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Thyrosin Kinase Inhibitors: Nilotinib F Hematology Meeting Reports 2008;2(5):22-26 SESSION II F. Castagnetti Thyrosin kinase inhibitors: nilotinib F. Palandri G. Gugliotta A. Poerio M. Amabile S. Soverini G. Martinelli M. Baccarani G. Rosti Nilotinib is an aminopyrimidine The only BCR-ABL mutant that derivative that inhibits the tyro- was not inhibited by nilotinib was Department of Hematology, St. Orsola University Hospital sine kinase activity of the T315I. Bologna, Italy chimeric protein BCR-ABL. The unregulated activity of the ABL tyrosine kinase in the BCR-ABL Pharmacokinetic profile protein causes CML, and inhibi- tion of tyrosine kinase activity is The extent of nilotinib absorp- key to the treatment of the disor- tion following oral administration der. Nilotinib acts via competitive was estimated to be approximate- inhibition at the binding site of the ly 30%. The bioavailability of BCR-ABL protein in a similar nilotinib was increased when manner to imatinib, although nilo- given with a meal. Compared to tinib has a higher binding affinity the fasted state, the systemic and selectivity for the ABL exposure (AUC) in the fed state kinase. Once bound to the ATP- increased by 15% (drug adminis- binding site, nilotinib inhibits tered 2 hours after a light meal), tyrosine phosphorylation of pro- 29% (30 minutes after a light teins involved in BCR-ABL- meal), or 82% (30 minutes after a mediated intracellular signal high fat meal), and the Cmax transduction. increased by 33% (2 hours after a The inhibitory activity of nilo- light meal), 55% (30 minutes tinib in CML cell is markedly after a light meal), or 112% (30 higher than that of imatinib. In minutes after a high fat meal). In sensitive CML cell lines, the the large phase I study, with oral inhibitory ctivity of nilotinib is nilotinib at dosages of 50-1200 20-50 times that of imatinib. For mg once daily, as well as 400 or example, mean 50% inhibitory 600 mg twice daily, trough serum concentrations (IC50) of cellular concentrations exceeded the IC50 BCR-ABL autophosphorylation for cellular phosphorylation of and proliferation of Ba/F3 BCR- BCR-ABL. With once daily dos- ABL cells were 21 and 25 ing at steady-state, Cmax and AUC nmol/L, respectively, for nilotinib increased with increasing dose compared with 220 and 649 from 50 mg to 400 mg in a gener- nmol/L for imatinib. The inhibito- ally dose-proportional manner, ry activity of nilotinib is 3- to 7- but appeared to plateau at dose fold that of imatinib in imatinib- levels starting at 400 mg, remain- resistant. Nilotinib demonstrated ing relatively constant over the inhibitory activity in 32 of 33 dose range from 400 mg to 1200 imatinib-resistant CML cell lines mg. Dividing the daily dose in a | 22 | New Drugs in Hematology twice daily schedule overcame the dose-limit- that nilotinib pharmacokinetics is not affected ing exposure to some extent with daily steady- by age. Pharmacokinetics of nilotinib has not state serum exposure to nilotinib with 400 mg been investigated in subjects with impaired twice daily dose being approximately 35% hepatic function. Impaired renal function is greater than with 800 mg once daily dose. not expected to influence nilotinib pharmaco- However, there was no further relevant kinetics. increase in exposure to nilotinib when given 600 mg dose with the twice daily schedule (1200 mg/day). With multiple oral doses of Efficacy nilotinib, steady-state conditions were achieved by day 8 after initiating nilotinib Phase I study treatment. There was a 2-fold or 3.8-fold accu- A Phase I study was conducted in 119 mulation with once daily dosing or twice daily patients with imatinib resistant CML in BP dosing, respectively, in serum concentrations (n=33), AP (n=56), CP (n=17) and Ph pos ALL between the first-dose and steady-state. The (n=13).39 Patients in this study were treated at median time to reach ma of nilotinib (tmax) was 3 once daily dose levels ranging from 50 mg QD hours. Drug elimination half-lives calculated to 1200 mg QD, and at twice daily dose levels during the dose interval averaged 17 hours for of 400 mg BID and 600 mg BID. Intrapatient once daily dosing, consistent with the dose escalations were permitted. The 400 mg observed accumulation in serum concentra- BID dose level was chosen for further devel- tions. Elimination half-lives of the biphasic opment in Phase II trials, with dose escalation plasma profile were 1.5 h (83% of AUC) and to 600 mg BID permitted for lack of response. 