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Imbruvica

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Imbruvica

CLINICAL PHARMACOLOGY

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.

Pharmacodynamics

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).

Pharmacokinetics

Absorption

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. 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.

Distribution

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 apparent volume of distribution at steady state (Vd,ss /F) is approximately 10000 L.

Metabolism

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.

Elimination

Apparent clearance (CL/F) is approximately 1000 L/h. 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

Age (37 to 84 years) does not alter ibrutinib systemic clearance.

Gender

Gender does not alter ibrutinib systemic clearance.

Renal Impairment

Ibrutinib is not significantly cleared renally; urinary excretion of metabolites is < 10% of the dose. Creatinine clearance > 25 mL/min had no influence on the exposure to IMBRUVICA. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or in patients on dialysis.

Hepatic Impairment

Ibrutinib is metabolized in the liver. No clinical trials have been completed in subjects with impaired hepatic function. Preliminary PK data from an ongoing trial in subjects with hepatic impairment indicate that ibrutinib exposure is approximately 6-fold higher in subjects (N=3) with moderate hepatic impairment (Child-Pugh B) compared with mean exposures observed in healthy volunteer trials.

Drug Interactions

Coadministration of Ibrutinib with CYP3A Inhibitors

In a sequential design trial of 18 healthy 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 physiologically-based pharmacokinetic (PBPK) models suggested that moderate CYP3A inhibitors (diltiazem and erythromycin) may increase the AUC of ibrutinib 6 to 9-fold in fasted condition.

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-glycoprotein (P-gp). Systemic ibrutinib is unlikely to be an inhibitor of P-gp at clinical doses ([I] 1/Ki < 0.1). However, it may have an effect on P-gp substrates in the GI tract due to higher local concentrations after an oral dose. Co-administration of oral narrow therapeutic index P-gp substrates (e.g., digoxin) with IMBRUVICA may increase their blood concentration.

Clinical Studies

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 7.

Table 7: Overall Response Rate (ORR) and Duration of Response (DOR) Based on Investigator Assessment in Patients with MCL

  Total
(N=111)
ORR (%) 65.8
  95% CI (%) (56.2, 74.5)
  CR (%) 17.1
  PR (%) 48.6
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.

Lymphocytosis

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 who have received at least one prior therapy were demonstrated in one uncontrolled trial and one randomized, controlled trial.

Study 1

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.

Study 2

A randomized, multicenter, 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.

Progression free survival (PFS) as assessed by independent review committee (IRC) according to IWCLL criteria indicated a 78% statistically significant reduction in the risk of death or progression. Analysis of overall survival (OS) demonstrated a 57% statistically significant reduction in the risk of death for patients in the IMBRUVICA arm. Efficacy results for Study 2 are shown in Table 8 and the Kaplan-Meier curves for PFS and OS are shown in Figures 1 and 2, respectively.

Table 8: Efficacy Results in Study 2

Endpoint IMBRUVICA N=195 Ofatumumab N=196
Median Progression Free Not reached 8.1 months
Survival HR=0.22 [95% CI: 0.15; 0.32]
Overall Survivala HR=0.43 [95% CI: 0.24; 0.79]
Overall Response Rateb 42.6% 4.1%
aMedian OS not reached for either arm
bIRC evaluated. All partial responses achieved; none of the patients achieved a complete response.
HR = hazard ratio

Figure 1: Kaplan-Meier Curve of progression-Free Suvival (ITT Population) in Study 2

Kaplan-Meier Curve of progression-Free Suvival (ITT Population) - Illustration

Figure 2: Kaplan-Meier Curve of Overall Survival (ITT Population) in Study 2

Kaplan-Meier Curve of Overall Survival (ITT Population) in Study 2 - Illustration

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 9.

Table 9: Efficacy Results in Patients with del 17p CLL

Endpoint IMBRUVICA
N=63
Ofatumumab
N=64
Median Progression Free Not reached 5.8 months
Survival HR=0.25 [95% CI: 0.14; 0.45]
Overall Response Ratea 47.6% 4.7%
aIRC evaluated. All partial responses achieved; none of the patients achieved a complete response.
HR = hazard ratio

Lymphocytosis

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 77% of patients in the CLL study. The onset of isolated lymphocytosis occurs during the first month of IMBRUVICA therapy and resolves by a median of 23 weeks (range 1 -104+ weeks).

Last reviewed on RxList: 8/7/2014
This monograph has been modified to include the generic and brand name in many instances.

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