
Erba ’ pazjenti oħra instabu posittivi għal FIP1L1- PDGFRα f’ 3 rapporti oħra li ġew publikati.
All 65 FIP1L1-PDGFRα fusion kinase positive patients achieved a CHR sustained for months (range from 1+ to 44+ months censored at the time of the reporting).
Il- 65 pazjenti kollha li kienu posittivi għal FIP1L1- PDGFRα fusion kinase kisbu CHR li nżamm għal xhur (medda bejn 1+ sa 44+ xhur ċensurati fil- ħin meta ġew rappurtati).
As reported in a recent publication 21 of these 65 patients also achieved complete molecular remission with a median follow-up of 28 months (range 13-67 months).
Hekk kif rappurtat f’ publikazzjoni riċenti, 21 minn dawn is- 65 pazjent kisbu wkoll remissjoni kompleta molekulari b’ follow- up medju ta ’ 28 xahar (medda 13- 67 xahar).
The age of these patients ranged from 25 to 72 years.
L- etajiet ta ’ dawn il- pazjenti kienu bejn 25 u 72 sena.
Additionally, improvements in symptomatology and other organ dysfunction abnormalities were reported by the investigators in the case reports.
Minbarra hekk, titjieb fis- sintomoloġija u anormalitajiet oħrajn fil- funzjoni ħażina ta ’ l- organi kienu rappurtati mill - investigaturi fir- rapporti ta ’ dawn il- każijiet.
Improvements were reported in cardiac, nervous, skin/ subcutaneous tissue, respiratory/ thoracic/ mediastinal, musculoskeletal/ connective tissue/ vascular, and gastrointestinal organ systems.
Titjieb kienu rappurtati fis- sistemi kardijaċi, nervużi, ġilda/ tessut ta ’ taħt il- ġilda, respiratorju/ toraċiku/ medjastinali/ muskolu- skeletrali / connective tissue/ vaskulari, u gastro- intestinali.
Clinical studies in GIST One phase II, open-label, randomised, uncontrolled multinational study was conducted in patients with unresectable or metastatic malignant gastrointestinal stromal tumours (GIST).
Provi kliniċi fuq GIST Sar studju wieħed ta ’ fażi II, open- label, randomised, mingħajr kontroll, u multinazzjonali f’ pazjenti li kellhom tumuri ta ’ l- istroma gastro- intestinali (GIST) li ma setgħux ikunu operati jew inkella li kienu malinni u mifruxin.
In this study 147 patients were enrolled and randomised to receive either 400 mg or 600 mg orally once daily for up to 36 months.
F’ dan l- istudju 147 pazjent ġew reklutati u mqassma b’ mod randomised biex jieħdu jew 400 mg jew inkella 600 mg mill- ħalq, darba kuljum għal sa 36 xahar.
These patients ranged in age from 18 to 83 years old and had a pathologic diagnosis of Kit-positive malignant GIST that was unresectable and/ or metastatic.
L- età ta ’ dawn il - pazjenti kienet tvarja bejn it- 18 u 83 sena u dawn il- pazjenti kellhom dijanjosi patoloġika ta ’ GIST malinn pożittiv għall- Kit li ma setgħax ikun operat/ jew inkella li kien metastatiku.
Immunohistochemistry was routinely performed with Kit antibody (A-4502, rabbit polyclonal antiserum, 1:100; DAKO Corporation, Carpinteria, CA) according to analysis by an avidin-biotin-peroxidase complex method after antigen retrieval.
Bħala rutina, kienu dejjem isiru testijiet ta ’ l- immunoistokimika b’ anti- korpi Kit (A- 4502, anti- serum poliklonali tal- fenek, 1; 100; Korporazzjoni DAKO, Carpinteria, CA) skond analiżi permezz ta ’ metodu ta ’ kumpless magħmul minn avidin- biotin- peroxidase wara li jkun irkuprat l- antiġen.
The primary evidence of efficacy was based on objective response rates.
L- evidenza ewlenija ta ’ l- effikaċja kienet ibbażata fuq rati ta ’ rispons mkejjla b’ mod oġġettiv.
Tumours were required to be measurable in at least one site of disease, and response characterisation based on Southwestern Oncology Group (SWOG) criteria.
It - tumuri riedu jkunu jistgħu jitkejjlu f’ mill- inqas sit wieħed tal- marda u l- karatterizzazzjoni kellha tkun ibbażata fuq il- kriterji tas- Southwestern Oncology Group (SWOG).
