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Sprycel (Dasatinib) - Description and Clinical Pharmacology

 
 



DESCRIPTION

SPRYCEL (dasatinib) is a kinase inhibitor. The chemical name for dasatinib is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate. The molecular formula is C22H26ClN7O2S • H2O, which corresponds to a formula weight of 506.02 (monohydrate). The anhydrous free base has a molecular weight of 488.01. Dasatinib has the following chemical structure:

Dasatinib is a white to off-white powder. The drug substance is insoluble in water and slightly soluble in ethanol and methanol. SPRYCEL tablets are white to off-white, biconvex, film-coated tablets containing dasatinib, with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate. The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol.

CLINICAL PHARMACOLOGY

Mechanism of Action

Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase.

In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate sensitive and resistant disease. Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib was able to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression.

Pharmacokinetics

Absorption

Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and 6 hours (Tmax) following oral administration. Dasatinib exhibits dose proportional increases in AUC and linear elimination characteristics over the dose range of 15 mg to 240 mg/day. The overall mean terminal half-life of dasatinib is 3–5 hours.

Data from a study of 54 healthy subjects administered a single, 100-mg dose of dasatinib 30 minutes following consumption of a high-fat meal resulted in a 14% increase in the mean AUC of dasatinib. The observed food effects were not clinically relevant.

Distribution

In patients, dasatinib has an apparent volume of distribution of 2505 L, suggesting that the drug is extensively distributed in the extravascular space. Binding of dasatinib and its active metabolite to human plasma proteins in vitro was approximately 96% and 93%, respectively, with no concentration dependence over the range of 100–500 ng/mL.

Metabolism

Dasatinib is extensively metabolized in humans, primarily by the cytochrome P450 enzyme 3A4. CYP3A4 was the primary enzyme responsible for the formation of the active metabolite. Flavin-containing monooxygenase 3 (FMO-3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of dasatinib metabolites.

The exposure of the active metabolite, which is equipotent to dasatinib, represents approximately 5% of the dasatinib AUC. This indicates that the active metabolite of dasatinib is unlikely to play a major role in the observed pharmacology of the drug. Dasatinib also had several other inactive oxidative metabolites.

Dasatinib is a weak time-dependent inhibitor of CYP3A4. At clinically relevant concentrations, dasatinib does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1. Dasatinib is not an inducer of human CYP enzymes.

Elimination

Elimination is primarily via the feces. Following a single oral dose of [14C]-labeled dasatinib, approximately 4% and 85% of the administered radioactivity was recovered in the urine and feces, respectively, within 10 days. Unchanged dasatinib accounted for 0.1% and 19% of the administered dose in urine and feces, respectively, with the remainder of the dose being metabolites.

Effects of Age and Gender

Pharmacokinetic analyses of demographic data indicate that there are no clinically relevant effects of age and gender on the pharmacokinetics of dasatinib.

Hepatic Impairment

Dasatinib doses of 50 mg and 20 mg were evaluated in eight patients with moderate (Child-Pugh class B) and seven patients with severe (Child-Pugh class C) hepatic impairment, respectively. Matched controls with normal hepatic function (n=15) were also evaluated and received a dasatinib dose of 70 mg. Compared to subjects with normal liver function, patients with moderate hepatic impairment had decreases in dose normalized Cmax and AUC by 47% and 8%, respectively. Patients with severe hepatic impairment had dose normalized Cmax decreased by 43% and AUC decreased by 28% compared to the normal controls.

These differences in Cmax and AUC are not clinically relevant. Dose adjustment is not necessary in patients with hepatic impairment.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two-year carcinogenicity study, rats were administered oral doses of dasatinib at 0.3, 1, and 3 mg/kg/day. The highest dose resulted in a plasma drug exposure (AUC) level equivalent to human exposure at 70 mg twice daily. Dasatinib induced a statistically significant increase in the combined incidence of squamous cell carcinomas and papillomas in the uterus and cervix of high-dose females and prostate adenoma in low-dose males.

Dasatinib was clastogenic when tested in vitro in Chinese hamster ovary cells, with and without metabolic activation. Dasatinib was not mutagenic when tested in an in vitro bacterial cell assay (Ames test) and was not genotoxic in an in vivo rat micronucleus study.

The effects of dasatinib on male and female fertility have not been studied. However, results of repeat-dose toxicity studies in multiple species indicate the potential for dasatinib to impair reproductive function and fertility. Effects evident in male animals included reduced size and secretion of seminal vesicles, and immature prostate, seminal vesicle, and testis. The administration of dasatinib resulted in uterine inflammation and mineralization in monkeys, and cystic ovaries and ovarian hypertrophy in rodents.

