Sprycel (Dasatinib) - Description and Clinical Pharmacology

Patient Information Included

DESCRIPTION

SPRYCEL^® (dasatinib) is an inhibitor of multiple tyrosine kinases. 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 and has a melting point of 280°–286° C. 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

The pharmacokinetics of dasatinib have been evaluated in 229 healthy subjects and in 137 patients with leukemia.

Absorption

Maximum plasma concentrations (C_max) of dasatinib are observed between 0.5 and 6 hours (T_max) 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. In human liver microsomes, dasatinib was a weak time-dependent inhibitor of CYP3A4.

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.

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.

Special Populations

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

The pharmacokinetics of SPRYCEL have not been evaluated in pediatric patients.

Hepatic Impairment

No clinical studies were conducted with SPRYCEL in patients with impaired hepatic function. (See PRECAUTIONS.)

Renal Impairment

No clinical studies were conducted with SPRYCEL in patients with decreased renal function. Less than 4% of SPRYCEL and its metabolites are excreted via the kidney. (See PRECAUTIONS.)

Drug-Drug Interactions

SPRYCEL is not an inducer of human CYP enzymes. SPRYCEL is a time-dependent inhibitor of CYP3A4 and may decrease the metabolic clearance of drugs that are primarily metabolized by CYP3A4. (See PRECAUTIONS.) At clinically relevant concentrations, dasatinib does not inhibit CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1.

Drugs that may increase dasatinib plasma concentrations

CYP3A4 Inhibitors: In a study of 18 patients with solid tumors, 20-mg dasatinib QD coadministered with 200 mg of ketoconazole BID increased the dasatinib C_max and AUC by four- and five-fold, respectively. Substances that inhibit CYP3A4 activity (eg, ketoconazole, itraconazole, erythromycin, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) may decrease metabolism and increase concentrations of dasatinib (see PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION: Dose Modification).

Drugs that may decrease dasatinib plasma concentrations

CYP3A4 Inducers: Data from a study of 20 healthy subjects indicate that when a single morning dose of SPRYCEL was administered following 8 days of continuous evening administration of 600 mg of rifampicin, a potent CYP3A4 inducer, the mean C_max and AUC of dasatinib were decreased by 81% and 82%, respectively (see PRECAUTIONS: Drug Interactions).

Antacids: Nonclinical data indicate that dasatinib has pH dependent solubility. In a study of 24 healthy subjects, administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50-mg dose of SPRYCEL was associated with no relevant change in dasatinib AUC; however, the dasatinib C_max increased 26%. When 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjects concomitantly with a 50-mg dose of SPRYCEL, a 55% reduction in dasatinib AUC and a 58% reduction in C_max were observed. (See PRECAUTIONS: Drug Interactions.)

Famotidine: In a study of 24 healthy subjects, administration of a single 50-mg dose of SPRYCEL 10 hours following famotidine reduced the AUC and C_max of dasatinib by 61% and 63%, respectively. (See PRECAUTIONS: Drug Interactions.)

Drugs that may have their plasma concentrations altered by dasatinib

CYP3A4 Substrates: Single dose data from a study of 54 healthy subjects indicate that the mean C_max and AUC of simvastatin, a CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin was administered in combination with a single 100-mg dose of SPRYCEL. (See PRECAUTIONS: Drug Interactions.)

CLINICAL STUDIES

Four single-arm multicenter studies were conducted to determine the efficacy and safety of SPRYCEL in patients with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resistant to or intolerant of treatment with imatinib. Resistance to imatinib included failure to achieve a complete hematologic response (within 3–6 months) or major cytogenetic response (by month 12) or progression of disease after a previous cytogenetic or hematologic response. Imatinib intolerance included inability to tolerate 400 mg or more of imatinib per day or discontinuation of imatinib because of toxicity. The chronic phase CML study enrolled 186 patients, the accelerated phase CML study 107 patients, the myeloid blast phase study 74 patients, and the lymphoid blast phase CML/Ph+ ALL study 78 patients. The studies are ongoing. The results are based on a minimum of 6 months follow-up after the start of dasatinib therapy. Across all studies, 49% of patients were women, 89% were white, 10% were black or Asian, 23% were over the age of 65 years, and 3% were over the age of 75 years. Most patients had long disease histories with extensive prior treatment, including imatinib, cytotoxic chemotherapy, interferon, and stem cell transplant (Table 1). The maximum imatinib dose had been 400–600 mg/day in about one-half of the patients and >600 mg/day in the other half.

