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Tasigna (Nilotinib) - Description and Clinical Pharmacology

 
 



      DESCRIPTION

Tasigna (nilotinib) belongs to a pharmacologic class of drugs known as kinase inhibitors.

Nilotinib drug substance, a monohydrate mono-hydrochloride, is a white to slightly yellowish to slightly greenish yellow powder with the anhydrous molecular formula and weight, respectively, of C28H22F3N7O•HCl • H2O and 565.98. The solubility of nilotinib in aqueous solutions decreases with increasing pH. Nilotinib is not optically active. The pKa1 was determined to be 2.1; pKa2 was estimated to be 5.4.

The chemical name of nilotinib is 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide, monohydrochloride, monohydrate. Its structure is shown below:

  

Tasigna (nilotinib) capsules, for oral use, contain 200 mg nilotinib base, anhydrous (as hydrochloride, monohydrate) with the following inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate and polyoxamer 188. The capsules contain gelatin, iron oxide (red), iron oxide (yellow), and titanium dioxide.

      CLINICAL PHARMACOLOGY

      Mechanism of A ction

Nilotinib is an inhibitor of the Bcr-Abl kinase. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of Abl protein. In vitro, nilotinib inhibited Bcr-Abl mediated proliferation of murine leukemic cell lines and human cell lines derived from Ph+ CML patients. Under the conditions of the assays, nilotinib was able to overcome imatinib resistance resulting from Bcr-Abl kinase mutations, in 32 out of 33 mutations tested. In vivo, nilotinib reduced the tumor size in a murine Bcr-Abl xenograft model. Nilotinib inhibited the autophosphorylation of the following kinases at IC50 values as indicated: Bcr-Abl (20-60 nM), PDGFR (69 nM) and c-Kit (210 nM).

. 3       Pharmacokinetics

Absorption and Distribution :

Peak concentrations of nilotinib are reached 3 hours after oral administration.

Steady-state nilotinib exposure was dose-dependent with less than dose-proportional increases in systemic exposure at dose levels higher than 400 mg given as once daily dosing. Daily serum exposure to nilotinib of 400 mg twice daily dosing at steady state was 35% higher than with 800 mg once daily dosing. There was no relevant increase in exposure to nilotinib when the dose was increased with 400 mg twice daily to 600 mg twice daily.

The bioavailability of nilotinib was increased when given with a meal. Compared to the fasted state, the systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high fat meal. 

The blood-to-serum ratio of nilotinib is 0.68. Serum protein binding is approximately 98% on the basis of in vitro experiments.  

Pharmacokinetics, Metabolism and Excretion :

The apparent elimination half-life estimated from the multiple dose pharmacokinetic studies with daily dosing was approximately 17 hours. Inter-patient variability in nilotinib AUC was 32% to 64%. Steady state conditions were achieved by day 8. An increase in serum exposure to nilotinib between the first dose and steady state was approximately 2-fold for daily dosing and 3.8-fold for twice-daily dosing.

Main metabolic pathways identified in healthy subjects are oxidation and hydroxylation. Nilotinib is the main circulating component in the serum. None of the metabolites contribute significantly to the pharmacological activity of nilotinib.

After a single dose of radiolabeled nilotinib in healthy subjects, more than 90% of the administered dose was eliminated within 7 days mainly in feces (93% of the dose). Parent drug accounted for 69% of the dose.  

Age, body weight, gender, or ethnic origin did not significantly affect the pharmacokinetics of nilotinib.

      QT/QTc Prolongation

      In a placebo-controlled study in healthy volunteers designed to assess the effects of Tasigna on the QT interval, administration of Tasigna was associated with concentration-dependent QT prolongation; the maximum mean placebo-adjusted QTcF change from baseline was 18 msec (1-sided 95% Upper CI: 26 msec).  A positive control was not included in the QT study of healthy volunteers. Peak plasma concentrations in the QT study were 26% lower than those observed in patients enrolled in the single-arm study [ See Boxed Warning , Warnings and Precautions (5.2 ) and Clinical Studies (14) ] .

      Pharmacogenomics

      Tasigna can increase bilirubin levels. A pharmacogenetic analysis of 97 patients evaluated the polymorphisms of UGT1A1 and its potential association with hyperbilirubinemia during Tasigna treatment. In this study, the (TA)7/(TA)7 genotype was associated with a statistically significant increase in the risk of hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes. However, the largest increases in bilirubin were observed in the (TA)7/(TA)7 genotype (UGT1A1*28) patients [ See Warnings and Precautions (5. 5 ) ] .

      NONCLINICAL TOXICOLOGY

      Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed. 

Nilotinib was not mutagenic in a bacterial mutagenesis (Ames) assay, was not clastogenic in a chromosome aberration assay in human lymphocytes, did not induce DNA damage (comet assay) in L5178Y mouse lymphoma cells, nor was it clastogenic in an in vivo rat bone marrow micronucleus assay with two oral treatments at doses up to 2000 mg/kg/dose.