Results are provided in Table 6.
Ir- riżultati jidhru f’ Tabella 6.
Best tumour response in trial STIB2222 (GIST)
L- aqwa rispons tat- tumur fil- prova STIB2222 (GIST)
All doses (n=147) 400 mg (n=73) 600 mg (n=74)
L- aqwa rispons Rispons komplet
Best response Complete response
Id- dożi 400 600
n (%) 1 (0.7)
kollha (n=147) mg (n=73) mg (n=74) n (%) 1 (0. 7)
Partial response Stable disease Progressive disease Not evaluable Unknown
Rispons parzjali Marda stabbli Marda li qed tavvanza Ma jistgħux ikunu evalwati Mhux magħrufa
98 (66.7) 23 (15.6) 18 (12.2) 5 (3.4) 2 (1.4)
98 (66. 7)) 23 (15. 6) 18 (12. 2) 5 (3. 4) 2 (1. 4)
There were no differences in response rates between the two dose groups.
Ma kienx hemm differenzi fir- rati tar- rispons bejn iż- żewġ gruppi ta ’ dożi differenti.
patients who had stable disease at the time of the interim analysis achieved a partial response with longer treatment (median follow-up 31 months).
Numru sinifikanti ta ’ pazjenti li kellhom mard li kien stabbli fil- ħin ta ’ l- analiżi li sar fl- intervall kisbu rispons parzjali b’ kura itwal (medjan tal- follow- up 31 xahar).
Median time to response was 13 weeks (95% C. I.
Iż- żmien medjan għar- rispons kien ta ’ 13- il ġimgħa (95% C. I.
12– 23).
12- 23).
Median time to treatment failure in responders was 122 weeks (95% C. I 106– 147), while in the overall study population it was 84 weeks (95% C. I 71– 109).
71- 109).
The median overall survival has not been reached.
Il- medjan tas- sopravivenza globali ma nstabx.
The Kaplan-Meier estimate for survival after 36-month follow-up is 68%.
L- istima tas- sopravivenza Kaplan- Meier wara 36- xahar ta ’ follow- up hija 68%.
20 In two clinical studies (study B2222 and an intergroup study S0033) the daily dose of Glivec was escalated to 800 mg in patients progressing at the lower daily doses of 400 mg or 600 mg.
F’ żewġ studji kliniċi (studju B2222 u studju b’ grupp intern S0033), id- doża ta ’ Glivec kienet miżjuda għall 800 mg kuljum fil- pazjenti li kienu għaddejin tajjeb bid- dożi aktar baxxi ta ’ 400 mg u 600 mg kuljum.
The daily dose was escalated to 800 mg in a total of 103 patients; 6 patients achieved a partial response and 21 stabilisation of their disease after dose escalation for an overall clinical benefit of 26%.
Id- doża kienet miżjuda għal 800 mg kuljum f’ total ta ’ 103 pazjenti, 6 pazjenti kisbu rispons parzjali u f’ 21 il- marda ġiet stabbli wara żieda fid- doża b’ benefiċju kliniku globali ta ’ 26%.
From the safety data available, escalating the dose to 800 mg daily in patients progressing at lower doses of 400 mg or 600 mg daily does not seem to affect the safety profile of Glivec.
Mit - tagħrif ta ’ sigurtà disponibbli, żieda fid- doża għal 800 mg kuljum f’ pazjenti li kienu għaddejin tajjeb bid- dożi aktar baxxi ta ’ 400 mg u 600 mg kuljum ma jishirx li taffettwa l- profil ta ’ sigurtà ta ’ Glivec.
Clinical studies in DFSP One phase II, open label, multicentre clinical trial (study B2225) was conducted including 12 patients with DFSP treated with Glivec 800 mg daily.
21 Studji kliniċi f’ DFSP Prova klinika waħda ta ’ Fażi II, open label, f’ ħafna ċentri (studju B2225) kien imwettaq b’ 12- il pazjent b’ DFSP kurata b’ Glivec 800 mg kuljum.
The age of the DFSP patients ranged from 23 to 75 years; DFSP was metastatic, locally recurrent following initial resective surgery and not considered amenable to further resective surgery at the time of study entry.
