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Mechanism Of Action
Ponatinib is a kinase inhibitor. Ponatinib inhibited the in vitro tyrosine kinase activity of ABL and T315I mutant ABL with IC50 concentrations of 0.4 and 2.0 nM, respectively. Ponatinib inhibited the in vitro activity of additional kinases with IC50 concentrations between 0.1 and 20 nM, including members of the VEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2, and FLT3. Ponatinib inhibited the in vitro viability of cells expressing native or mutant BCR-ABL, including T315I. In mice, treatment with ponatinib reduced the size of tumors expressing native or T315I mutant BCR-ABL when compared to controls.
In a cell-based assay, ponatinib concentrations of 20 nM (10.65 ng/mL) were sufficient to suppress most BCR-ABL mutant clones. However, ponatinib concentrations of 40 nM (21.3 ng/mL) were required to suppress T315I mutants. The median and range of steady-state Cmax and trough (Cmin) concentrations of ponatinib following 29 days of once-daily dosing of 15 mg, 30 mg and 45 mg are listed in Table 9.
Table 9: Median, Maximum,
and Minimum Ponatinib Exposure at Steady-State by Dose Group: PK Evaluable
|Dose||Median Cmax (Range) (nM)||Median Cmin (Range) (nM)|
|15 mg QD (n = 8)||49 (23 - 105)||28 (11 - 68)|
|30 mg QD (n = 9)||125 (67 - 178)||54 (41 - 89)|
|45 mg QD (n = 21)||161 (64 - 336)||67 (22 - 137)|
Concentrations of ponatinib shown in cell-based assays to suppress unmutated BCR-ABL and most mutant BCR-ABL clones may be achieved at once daily dosing of 15 mg or 30 mg.
The dose intensity-safety relationship indicated that there are significant increases in grade ≥ 3 adverse events (hypertension, thrombocytopenia, pancreatitis, neutropenia, rash, ALT increase, AST increase, lipase increase, myelosuppression) over the dose range of 15 to 45 mg once-daily.
In vitro, there was no significant inhibition of platelet aggregation with ponatinib at concentrations seen clinically and up to 0.7 μg/mL (1.23 μM).
A QT assessment was performed in 39 patients with cancer who received 30 mg, 45 mg, or 60 mg Iclusig once daily. No large changes in the mean QTc interval (i.e., > 20 ms) from baseline were detected in the study. However, a small increase in the mean QTc interval (i.e., < 10 ms) cannot be excluded because of study design limitations.
The geometric mean (CV%) Cmax and AUC(0-τ) of Iclusig 45 mg daily at presumed steady state in patients with advanced hematologic malignancies were 73 ng/mL (74%) and 1253 ng•hr/mL (73%), respectively. Ponatinib administered as an investigational capsule formulation to patients with cancer exhibited approximately dose proportional increases in both Cmax and AUC over the dose range of 15 to 60 mg. A dose intensity safety analysis showed a significant increase in grade 3 or higher adverse reactions (i.e., thrombocytopenia, neutropenia, rash, ALT elevation, AST elevation, pancreatitis, and lipase elevation) with an increase in dose intensity.
The absolute bioavailability of ponatinib is unknown. Peak concentrations of ponatinib are observed within 6 hours after Iclusig oral administration. Following ingestion of either a high-fat or low-fat meal by 22 healthy volunteers, plasma ponatinib exposures (AUC and Cmax) were not different when compared to fasting conditions.
Ponatinib is greater than 99% bound to plasma proteins in vitro. There was no plasma protein binding displacement of ponatinib (145 nM) in vitro by other highly protein bound medications (ibuprofen, nifedipine, propranolol, salicylic acid, and warfarin). The geometric mean (CV%) apparent steady state volume of distribution is 1223 liters (102%) following oral administration of Iclusig 45 mg once daily for 28 days in patients with cancer. Ponatinib is a weak substrate for both P-gp and ABCG2 in vitro. Ponatinib is not a substrate for organic anion transporting polypeptides (OATP1B1, OATP1B3) and organic cation transporter 1 (OCT1) in vitro.