There were no effects on male or female rat and female rabbit mating or fertility at doses up to 180 mg/kg in rats (approximately 4-7 fold for males and females, respectively, the AUC in patients at the recommended human dose) or 300 mg/kg in rabbits (approximately one-half the AUC in patients at the recommended human dose). The effect of Tasigna on human fertility is unknown. In a study where male and female rats were treated with nilotinib at oral doses of 20-180 mg/kg/day (approximately 1-6.6 fold the AUC in patients at the recommended human dose) during the pre-mating and mating periods and then mated, and dosing of pregnant rats continued through gestation day 6, nilotinib increased post-implantation loss and early resorption, and decreased the number of viable fetuses and litter size at all doses tested.

      CLINICAL STUDIES

A single open label multicenter study was conducted to evaluate the efficacy and safety of Tasigna in patients with imatinib-resistant or -intolerant CML with separate cohorts for chronic and accelerated phase disease. The definition of imatinib resistance included failure to achieve a complete hematologic response (by 3 months), cytogenetic response (by 6 months) or major cytogenetic response (by 12 months) or progression of disease after a previous cytogenetic or hematologic response. Imatinib intolerance was defined as discontinuation of treatment due to toxicity and lack of a major cytogenetic response at time of study entry. At the time of data cut-off, 280 CML-CP patients with a minimum follow-up of 6 months and 105 CML-AP patients with a minimum follow-up of 4 months were enrolled. Of these, 232 CML-CP and all CML-AP patients were evaluable for efficacy. In this study, about 50% of CML-CP and CML-AP patients were males, over 80% were Caucasian, and approximately 30% were age 65 years or older.  

Overall, 73% of patients were imatinib resistant while 27% were imatinib intolerant.  The median time of prior imatinib treatment was approximately 31 months.  Prior therapy included hydroxyurea in 85% of patients, interferon in 62% and stem cell or bone marrow transplant in 8%.  The median highest prior imatinib dose was 600 mg/day for CML-CP patients and 800 mg/day for CML-AP patients, and the highest prior imatinib dose was ≥600 mg/day in 77% of all patients with 44% of patients receiving imatinib doses ≥ 800 mg/day.

      Median duration of nilotinib treatment was 8.7 months in CML-CP patients and 5.6 months in CML-AP patients.  

The efficacy endpoint in chronic phase CML was unconfirmed major cytogenetic response (MCyR) which included complete and partial cytogenetic responses.  

 The efficacy endpoint in accelerated phase CML was confirmed hematologic response (HR), defined as either a complete hematologic response (CHR) or no evidence of leukemia (NEL). The rates of response for CML-CP and CML-AP patients are reported in Table 6. 

Table 6       Efficacy of Tasigna in CML

Cytogenetic Response Rate   (Unconfirmed)   (%) a Chronic Phase
n=232
Major (95%CI)40% (33,46)
Complete (95% CI)28% (22,34)
Partial (95% CI)12% (8,16)
Accelerated Phase
n=105
Hematologic Response R ate (95%CI) b 26% (18,35)
Complete Hematologic Response Rate (95% CI)18% (11,27)
No Evidence of Leukemia (95% CI)
8% (3,15)

a Cytogenetic response criteria: Complete (0% Ph + metaphases) or partial (1-35%). Cytogenetic responses were based on the percentage of Ph-positive metaphases among ≥ 20 metaphase cells in each bone marrow sample.

b  Hematologic response = CHR + NEL (all responses confirmed after 4 weeks).

CHR (CML-CP): WBC <10 x 109 /L, platelets < 450,000/mm3, no blasts or promyelocytes in peripheral blood, < 5% myelocytes + metamyelocytes in bone marrow, <20% basophils in peripheral blood, and no extramedullary involvement.

CHR (CML-AP): neutrophils > 1.5 x 109 /L, platelets > 100 x 109 /L, no myeloblasts in peripheral blood, myeloblasts < 5% in bone marrow, and no extramedullary involvement.

NEL: same criteria as for CHR but neutrophils > 1.0 x 109 /L and platelets > 20 x 109 /L without       transfusions or bleeding.

The median duration of response has not been reached for CML-CP and CML-AP. Based on current follow-up, 59% of CML-CP patients with a major cytogenetic response had a duration of response of at least 6 months. Based on current follow-up, 63% of CML-AP patients with a confirmed hematologic response had a duration of response of at least 6 months. 

After imatinib failure, 24 different BCR-ABL mutations were noted in 19% of chronic phase and 25% of accelerated phase CML patients who were evaluated for mutations. Patients harboring a variety of BCR-ABL mutations associated with imatinib resistance, except T315I, responded to Tasigna.

      In this study of imatinib-resistant or intolerant CML patients, the maximum mean QTcF change from baseline at steady state was 10 msec. Increase in QTcF > 60 msec from baseline was observed in 2.1% of the patients and QTcF of > 500 msec was observed in 3 patients (< 1%). No episodes of torsade de pointes were observed in clinical studies. [ See Boxed Warning, Warnings and Precautions (5.2) and Clinical Pharmacology (12.4) ].

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