L- etajiet tal- pazjenti kienu bejn 23 u 75 sena; DFSP kien metastatiku, reġa ħareġ fil- post wara li kien tneħħa b’ operazzjoni, u kien meqjus li aħjar ma jerġax issir operazzjoni oħra ta ’ tneħħija fil- ħin tad- dħul fl- istudju.
The primary evidence of efficacy was based on objective response rates.
L- evidenza primarja ta ’ l - effikaċja kienet bażata fuq rati ta ’ rispons oġġettivi.
Out of the 12 patients enrolled, 9 responded, one completely and 8 partially.
Mit- 12- il pazjent reklutat, 9 wrew rispons, wieħed komplet u 8 parzjali.
Three of the partial responders were subsequently rendered disease free by surgery.
Wara, tlieta minn dawk li wrew rispons parzjali tneħħitilhom il- marda permezz ta’ operazzjoni.
The median duration of therapy in study B2225 was 6.2 months, with a maximum duration of 24.3 months.
It- terapija fi studju B2225 damet medja ta ’ 6. 2 xhur, l- aktar li damet kienet 24. 3 xhur.
A further 6 DFSP patients treated with Glivec were reported in 5 published case reports, their ages ranging from 18 months to 49 years.
6 pazjenti oħra b’ DFSP kurati b’ Glivec kienu rappurtati f’ 5 rapporti dwar każijiet, b’ etajiet li jvarjaw minn 18- il xahar sa 49 sena.
The adult patients reported in the published literature were treated with either 400 mg (4 cases) or 800 mg (1 case) Glivec daily.
Il- pazjenti adulti rappurtati fil- publikazzjoni kienu kurati jew b’ 400 mg (4 każijiet) jew 800 mg (każ 1) Glivec kuljum.
The paediatric patient received 400 mg/ m2/ daily, subsequently increased to 520 mg/ m2/ daily.
Il- pazjent pedjatriku rċieva 400 mg/ m2/ kuljum, u wara kien miżjud għal 520 mg/ m2/ kuljum.
5 patients responded, 3 completely and 2 partially.
5 pazjenti wrew rispons, 3 komplet u 2 parzjali.
The median duration of therapy in the published literature ranged between 4 weeks and more than 20 months.
Il- tul medjan tat - terapija tal- publikazzjoni kien ivarja bejn 4 ġimgħat u aktar minn 20 xahar.
The translocation t(17:22)[(q22: q13)], or its gene product, was present in nearly all responders to Glivec treatment.
It- translokazzjoni t17: 22) [(q22: q13)], jew il- prodott tal- ġene tiegħu, instab fil- pazjenti kollha li wrew rispons għall- kura b’ Glivec.
Pharmacokinetics of Glivec The pharmacokinetics of Glivec have been evaluated over a dosage range of 25 to 1,000 mg.
Il- farmakokinetiċi ta ’ Glivec Il- farmakokinetiċi ta ’ Glivec kienu stmati għal dożaġġ li jvarja minn 25 sa 1, 000 mg.
Plasma pharmacokinetic profiles were analysed on day 1 and on either day 7 or day 28, by which time plasma concentrations had reached steady state.
Il- profili farmakokinetiċi fil- plażma kienu analizzati fl- 1 jum u jew fis- 7 jum jew inkella fit- 28 jum, sakemm il - konċentrazzjonijiet fil- plażma kienu laħqu stat fiss.
Absorption Mean absolute bioavailability for the capsule formulation is 98%.
Assorbiment Il- biodisponibiltà assoluta medja għall- formulazzjoni f’ għamla ta ’ kapsula hija ta ’ 98%.
There was high between-patient variability in plasma imatinib AUC levels after an oral dose.
Il- varjabilità minn pazjent għall- ieħor tal- livelli ta ’ l- AUC ta ’ imatinib fil- plażma wara li tkun ingħatat doża mill - ħalq, kienet kbira.
When given with a high-fat meal, the rate of absorption of imatinib was minimally reduced (11% decrease in Cmax and prolongation of tmax by 1.5 h), with a small reduction in AUC (7.4%) compared to fasting conditions.
Meta ingħata fl- istess ħin ma ’ ikla li kien fiha ħafna xaħam, ir- rata li biha imatinib ġie assorbit tnaqqset b’ ammont minimu (tnaqqis bi 11% fis- Cmax u titwil tat- tmax b ’ 1. 5 sigħat), bi tnaqqis żgħir fl- AUC (7. 4%) meta mqabbla ma ’ dawk ta ’ pazjenti sajmin.