At least 64% of a ponatinib dose undergoes phase I and phase II metabolism. CYP3A4 and to a lesser extent CYP2C8, CYP2D6 and CYP3A5 are involved in the phase I metabolism of ponatinib in vitro. Ponatinib is also metabolized by esterases and/or amidases.
The geometric mean (range) terminal elimination half-life of ponatinib was approximately 24 (12 to 66) hours following Iclusig 45 mg oral administration once daily for 28 days in patients with cancer. Exposure increased by approximately 90% (median) [range: 20% to 440%] between the first dose and presumed steady state. Ponatinib is mainly eliminated via feces. Following a single oral dose of [14C]-labeled ponatinib, approximately 87% of the radioactive dose is recovered in the feces and approximately 5% in the urine.
Coadministration of Ponatinib and CYP3A Inhibitors
Coadministration of a single 15 mg oral dose of ponatinib in the presence of ketoconazole (400 mg daily), a strong CYP3A inhibitor, to 22 healthy volunteers, increased the AUC0-inf and Cmax of ponatinib by 78% and 47%, respectively, when compared to administration of ponatinib alone [see DRUG INTERACTIONS].
Coadministration of Ponatinib and CYP3A Inducers
Co-administration of a single 45 mg dose of ponatinib in the presence of rifampin (600 mg daily), a strong CYP3A inducer, to 19 healthy volunteers, decreased the AUC0-inf and Cmax of ponatinib by 62% and 42%, respectively, when compared to administration of ponatinib alone [see DRUG INTERACTIONS].
Coadministration With Other CYP Substrates
In vitro studies indicate that ponatinib does not inhibit the metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A, or CYP2D6 and does not induce the metabolism of substrates for CYP1A2, CYP2B6, or CYP3A.
Coadministration With Substrates of Transporters
In vitro, ponatinib is an inhibitor of P-gp and ABCG2, and BSEP [see DRUG INTERACTIONS].
In vitro, ponatinib did not inhibit the human organic anion transporting polypeptides OATP1B1 or OATP1B3, or the organic cation transporters OCT1, OCT2, OAT1, and OAT3.
Coadministration of Ponatinib and Gastric pH elevating Medications
The aqueous solubility of ponatinib is pH dependent, with higher pH resulting in lower solubility [see DESCRIPTION]. Co-administration of a single 45 mg dose of ponatinib in the presence of lansoprazole (60 mg daily), a proton pump inhibitor, to 18 healthy volunteers decreased the AUC0-inf and Cmax of ponatinib by 6% and 25%, respectively, when compared to administration of ponatinib alone [see DRUG INTERACTIONS].
Pharmacokinetics in Specific Populations
A single 30 mg oral dose of ponatinib was administered to subjects with normal liver function (N=8) and to subjects with mild [Child-Pugh A (N=6)], moderate [Child-Pugh B (N=6)], and severe [Child-Pugh C (N=4)] hepatic impairment. Compared to subjects with normal liver function, there was no trend of increased ponatinib exposure in subjects with hepatic impairment. There was an increased incidence of adverse reactions in patients with hepatic impairment compared to subjects with normal liver function [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].
Iclusig has not been studied in patients with renal impairment. Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined [see Use in Specific Populations].
The safety and efficacy of Iclusig in patients with CML and Ph+ ALL whose disease was considered to be resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy were evaluated in a single-arm, open-label, international, multicenter trial. Efficacy results described below should be interpreted within the context of updated safety information [see BOXED WARNING, DOSAGE AND ADMINISTRATION, and WARNINGS AND PRECAUTIONS]
All patients were administered a starting dose of 45 mg of Iclusig once daily. Patients were assigned to one of six cohorts based on disease phase (chronic phase CML [CP-CML]; accelerated phase CML [AP-CML]; or blast phase CML /Philadelphia-positive acute lymphoblastic leukemia [BP-CML/Ph+ ALL]), resistance or intolerance (R/I) to prior TKI therapy, and the presence of the T315I mutation.