CLINICAL STUDIES

Newly Diagnosed Chronic Phase CML

An open-label, multicenter, international, randomized trial was conducted in adult patients with newly diagnosed chronic phase CML. A total of 519 patients were randomized to receive either SPRYCEL 100 mg once daily or imatinib 400 mg once daily. The primary endpoint was the rate of confirmed complete cytogenetic response (CCyR) within 12 months. Confirmed CCyR was defined as a CCyR noted on two consecutive occasions (at least 28 days apart).

Median age was 46 years in the SPRYCEL group and 49 years in the imatinib groups, with 10% and 11% of patients ≥65 years of age. There were slightly more male than female patients in both groups (59% vs 41%). Fifty-three percent of all patients were Caucasian, and 39% were Asian. At baseline, the distribution of Hasford Scores was similar in the SPRYCEL and imatinib treatment groups (low risk: 33% and 34%; intermediate risk: 48% and 47%; high risk: 19% and 19%, respectively).

The median duration of treatment was 14 months for SPRYCEL and 14 months for imatinib. With a minimum of 12 months follow-up, 85% of patients randomized to SPRYCEL and 81% of patients randomized to imatinib were still on study.

Efficacy results are summarized in Table 6.

Table 6: Efficacy Results in Newly Diagnosed Patients with Chronic Phase CML
  SPRYCEL
(n=259)
Imatinib
(n=260)
p-value
  Response rate (95% CI)  
a Confirmed CCyR is defined as a CCyR noted on two consecutive occasions at least 28 days apart.
b Major molecular response (at any time) was defined as BCR-ABL ratios ≤0.1% by RQ-PCR in peripheral blood samples standardized on the International scale.
*Adjusted for Hasford Score and indicated statistical significance at a pre-defined nominal level of significance.
CI = confidence interval.
Confirmed CCyR within 12 months a 76.8% (71.2–81.8) 66.2% (60.1–71.9) p=0.007*
Major Molecular Response b 52.1% (45.9–58.3) 33.8% (28.1–39.9) p<0.0001*

Median time to confirmed CCyR was 3.1 months in 199 SPRYCEL responders and 5.6 months in 177 imatinib responders. Median time to MMR was 6.3 months in 135 SPRYCEL responders and 9.2 months in 88 imatinib responders.

Five patients on the dasatinib arm progressed to either accelerated phase or blast crisis while nine patients on the imatinib arm progressed to either accelerated phase or blast crisis.

Imatinib Resistant or Intolerant CML or Ph+ ALL

The efficacy and safety of SPRYCEL were investigated in adult patients with CML or Ph+ ALL whose disease was resistant to or who were intolerant to imatinib: 1158 patients had chronic phase CML, 858 patients had accelerated phase, myeloid blast phase, or lymphoid blast phase CML, and 130 patients had Ph+ ALL. In a clinical study in chronic phase CML, resistance to imatinib was defined as failure to achieve a complete hematologic response (CHR; after 3 months), major cytogenetic response (MCyR; after 6 months), or complete cytogenetic response (CCyR; after 12 months); or loss of a previous molecular response (with concurrent ≥10% increase in Ph+ metaphases), cytogenetic response, or hematologic response. Imatinib intolerance was defined as inability to tolerate 400 mg or more of imatinib per day or discontinuation of imatinib because of toxicity.

Results described below are based on a minimum of 2 years follow-up after the start of SPRYCEL therapy in patients with a median time from initial diagnosis of approximately 5 years. Across all studies, 48% of patients were women, 81% were white, 15% were black or Asian, 25% were 65 years of age or older, and 5% were 75 years of age or older. Most patients had long disease histories with extensive prior treatment, including imatinib, cytotoxic chemotherapy, interferon, and stem cell transplant. Overall, 80% of patients had imatinib-resistant disease and 20% of patients were intolerant to imatinib. The maximum imatinib dose had been 400–600 mg/day in about 60% of the patients and >600 mg/day in 40% of the patients.

The primary efficacy endpoint in chronic phase CML was MCyR, defined as elimination (CCyR) or substantial diminution (by at least 65%, partial cytogenetic response) of Ph+ hematopoietic cells. The primary efficacy endpoint in accelerated phase, myeloid blast phase, lymphoid blast phase CML, and Ph+ ALL was major hematologic response (MaHR), defined as either a CHR or no evidence of leukemia (NEL).

Chronic Phase CML

Dose-Optimization Study: A randomized, open-label study was conducted in patients with chronic phase CML to evaluate the efficacy and safety of SPRYCEL administered once daily compared with SPRYCEL administered twice daily. Patients with significant cardiac diseases, including myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation were excluded from the study. The primary efficacy endpoint was MCyR in patients with imatinib-resistant CML. A total of 670 patients, of whom 497 had imatinib-resistant disease, were randomized to the SPRYCEL 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily group. Median duration of treatment was 22 months.

Efficacy was achieved across all SPRYCEL treatment groups with the once daily schedule demonstrating comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint (difference in MCyR 1.9%; 95% CI [-6.8%–10.6%]).