The effect of prior gastrointestinal surgery on drug absorption has not been investigated.
L- effett ta ’ operazzjonijiet gastro- intestinali li jkunu saru fl- imgħoddi fuq l- assorbiment tal- mediċina ma ġewx investigati.
Distribution At clinically relevant concentrations of imatinib, binding to plasma proteins was approximately 95% on the basis of in vitro experiments, mostly to albumin and alpha-acid-glycoprotein, with little binding to lipoprotein.
Distribuzzjoni F’ konċentrazzjonijiet ta ’ imatinib li kienu klinikament relevanti, l- irbit mal- proteini tal- plażma kien ta ’ xi 95% bażati fuq esperimenti li saru in vitro, l- aktar ma ’ l- albumina u ma ’ alpha acid glycoprotein, bi ftit li xejn irbit mal- lipoprotein.
Metabolism The main circulating metabolite in humans is the N-demethylated piperazine derivative, which shows similar in vitro potency to the parent.
Metaboliżmu Il- metabolu ewlieni fiċ- ċirkolazzjoni li jirriżulta mill- metaboliżmu ta ’ imatinib fil- bniedem huwa d - derivat ta ’ N- demethylated piperazine, li in vitro għandu saħħa daqs is- sustanza oriġinali.
The plasma AUC for this metabolite was found to be only 16% of the AUC for imatinib.
L- AUC tal - plażma għal dan il- metabolu kienet biss 16% ta ’ l- AUC għal imatinib.
Imatinib and the N-demethyl metabolite together accounted for about 65% of the circulating radioactivity (AUC(0-48h)).
Imatinib u l- metabolu N- demethyl flimkien kienu jgħoddu għal xi 65% tar- radjuattività fiċ - ċirkolazzjoni (AUC( 0- 48h)).
The remaining circulating radioactivity consisted of a number of minor metabolites.
Ir- radjuattività l- oħra fiċ- ċirkolazzjoni kienet minħabba numru ta’ metaboli minuri.
The in vitro results showed that CYP3A4 was the major human P450 enzyme catalysing the biotransformation of imatinib.
Ir- riżultati in vitro wrew li CYP3A4 kienet l- enzima prinċipali fil- bniedem tat- tip P450 li tikkatalizza l- biotransformazzjoni ta ’ imatinib.
Of a panel of potential comedications (acetaminophen, aciclovir, allopurinol, amphotericin, cytarabine, erythromycin, fluconazole, hydroxyurea, norfloxacin, penicillin V) only erythromycin (IC50 50 µM) and fluconazole (IC50 118 µM) showed inhibition of imatinib metabolism which could have clinical relevance.
Minn fost għadd ta ’ medikazzjonijiet li jistgħu jingħataw fl- istess ħin (acetaminophen, aciclovir, allopurinol, amphoteracin, cytarabine, erythromycin, fluconazole, hydroxyurea, norfloxacin, penicillin V), kienu biss erythromycin (IC50 50 µM) u fluconazole (IC50 118 µM) li inibixxew il- metaboliżmu ta ’ imatinib b’ mod li seta ’ kellu xi relevanza klinika.
21 Imatinib was shown in vitro to be a competitive inhibitor of marker substrates for CYP2C9, CYP2D6 and CYP3A4/ 5.
Ir- riżultati in vitro wrew li imatinib jinibixxi b’ mod kompetittiv lis- sustanzi markaturi li fuqhom jaħdmu l- enzimi CYP2C9, CYP2D6 u CYP3A4/ 5.
Ki values in human liver microsomes were 27, 7.5 and 7.9 µmol/ l, respectively.
Il- valuri Ki fil- mikrosomi tal- fwied tal- bniedem kienu 27, 7. 5 u 7. 9 µmol/ l, rispettivament.
Maximal plasma concentrations of imatinib in patients are 2– 4 µmol/ l, consequently an inhibition of CYP2D6 and/ or CYP3A4/ 5-mediated metabolism of co-administered drugs is possible.
L- ogħla konċentrazzjonijiet fil- plażma ta ’ imatinib fil - pazjenti jvarjaw minn 2- 4 µmol/ l, u għaldaqstant huwa possibbli li jinibixxi l- metaboliżmu permezz ta ’ CYP2D6 u / jew CYP3A4/ 5 ta ’ mediċini li jingħataw fl- istess ħin miegħu.