Table 1: Disease History Characteristics

	Chronic (n=186)	Accelerated (n=107)	Myeloid Blast (n=74)	Lymphoid Blast (n=42)	Ph+ ALL (n=36)
Median time since diagnosis in months (range)	64 (4–251)	91 (4–355)	49 (3–216)	28 (2–186)	20 (3–97)
Imatinib
Resistant	68%	93%	92%	88%	94%
Intolerant	32%	7%	8%	12%	6%
Imatinib
>3 years	54%	68%	47%	24%	3%
>1 year	80%	92%	85%	52%	56%
Cytotoxic chemotherapy	42%	67%	66%	79%	92%
Interferon	70%	75%	55%	48%	8%
Stem cell transplant	9%	18%	12%	33%	42%

All patients were treated with dasatinib 70 mg BID on a continuous basis. The median durations of treatment are shown in Table 2.

Table 2: Duration of Treatment with SPRYCEL

	Chronic (n=186)	Accelerated (n=107)	Myeloid Blast (n=74)	Lymphoid Blast (n=42)	Ph+ ALL (n=36)
Median duration of therapy in months (range)	5.6 (0.03–8.3)	5.5 (0.2–10.1)	3.5 (0.03–9.2)	2.8 (0.1–6.4)	3.2 (0.2–8.1)

The primary efficacy endpoint in chronic phase CML was major cytogenetic response (MCyR), defined as elimination (complete cytogenetic response, CCyR) or substantial diminution (by at least 65%, partial cytogenetic response) of Ph+ hematopoietic cells. The primary endpoint in accelerated phase, myeloid blast phase, and lymphoid blast phase CML, and Ph+ ALL was major hematologic response (MaHR), defined as either a complete hematologic response or no evidence of leukemia (defined in Table 3).

Dasatinib treatment resulted in cytogenetic and hematologic responses in patients with all phases of CML and with Ph+ ALL. The response rates for the single-arm studies are reported in Table 3. In chronic phase CML patients, the MCyR rate was 45% with a complete response (0% Ph+ cells) rate of 33%. The MaHR rate was 59% in accelerated phase patients, 32% in myeloid phase patients, 31% in lymphoid blast phase patients, and 42% in Ph+ ALL patients.

Most cytogenetic responses occurred after 12 weeks of treatment, when the first cytogenetic analyses were performed. Hematologic and cytogenetic responses were stable during the 6-month follow-up of patients with chronic phase, accelerated phase, and myeloid blast phase CML. The median durations of major hematologic response were 3.7 months in lymphoid blast CML and 4.8 months in Ph+ ALL.

There were no age- or gender-related response differences.

Table 3: Efficacy in SPRYCEL Clinical Studies (All Treated Populations)^a

	Chronic (n=186)	Accelerated (n=107)	Myeloid Blast (n=74)	Lymphoid Blast (n=42)	Ph+ ALL (n=36)
a Numbers in bold font are the results of primary endpoint.
b Hematologic response criteria (all responses confirmed after 4 weeks): Major hematologic response: (MaHR) = complete hematologic response (CHR) + no evidence of leukemia (NEL).    CHR (chronic CML): 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 ≤ institutional ULN, and no extramedullary involvement.
CHR (advanced CML/Ph+ ALL): 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 ≤ institutional ULN, and no extramedullary involvement.
NEL: same criteria as for CHR but ANC ≥500/mm3 and <1000/mm3, and/or platelets ≥20,000/mm3 and ≤100,000/mm3.
c Cytogenetic response criteria: complete (0% Ph+ metaphases) or partial (>0%–35%). MCyR (0%–35%) combines both complete and partial responses.
n/a = not applicable.
Hematologic Response Rateb (%)
MaHR (95% CI)	n/a	59 (49–68)	32 (22–44)	31 (18–47)	42 (26–59)
CHR (95% CI)	90 (85–94)	33 (24–42)	24 (15–36)	26 (14-42)	31 (16–48)
NEL (95% CI)	n/a	26 (18–36)	8 (3–17)	5 (0.6–16)	11 (3.1–26)
Cytogenetic Responsec (%)
MCyR (95% CI)	45 (37–52)	31 (22–41)	30 (20–42)	50 (34–66)	58 (41–74)
CCyR (95% CI)	33 (26–40)	21 (14–30)	27 (17–39)	43 (28–59)	58 (41–74)