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Mechanism Of Action
Ibrutinib is a small-molecule inhibitor of BTK. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK's role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.
In patients with recurrent B-cell lymphoma > 90% occupancy of the BTK active site in peripheral blood mononuclear cells was observed up to 24 hours after ibrutinib doses of ≥ 2.5 mg/kg/day ( ≥ 175 mg/day for average weight of 70 kg).
Ibrutinib is absorbed after oral administration with a median Tmax of 1 to 2 hours. Ibrutinib exposure increases with doses up to 840 mg. The steady-state AUC (mean ± standard deviation) observed in patients at 560 mg is 953 ± 705 ng•h/mL and in patients at 420 mg is 680 ± 517 ng•h/mL. Absolute bioavailability in fasted condition (n = 8) was 2.9% (90% CI = 2.1 – 3.9) and doubled when combined with a meal. Administration with food increased ibrutinib Cmax and AUC by approximately 2 to 4- and 2-fold, respectively, compared with administration of ibrutinib after overnight fasting.
Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence in the range of 50 to 1000 ng/mL. The volume of distribution (Vd) was 683 L, and the apparent volume of distribution at steady state (Vd,ss/F) was approximately 10000 L.
Metabolism is the main route of elimination for ibrutinib. It is metabolized to several metabolites primarily by cytochrome P450, CYP3A, and to a minor extent by CYP2D6. The active metabolite, PCI-45227, is a dihydrodiol metabolite with inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib. The range of the mean metabolite to parent ratio for PCI-45227 at steady-state is 1 to 2.8.
Intravenous clearance was 62 and 76 L/h in fasted and fed conditions, respectively. In line with the high first-pass effect, the apparent oral clearance is approximately 2000 and 1000 L/h in fasted and fed conditions, respectively. The half-life of ibrutinib is 4 to 6 hours.
Ibrutinib, mainly in the form of metabolites, is eliminated primarily via feces. After a single oral administration of radiolabeled [14C]-ibrutinib in healthy subjects, approximately 90% of radioactivity was excreted within 168 hours, with the majority (80%) excreted in the feces and less than 10% accounted for in urine. Unchanged ibrutinib accounted for approximately 1% of the radiolabeled excretion product in feces and none in urine, with the remainder of the dose being metabolites.
Age (37 to 84 years) does not alter ibrutinib systemic clearance.
Gender does not alter ibrutinib systemic clearance.
Ibrutinib is not significantly cleared renally; urinary excretion of metabolites is < 10% of the dose. Creatinine clearance (CrCL) > 25 mL/min had no influence on the exposure to IMBRUVICA. There are no data in patients with severe renal impairment (CrCL < 25 mL/min) or in patients on dialysis.
Ibrutinib is metabolized in the liver. In a hepatic impairment trial, a single dose of 140 mg of IMBRUVICA was administered in non-cancer subjects. Ibrutinib AUC increased 2.7-, 8.2- and 9.8-fold, respectively, in subjects with mild (n=6), moderate (n=10) and severe (n=8) hepatic impairment relative to subjects with normal liver function. Ibrutinib Cmax increased 5.2-, 8.8- and 7.0-fold, respectively, in subjects with mild, moderate and severe hepatic impairment relative to subjects with normal liver function [see Use in Specific Populations].
Coadministration of Ibrutinib with CYP3A Inhibitors
In a sequential design trial of 18 healthy, fasted volunteers, a single dose of 120 mg of IMBRUVICA was administered alone on Day 1 and a single dose of 40 mg of IMBRUVICA was administered on Day 7 in combination with 400 mg of ketoconazole (given daily on Days 4 - 9). Ketoconazole increased ibrutinib dose-normalized Cmax and AUC 29-fold and 24-fold, respectively. Simulations using fasted conditions indicate that moderate CYP3A inhibitors diltiazem and erythromycin may increase AUC of ibrutinib by 5- to 8-fold.
Coadministration of Ibrutinib with CYP3A Inducers
PK data from a dedicated drug interaction trial showed that rifampin (a strong CYP3A inducer) decreases ibrutinib Cmax and AUC by more than 13- and 10-fold. Simulations using PBPK suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC of ibrutinib by up to 3-fold.
Coadministration of Ibrutinib with CYP Substrates
In vitro studies indicated that ibrutinib (I/Ki < 0.07 using mean Cmax at 560 mg) and PCI-45227 (I/Ki < 0.03) are unlikely to be inhibitors of any major CYPs at clinical doses. Both ibrutinib and the PCI-45227 are weak inducers of CYP450 isoenzymes in vitro.