116 h for the rat. The binding of nilotinib to Complete hematologic and cytogenetic plasma proteins was high and there were no response by CML disease classification species differences. When radiolabeled nilo- (n=106) is shown in Table 1. The response in tinib was administered intravenously to rats, Ph pos ALL patients (n=13) is not shown. drug-related radioactivity was widely distrib- uted to most tissues, consistent with a large volume of distribution. There was a minimal passage for drug-related radioactivity across the blood:brain and blood:testis barriers. Table 1. Response in Phase I study by disease classification Nilotinib was eliminated in the rats mainly via CML-CP CML-AP CML-AP CML-BP oxidative metabolism. Based on its inhibition (clonal (myeloid evolution)1 and (IC50 ≤7.5 µM) for CYP enzymes, 2C8, 2C9, 2C19, 2D6, and 3A4/5, nilotinib may inhibit lymphoid) the metabolic clearance of comedications N=17 (%) N=46 (%) N=102 (%) N=33 (%) metabolized by these CYP enzymes, if suffi- Complete 11 (92) 28 (61) 5 (100) 2 (8) ciently high concentrations of nilotinib are Hematologic achieved in vivo. Exposure to nilotinib in Response female patients was approximately 20% Complete 6 (35) 9 (20) 5 (50) 2 (6) greater than in male patients. There was no Cytogenetic difference in nilotinib apparent clearance Response between Caucasians and non- Caucasians. The 1CML-AP (clonal evolution) includes patients whose only AP criterion was clonal evolution; 2CML-AP clonal evolution group had a total n of 10 population pharmacokinetic analysis showed patients, but only 5 were evaluable for hematologic response. Hematology Meeting Reports 2008;2(5) | 23 | F. Castagnetti et al. Phase II study in late chronic phase obtained in 26% of patients, and a PHR in A phase II open-label study (NCT0010 21% of patients. The CgR was complete in 9707) was designed to evaluate the safety and 16% of pts, partial in 14% of patients, and efficacy as defined by hematologic/cytoge- minor in 13% of pts, for an overall CgR rate netic response rates (HR/CgR) of nilotinib of 43%. After 6 months, 40% of pts were still administered at a daily dose of 400 mg BID to on treatment, while 60% had discontinued, imatinib resistant or intolerant CML-CP for disease progression (29%), AEs (13%), or patients. Daily doses of nilotinib could be other causes (18%). escalated to 600 mg BID for patients who did 132 patients with IM-resistant or intolerant not adequately respond to treatment, and in Ph pos CML in BP were treated with NIL 400 the absence of safety concerns. mg twice daily.45 A HR was achieved in 39% The majority of patients were imatinib of patients, and was complete in 25%. resistant (91 patients, 69%) and 41 (31%) were imatinib intolerant. Nearly half (49%) Nilotinib front-line in early CP CML, phase II and III studies had the disease for ≥5 years. Patients have been treated with nilotinib for a median dura- A phase 2 exploratory study of NIL front- tion of 226 days (range 3-379 days). line, 400 mg twice daily, is currently running Complete hematologic response (CHR) in at the MD Anderson Hospital, Houston. patients without CHR at baseline was Twenty-two patients were treated for at least achieved in 69% of patients (60 of 87 3 months and 95% of them achieved a CCgR. patients). Major cytogenetic response was Eleven patients were treated for 12 months, achieved in 42% (55 of 132 patients). A com- and were all in CCgR. Grade 3/4 neutropenia plete cytogenetic response was achieved in 33 and thrombocytopenia were observed in 7% (25%) and 22 (17%) were partial cytogenetic and 3% of patients. Other grade 3/4 AEs responses in this imatinib resistant/intolerant included transitory elevation of lipase (9%), population. The median time to CHR was 1.4 bilirubine (6%), amylase (3%), and infection months and MCyR was 2.6 months. A total of (3%). 50 (38%) patients have discontinued treat- A phase 2 exploratory study of NIL front- ment (26 for adverse events, 15 for disease line in Ph pos CML has been promoted and progression, 7 for other/administrative prob- sponsored by the GIMEMA CML WP lems, and 2 for patient deaths (one myocar- (EUDRACT No. 2007 000597 22). The study dial infarction in a patient with previous has enrolled 73 patients from July 2007 to infarctions noted and one with progressive February 2008. First available results have disease). Overall, most frequent Grade 3 or 4 been presented at 2008 EHA meeting: the adverse events included thrombocytopenia in complete cytogenetic response and the major 34 patients (26%), neutropenia in 24 (18%), molecular response were 84% and 62% at 3 elevated serum lipase in 10 (8%) and anemia months and 97% and 74% at 6 months, in 9 (7%). respectively. A phase III study of NIL vs IM in the treatment front-line of Ph pos CML has Phase II studies in accelerated phase and in blast phase been promoted and sponsored by Novartis 119 patients with IM-resistant or intolerant Pharma, and has already enrolled more than Ph pos CML in AP were treated with NIL 400 200 patients (Study CAMN107A2303, mg twice daily.44 A confirmed CHR was EUDRACT 2007-000208-34).
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