Efficacy results are presented in Table 7 for patients with chronic phase CML who received the recommended starting dose of 100 mg once daily. Additional efficacy results in this patient population are described after the table. Results for all patients with chronic phase CML, regardless of dosage (a starting dosage of 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily), were consistent with those for patients treated with 100 mg once daily.

Table 7: Efficacy of SPRYCEL in Imatinib Resistant or Intolerant Chronic Phase CML
  100 mg Once Daily
(n=167)
a CHR (response confirmed after 4 weeks): WBC ≤ institutional ULN, platelets <450,000/mm3, no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <20%, and no extramedullary involvement.
b MCyR combines both complete (0% Ph+ metaphases) and partial (>0%–35%) responses.
CHRa% (95% CI) 92% (86–95)
MCyRb% (95% CI) 63% (56–71)
CCyR% (95% CI) 50% (42–58)

In the SPRYCEL 100 mg once daily group, median time to MCyR was 2.9 months (95% CI: [2.8–3.0]). Based on the Kaplan-Meier estimates, 93% (95% CI: [88%–98%]) of patients who had achieved an MCyR maintained that response for 18 months. The estimated rate of progression-free survival and overall survival in all patients treated with 100 mg once daily was 80% (95% CI: [73%–87%]) and 91% (95% CI: [86%–96%]), respectively, at 2 years.

Advanced Phase CML and Ph+ ALL

Dose-Optimization Study: One randomized open-label study was conducted in patients with advanced phase CML (accelerated phase CML, myeloid blast phase CML, or lymphoid blast phase CML) to evaluate the efficacy and safety of SPRYCEL administered once daily compared with SPRYCEL administered twice daily. The primary efficacy endpoint was MaHR. A total of 611 patients were randomized to either the SPRYCEL 140 mg once daily or 70 mg twice daily group. Median duration of treatment was approximately 6 months for both treatment groups. The once daily schedule demonstrated comparable efficacy (non-inferiority) to the twice daily schedule on the primary efficacy endpoint.

The efficacy and safety of SPRYCEL were also investigated in patients with Ph+ ALL in one randomized study (starting dosage 140 mg once daily or 70 mg twice daily) and one single-arm study (starting dosage 70 mg twice daily). The primary efficacy endpoint was MaHR. A total of 130 patients were enrolled in these studies. The median duration of therapy was 3 months.

Response rates are presented in Table 8.

Table 8: Efficacy of SPRYCEL in Imatinib Resistant or Intolerant Advanced Phase CML and Ph+ ALL
  140 mg Once Daily
  Accelerated
(n=158)
Myeloid Blast
(n=75)
Lymphoid Blast
(n=33)
Ph+ ALL
(n=40)
a Hematologic response criteria (all responses confirmed after 4 weeks): Major hematologic response: (MaHR) = complete hematologic response (CHR) + no evidence of leukemia (NEL).
     CHR: WBC ≤ institutional ULN, ANC ≥1000/mm3, platelets ≥100,000/mm3, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <20%, and no extramedullary involvement.
     NEL: same criteria as for CHR but ANC ≥500/mm3 and <1000/mm3, or platelets ≥20,000/mm3 and ≤100,000/mm3.
b MCyR combines both complete (0% Ph+ metaphases) and partial (>0%–35%) responses.
CI = confidence interval     ULN = upper limit of normal range.
MaHR a 66% 28% 42% 38%
          (95% CI) (59–74) (18–40) (26–61) (23–54)
     CHRa 47% 17% 21% 33%
          (95% CI) (40–56) (10–28) (9–39) (19–49)
     NELa 19% 11% 21% 5%
          (95% CI) (13–26) (5–20) (9–39) (1–17)
MCyR b 39% 28% 52% 70%
          (95% CI) (31–47) (18–40) (34–69) (54–83)
     CCyR 32% 17% 39% 50%
          (95% CI) (25–40) (10–28) (23–58) (34–66)

In the SPRYCEL 140 mg once daily group, the median time to MaHR was 1.9 months for patients with accelerated phase CML, 1.9 months for patients with myeloid blast phase CML, and 1.8 months for patients with lymphoid blast phase CML.

In patients with myeloid blast phase CML, the median duration of MaHR was 8 months and 9 months for the 140 mg once daily group and the 70 mg twice daily group, respectively. In patients with lymphoid blast phase CML, the median duration of MaHR was 5 months and 8 months for the 140 mg once daily group and the 70 mg twice daily group, respectively. In patients with Ph+ ALL who were treated with SPRYCEL 140 mg once daily, the median duration of MaHR was 4.6 months. The medians of progression-free survival for patients with Ph+ ALL treated with SPRYCEL 140 mg once daily and 70 mg twice daily were 4.0 months and 3.5 months, respectively.

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