Imatinib did not interfere with the biotransformation of 5-fluorouracil, but it inhibited paclitaxel metabolism as a result of competitive inhibition of CYP2C8 (Ki = 34.7 µM).
Imatinib ma fixkilx il - biotrasformazzjoni ta ’ 5- fluoruracil, iżda inibixxa l- metaboliżmu ta ’ paclitaxel billi inibixxa b’ mod
This Ki value is far higher than the expected plasma levels of imatinib in patients, consequently no interaction is expected upon co- administration of either 5-fluorouracil or paclitaxel and imatinib.
Dan il- valur ta ’ Ki huwa bill- wisq ogħla mill- livelli ta ’ imatinib mistennija li jkunu fil- plażma tal- pazjenti, u għaldaqstant mhux mistenni li jkun hemm interazzjoni meta jew 5- fluorouracil jew paclitaxel jingħataw flimkien ma ’ imatinib.
Elimination Based on the recovery of compound(s) after an oral 14C-labelled dose of imatinib, approximately 81% of the dose was recovered within 7 days in faeces (68% of dose) and urine (13% of dose).
Eliminazzjoni Mill- ammont ta ’ sustanza( i) li kien( u) rkuprat( i) wara doża mill- ħalq ta ’ imatinib immarkat bil- 14C, bejn wieħed u ieħor 81% tad- doża kienet irkuprata fi żmien 7 ijiem fl- ippurgar (68% tad- doża) u fl - awrina (13% tad- doża).
Unchanged imatinib accounted for 25% of the dose (5% urine, 20% faeces), the remainder being metabolites.
25% tad- doża ta ’ imatinib kienet eliminata fil- forma mhux mibdula (5% fl - awrina, 20% fl- ippurgar) u l- bqija kienu tneħħew bħala sustanzi li jirriżultaw mill- metaboliżmu.
Plasma pharmacokinetics Following oral administration in healthy volunteers, the t½ was approximately 18 h, suggesting that once-daily dosing is appropriate.
Farmakokinetiċi tal- plażma Wara li l- mediċina ngħatat mill- ħalq lil numru ta ’ voluntiera li kienu f’ saħħithom, it- t½ kien ta ’ bejn wieħed u ieħor 18- il siegħa, u dan jissuġerixxi li doża ta ’ darba kuljum hija xieraqa.
The increase in mean AUC with increasing dose was linear and dose proportional in the range of 25– 1,000 mg imatinib after oral administration.
L- AUC medja tiżdied b’ mod linjari ma ’ żieda fid- doża, u ż- żieda fl- AUC medja hija wkoll proporzjonali għad- doża f ’ dożi ta ’ bejn 25- 1, 000 mg ta ’ imatinib mill- ħalq.
There was no change in the kinetics of imatinib on repeated dosing, and accumulation was 1.5– 2.5-fold at steady state when dosed once daily.
Ma kien hemm l- ebda bidla fil- farmakokinetiċi ta ’ imatinib meta ngħataw dożi ripetuti, u kien hemm akkumulazjoni ta ’ 1. 5- 2. 5- il darba fl- istat fiss meta d- doża ingħatat darba kuljum.
Pharmacokinetics in GIST patients In patients with GIST steady-state exposure was 1.5-fold higher than that observed for CML patients for the same dosage (400 mg daily).
Farmakokinetiċi f’ pazjenti b’ GIST F’ pazjenti b’ GIST l- esponiment f’ livelli fissi, kien 1. 5- il darba ogħla minn dak li ġie osservat f ’ pazjenti b ’ CML li kienu fuq l- istess doża (400 mg kuljum).
Based on preliminary population pharmacokinetic analysis in GIST patients, there were three variables (albumin, WBC and bilirubin) found to have a statistically significant relationship with imatinib pharmacokinetics.
Skond analiżi farmakokinetika preliminari tal- popolazzjoni f ’ pazjenti b’ GIST, jidher li kien hemm tlett varjanti (albumina, WBC, u bilirubin) li kellhom relazzjoni mal- farmakokinetiċi ta ’ imatinib li kienet statistikament sinifikanti.
Decreased values of albumin caused a reduced clearance (CL/ f); and higher levels of WBC led to a reduction of CL/ f.
Tnaqqis fil - livell ta ’ albumina rriżulta fi tnaqqis fil- clearance (CL/ f); u livelli ogħla ta ’ WBC wasslu għal tnaqqis ta ’ CL/ f.