Resistance in CP-CML while on prior TKI therapy, was defined as failure to achieve either a complete hematologic response (by 3 months), a minor cytogenetic response (by 6 months), or a major cytogenetic response (by 12 months). Patients with CP-CML who experienced a loss of response or development of a kinase domain mutation in the absence of a complete cytogenetic response or progression to AP-CML or BP-CML at any time on prior TKI therapy were also considered resistant. Resistance in AP-CML, BP-CML, and Ph+ ALL was defined as failure to achieve either a major hematologic response (by 3 months in AP-CML, and by 1 month in BP-CML and Ph+ ALL), loss of major hematologic response (at any time), or development of a kinase domain mutation in the absence of a complete major hematologic response while on prior TKI therapy.
Intolerance was defined as the discontinuation of prior TKI therapy due to toxicities despite optimal management in the absence of a complete cytogenetic response in patients with CP-CML or major hematologic response for patients with APCML, BP-CML, or Ph+ ALL.
The primary efficacy endpoint in CP-CML was major cytogenetic response (MCyR), which included complete and partial cytogenetic responses (CCyR and PCyR). The primary efficacy endpoint in AP-CML, BP-CML, and Ph+ ALL was major hematologic response (MaHR), defined as either a complete hematologic response (CHR) or no evidence of leukemia (NEL).
The trial enrolled 449 patients, of which 444 were eligible for efficacy analysis: 267 patients with CP-CML (R/I Cohort: n=203, T315I: n=64), 83 patients with AP-CML, 62 patients with BP-CML, and 32 patients with Ph+ ALL. Five patients were not eligible for efficacy analysis due to lack of confirmation of T315I mutation status, and these patients had not received prior dasatinib or nilotinib.
At the time of analysis, the median follow-up was 10 months (minimum of 6 months of follow-up for all ongoing patients). Baseline demographic characteristics are described in Table 10.
Table 10: Demographic and
|Patient Characteristics at Entry||Efficacy Population
|Median, years (range)||59 (18 to 94)|
|Gender, n (%)|
|Race, n (%)|
|Black or African American||25 (6%)|
|ECOG Performance Status, n (%)|
|ECOG=0 or 1||409 (92%)|
|Median time from diagnosis to first dose, years (range)||6.1 (0.3 to 28.5)|
|Resistant to Prior TKI Therapy, n (%)||374 (88%)|
|Presence of one or more BCR-ABL kinase domain mutations*||244 (55%)|
|Prior TKI therapy- number of prior approved TKIs, n (%)|
|≥ 3||249 (56%)|
|*Of the patients with one or more BCR-ABL kinase domain mutations detected at entry, 37 unique mutations were detected.|
At the time of analysis, the median duration of Iclusig treatment was 281 days in patients with CP-CML, 286 days in patients with AP-CML, 89 days in patients with BP-CML, and 81 days in patients with Ph+ ALL. Efficacy results are summarized in Table 11, and Table 12.
Table 11: Efficacy of
Iclusig in Patients With Resistant or Intolerant Chronic Phase CML
|aPrimary endpoint for CP-CML Cohorts was MCyR, which combines both complete (no detectable Ph+ cells) and partial (1% to 35% Ph+ cells in at least 20 metaphases) cytogenetic responses.|
In patients with CP-CML patients who achieved MCyR, the median time to MCyR was 84 days (range: 49 to 334 days). At the time of analysis, the median durations of MCyR had not yet been reached.
Table 12: Efficacy of
Iclusig in Patients With Resistant or Intolerant Advanced Disease (includes R/I
and T315I cohorts)
|AP-CML Overall (N=83)||BP-CML Overall (N=62)||Ph+ ALL Overall (N=32)|
|aPrimary endpoint for patients with AP-CML, BP-CML, and Ph+
ALL was MaHR, which combines complete hematologic responses and no evidence of
bCHR: 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 < 5% in peripheral blood, No extramedullary involvement (including no hepatomegaly or splenomegaly).
The median time to MaHR in patients with AP-CML, BP-CML, and Ph+ ALL was 21 days (range: 12 to 176 days), 29 days (range 12 to 113 days), and 20 days (range: 11 to 168 days), respectively. The median duration of MaHR for patients with AP-CML, BP-CML, and Ph+ ALL was 9.5 months (range: 1.1 to 17.7 months), 4.7 months (range: 1.8 to 14.1+ months), and 3.2 months (range: 1.8 to 8.8+ months), respectively.
Last reviewed on RxList: 8/7/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Iclusig Information
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