Review of Selected NMEs 2014

Jack DeRuiter, PhD; Pamela L. Holston, RPh, BS, BA; Taylor Joseph DeRuiter, PharmD Candidate


US Pharmacist. 2014;39:HS-2-HS-15. 

In This Article

Ibrutinib (Imbruvica, Pharmacyclics, Janssen Biotech)

Indication and Clinical Profile3,4

The FDA has approved ibrutinib for second-line treatment of chronic lymphocytic leukemia (CLL). Earlier, ibrutinib was approved as a second-line treatment for mantle cell lymphoma (MCL), a rare and aggressive form of B-cell non-Hodgkin's lymphoma. Ibrutinib is the third drug approved to treat MCL, following Velcade (2006) and Revlimid (2013), and it is intended for patients with MCL who have received at least one prior therapy. It is the second drug with breakthrough-therapy designation and, therefore, accelerated FDA approval. The FDA also granted ibrutinib priority review and orphan-product designation for MCL because the drug demonstrated the potential to yield significant improvements in safety or effectiveness in the treatment of a serious condition and is intended to treat a rare disease.

The approval of ibrutinib for CLL was based on a multicenter trial of 48 previously treated patients. Ibrutinib 420 mg was administered orally once daily until occurrence of disease progression or unacceptable toxicity. The overall response rate (ORR) and duration of response (DOR) were assessed using a modified version of the International Workshop on CLL criteria by an independent review committee. The ORR was 58.3%, and all responses were partial; none of the patients achieved complete response. The DOR ranged from 5.6 to ≥24.2 months. The accelerated approval of ibrutinib for MCL was based on a study in which 111 participants were administered the drug daily until their disease progressed or adverse effects became intolerable. In this study, nearly 66% of participants experienced cancer shrinkage or disappearance after treatment (ORR). An improvement in survival or disease-related MCL symptoms has not yet been established.

Pharmacology and Pharmacokinetics3,4

Ibrutinib (Figure 2) is a pyrazolopyrimidine that functions as a selective inhibitor of Bruton's tyrosine kinase (BTK). It forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of enzymatic activity and downstream survival pathways activated by this kinase, including extracellular signal-regulated protein kinases 1 and 2, phosphoinositide 3-kinase, and nuclear factor kappa-B. BTK is a signaling molecule of the B-cell antigen receptor 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. Therefore, ibrutinib inhibition reduces cancer-cell chemotaxis toward the chemokines CXCL12 and -13, inhibits cellular adhesion following stimulation at the B-cell receptor, and drives cells into apoptosis and/or disrupts cell migration and adherence to protective tumor microenvironments. Ibrutinib is the first kinase inhibitor to be approved for CLL.

Figure 2.


Ibrutinib is readily absorbed after oral administration, with a median transport maximum of 1 to 2 hours. Administration with food increases ibrutinib exposure approximately twofold. The drug is extensively bound to plasma proteins (97.3%), and its apparent volume of distribution at steady state is approximately 10,000 L. Ibrutinib is metabolized primarily by CYP3A and to a minor extent by CYP2D6, yielding several metabolites. Its dihydrodiol metabolite is pharmacologically active, but less so than the parent drug. The half-life of ibrutinib is 4 to 6 hours, with elimination mainly in the feces (80%). In clinical trials in subjects with hepatic impairment, ibrutinib exposure was approximately sixfold higher in those with moderate hepatic impairment (Child-Pugh class B) compared with mean exposures observed in healthy volunteers.

Adverse Reactions and Drug Interactions3,4

The most common adverse reactions (>20%) reported in clinical trials were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, edema, upper respiratory infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting, and decreased appetite. Other clinically significant adverse reactions included bleeding, infections, kidney problems, and development of other types of cancer. Most adverse reactions were grade 1 or 2, except for cytopenias, infections, and bleeding, which were grade 3. Therefore, patients should be monitored for bleeding events, infection, and fever. Ibrutinib is a substrate of CYP3A; therefore, concurrent administration of strong or moderate CYP3A inhibitors or strong CYP3A inducers should be avoided. If a moderate CYP3A inhibitor must be used, the ibrutinib dosage should be reduced.

Ibrutinib is a Pregnancy Category D drug; therefore, female patients should be apprised of the potential hazard to the fetus. Also, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Dosage and Administration3,4

Ibrutinib is supplied as 140-mg capsules. The recommended dosage for CLL is 420 mg once daily and for MCL is 560 mg once daily. Capsules are to be taken with a glass of water; they should not be chewed or opened. If a moderate CYP3A inhibitor must be used, the dosage should be reduced to 140 mg/day. Ibrutinib should not be used in patients with hepatic impairment.