However, these associations are not sufficiently pronounced to warrant dose adjustment.
Madankollu, dawn l- assoċjazzjonijiet mhumiex qawwija biżżejjed biex ikun meħtieġ tibdil fid- doża.
In this patient population, the presence of hepatic metastases could potentially lead to hepatic insufficiency and reduced metabolism.
F’ dan il- grupp ta ’ pazjenti, jidher li metastasi fil- fwied setgħet twassal għal tnaqqis fil - funzjoni tal- fwied u allura għal tnaqqis fil- metaboliżmu.
Population pharmacokinetics Based on population pharmacokinetic analysis in CML patients, there was a small effect of age on the volume of distribution (12% increase in patients > 65 years old).
Farmakokinetiċi tal- popolazzjoni Skond analiżi tal- farmakokinetiċi tal- grupp ta ’ pazjenti b’ CML, kien hemm effett żgħir ta ’ l- età fuq il - volum ta ’ distribuzzjoni (żieda ta ’ 12% f ’ pazjenti li għandhom > 65 sena).
This change is not thought to be clinically significant.
Dan l- effett mhux maħsub li hu klinikament sinifikanti.
The effect of bodyweight on the clearance of imatinib is such that for a patient weighing 50 kg the mean clearance is expected to be 8.5 l/ h, while for a patient weighing 100 kg the clearance will rise to 11.8 l/ h.
L- effett tal- piż tal- ġisem fuq il- clearance ta ’ imatinib huwa tali li f’ pazjent li jiżen 50 kg il- clearance medja mistennija tkun 8. 5 l/ siegħa, filwaqt li f’ pazjent ta ’ 100 kg il- clearance titla ’ għal 11. 8 l/ siegħa.
These changes are not considered sufficient to warrant dose adjustment based on kg bodyweight.
Dawn l- effetti mhumiex meqjusa qawwija biżżejjed biex jiġġustifikaw xi aġġustament tad- doża li jkun bbażat fuq il- piż tal- ġisem f’ kilogrammi.
There is no effect of gender on the kinetics of imatinib.
Il - farmakokinetiċi ta ’ imatinib huma l- istess fin- nisa u fl- irġiel.
Pharmacokinetics in children As in adult patients, imatinib was rapidly absorbed after oral administration in paediatric patients in both phase I and phase II studies.
Farmakokinetiċi fit- tfal Bħal fl- adulti, imatinib kien assorbit malajr wara li ngħata mill- ħalq lill- pazjenti pedjatriċi fi studju ta ’ fażi I u ta ’ fażi II.
Dosing in children at 260 and 340 mg/ m2/ day achieved the same exposure, respectively, as doses of 400 mg and 600 mg in adult patients.
Dożi ta ’ 260 u 340 mg/ m2/ jum kisbu l- istess esponiment, rispettivament, bħalma jkun hemm fl- adulti b’ dożi ta ’ 400 mg u 600 mg.
The comparison of AUC(0-24) on day 8 and day 1 at the 340 mg/ m2/ day dose level revealed a 1.7-fold drug accumulation after repeated once-daily dosing.
Meta ġew imqabbla l- AUC( 0- 24) fit- 8 jum u fl- 1 jum fl- livell ta ’ doża ta ’ 340 mg/ m2/ jum, instab li l- mediċina kienet akkumulat b ’ 1. 7- il darba wara dożi ripetuti ta ’ darba kuljum.
Patients with mild and moderate impairment of renal function appear to have a higher plasma exposure than patients with normal renal function.
Indeboliment fil- funzjoni ta ’ l- organi Imatinib u s- sustanzi li jirriżultaw mill- metaboliżmu tiegħu ma jitneħħewx mill- kliewi f’ xi ammonti li huma sinifikanti. Pazjenti li jsofru minn indeboliment tal- kliewi ħafif u moderat jidher li jkollhom esponiment akbar milli f’ pazjenti b’ funzjoni normali tal- kliewi.
The increase is approximately 1.5- to 2-fold, corresponding to a 1.5-fold elevation of plasma AGP, to which imatinib binds strongly.
Iż- żieda tkun bejn 1. 5- il- darba għal darbtejn akbar, li tikkorrispondi għal żieda ta ’ 1. 5- il- darba fl- AGP tal- plasma, li miegħu imatinib jintrabat bil- qawwa.