Coadministration of Ibrutinib with Substrates of Transporters
In vitro studies indicated that ibrutinib is not a substrate of P-gp (p-glycoprotein) or BCRP (breast cancer resistance protein) transporters but is an in vitro inhibitor of P-gp and BCRP. Systemic ibrutinib is unlikely to be an inhibitor of P-gp at clinical doses ([I]1/Ki < 0.1) but may inhibit BCRP. Ibrutinib may have an effect on P-gp or BCRP substrates in the GI tract due to higher local concentrations after an oral dose. Co-administration of oral narrow therapeutic index P-gp or BCRP substrates (e.g., digoxin, methotrexate) with IMBRUVICA may increase their blood concentration.
Mantle Cell Lymphoma
The safety and efficacy of IMBRUVICA in patients with MCL who have received at least one prior therapy were evaluated in an open-label, multi-center, single-arm trial of 111 previously treated patients. The median age was 68 years (range, 40 to 84 years), 77% were male, and 92% were Caucasian. At baseline, 89% of patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 42 months, and median number of prior treatments was 3 (range, 1 to 5 treatments), including 11% with prior stem cell transplant. At baseline, 39% of subjects had at least one tumor ≥ 5 cm, 49% had bone marrow involvement, and 54% had extranodal involvement at screening.
IMBRUVICA was administered orally at 560 mg once daily until disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group (IWG) for non-Hodgkin's lymphoma (NHL) criteria. The primary endpoint in this study was investigator-assessed overall response rate (ORR). Responses to IMBRUVICA are shown in Table 10.
Table 10: Overall Response
Rate (ORR) and Duration of Response (DOR) Based on Investigator Assessment in
Patients with MCL
|95% CI (%)||(56.2, 74.5)|
|Median DOR months (95% CI)||17.5 (15.8, NR)|
|CI = confidence interval; CR = complete response; PR = partial response; NR = not reached|
An Independent Review Committee (IRC) performed independent reading and interpretation of imaging scans. The IRC review demonstrated an ORR of 69%.
The median time to response was 1.9 months.
Upon initiation of IMBRUVICA, a temporary increase in lymphocyte counts (i.e., ≥ 50% increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 33% of patients in the MCL study. The onset of isolated lymphocytosis occurs during the first few weeks of IMBRUVICA therapy and resolves by a median of 8 weeks.
Chronic Lymphocytic Leukemia
The safety and efficacy of IMBRUVICA in patients with CLL were demonstrated in one uncontrolled trial and two randomized, controlled trials.
An open-label, multi-center trial was conducted in 48 previously treated CLL patients. The median age was 67 years (range, 37 to 82 years), 71% were male, and 94% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 80 months and the median number of prior treatments was 4 (range, 1 to 12 treatments). At baseline, 46% of subjects had at least one tumor ≥ 5 cm.
IMBRUVICA was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The ORR and DOR were assessed using a modified version of the International Workshop on CLL Criteria by an Independent Review Committee. The ORR was 58.3% (95% CI: 43.2%, 72.4%), all partial responses. None of the patients achieved a complete response. The DOR ranged from 5.6 to 24.2+ months. The median DOR was not reached.
A randomized, multi-center, open-label Phase 3 study of IMBRUVICA versus ofatumumab was conducted in patients with previously treated CLL or SLL. Patients (n=391) were randomized 1:1 to receive either IMBRUVICA 420 mg daily until disease progression, or unacceptable toxicity or ofatumumab at an initial dose of 300 mg, followed one week later by a dose of 2000 mg weekly for 7 doses and then every 4 weeks for 4 additional doses. Fifty seven patients randomized to ofatumumab crossed over following progression to receive IMBRUVICA. The median age was 67 years (range, 30 to 88 years), 68% were male, and 90% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The trial enrolled 373 patients with CLL and 18 patients with SLL. The median time since diagnosis was 91 months and the median number of prior treatments was 2 (range, 1 to 13 treatments). At baseline, 58% of patients had at least one tumor ≥ 5 cm. Thirty-two percent of patients had 17p deletion.
Efficacy results for Study 2 are shown in Table 11 and the Kaplan-Meier curves for PFS, assessed by independent review committee (IRC) according to IWCLL criteria, and OS are shown in Figures 1 and 2, respectively.
Table 11: Efficacy Results in Study 2
|Progression Free Survivalb|
|Number of events (%)||35 (17.9)||111 (56.6)|
|Median (95% CI), months||NR||8.1 (7.2, 8.3)|
|HR (95% CI)||0.22 (0.15, 0.32)|
|Number of deaths (%)||16 (8.2)||33 (16.8)|
|HR (95% CI)||0.43 (0.24, 0.79)|
|Overall Response Rateb||42.6%||4.1%|
|a Median OS not reached for either arm
b IRC evaluated. All partial responses achieved; none of the patients achieved a complete response.
CI = confidence interval; HR = hazard ratio; NR = not reached
Figure 1: Kaplan-Meier Curve of Progression Free
Survival (ITT Population) in Study 2
Figure 2: Kaplan-Meier Curve of Overall Survival (ITT
Population) in Study 2
CLL With 17p Deletion (del 17p CLL)
Study 2 included 127 patients with del 17p CLL. The median age was 67 years (range, 30 to 84 years), 62% were male, and 88% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. PFS and ORR were assessed by IRC. Efficacy results for del 17p CLL are shown in Table 12.
Table 12: Efficacy Results in Patients with del 17p
|Progression Free Survival|
|Number of events (%)||16 (25.4)||38 (59.4)|
|Median (95% CI), months||NR||5.8 (5.3, 7.9)|
|HR (95% CI)||0.25 (0.14, 0.45)|
|Overall Response Ratea||47.6%||4.7%|
|a IRC evaluated. All partial responses
achieved; none of the patients achieved a complete response.
CI = confidence interval; HR = hazard ratio; NR = not reached
A randomized, multi-center, open-label study of IMBRUVICA versus chlorambucil was conducted in patients with treatment na´ve CLL or SLL who were 65 years of age or older. Patients (n = 269) were randomized 1:1 to receive either IMBRUVICA 420 mg daily until disease progression or unacceptable toxicity, or chlorambucil at a starting dose of 0.5 mg/kg on Days 1 and 15 of each 28-day cycle for a maximum of 12 cycles, with an allowance for intrapatient dose increases up to 0.8 mg/kg based on tolerability. After confirmed progression, patients on chlorambucil were able to crossover to ibrutinib.
The median age was 73 years (range, 65 to 90 years), 63% were male, and 91% were Caucasian. Ninety one percent of patients had a baseline ECOG performance status of 0 or 1 and 9% had an ECOG performance status of 2. The trial enrolled 249 patients with CLL and 20 patients with SLL. At baseline, 20% of patients had 11q deletion. The most common reasons for initiating CLL therapy include: progressive marrow failure demonstrated by anemia and/or thrombocytopenia (38%), progressive or symptomatic lymphadenopathy (37%), progressive or symptomatic splenomegaly (30%), fatigue (27%) and night sweats (25%).
Efficacy results for Study 3 are shown in Table 13 and the Kaplan-Meier curve for PFS, assessed by independent review committee (IRC) according to IWCLL criteria is shown in Figure 3.
Table 13: Efficacy Results in Study 3
|Progression Free Survivala|
|Number of events (%)||15 (11.0)||64 (48.1)|
|Median (95% CI), months||NR||18.9 (14.1, 22.0)|
|HRb (95% CI)||0.161 (0.091, 0.283)|
|Overall Response Ratea (CR + PR)||82.4%||35.3%|
|a IRC evaluated; Five subjects (3.7%) in the
IMBRUVICA arm and two subjects (1.5%) in the Chlorambucil arm achieved complete
b HR = hazard ratio; NR = not reached
Figure 3: Kaplan-Meier Curve of Progression-Free
Survival (ITT Population) in Study 3
Upon initiation of IMBRUVICA, an increase in lymphocyte counts (i.e., ≥ 50% increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 66% of patients in the CLL studies. The onset of isolated lymphocytosis occurs during the first month of IMBRUVICA therapy and resolves by a median of 14 weeks (range, 0.1 to 104 weeks).
The safety and efficacy of IMBRUVICA in WM were evaluated in an open-label, multi-center, single-arm trial of 63 previously treated patients. The median age was 63 years (range, 44 to 86 years), 76% were male, and 95% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 74 months, and the median number of prior treatments was 2 (range, 1 to 11 treatments). At baseline, the median serum IgM value was 3.5 g/dL (range, 0.7 to 8.4 g/dL).
IMBRUVICA was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The responses were assessed by investigators and an Independent Review Committee (IRC) using criteria adopted from the International Workshop of Waldenström's Macroglobulinemia. Responses, defined as partial response or better, per IRC are shown in Table 14.
Table 14: Overall Response Rate (ORR) and Duration of
Response (DOR) Based on IRC Assessment in Patients with WM
|Response rate (CR+VGPR+PR), (%)||61.9|
|95% CI (%)||(48.8, 73.9)|
|Complete Response (CR)||0|
|Very Good Partial Response (VGPR), (%)||11.1|
|Partial Response (PR), (%)||50.8|
|Median duration of response, months (range)||NR (2.8+, 18.8+)|
|CI = confidence interval; NR = not reached|
The median time to response was 1.2 months (range, 0.7-13.4 months).
Last reviewed on RxList: 1/25/2017
This monograph has been modified to include the generic and brand name in many instances.
Additional Imbruvica Information
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