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342 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 343

Clinical Pharmacology (PLCγ2). Currently, it is unclear whether dose escalation may overcome
Ruxolitinib is orally administered, rapidly absorbed, and with a high these resistance mechanisms.
bioavailability of at least 95 percent. It undergoes CYP3A4-dependent
metabolism and is primarily eliminated in urine. The elimination half- Adverse Effects
life is approximately 3 hours. High-throughput in vitro screens identi- The vast majority of adverse effects to ibrutinib are mild in nature.
fied mutations that confer primary resistance to ruxolitinib, including Almost half of the patients experience diarrhea, and approximately one-
the gatekeeper mutation M929I. 269 third of patients develop upper respiratory infections, cough, or fatigue.
Other adverse effects include nausea, vomiting, constipation, pyrexia,
Adverse Effects rashes, edema, hypertension, and headaches. Approximately 15 percent
Most nonhematologic adverse effects are relatively infrequent and mild of patients developed grades 3 to 4 neutropenia, dose reduction allowed
in nature. These include, but are not limited to, diarrhea, nausea, periph- continuation of the drug. 272,273
eral edema, nasopharyngitis, pyrexia, arthralgia, cough, and dyspnea.
Ruxolitinib can cause anemia and thrombocytopenia that may require PROTEAOSOME INHIBITORS
transfusions. However, toxicity can be ameliorated with dose reduction
or treatment interruptions and only a very small portion of patients had Bortezomib and Carfilzomib
to discontinue the drug. The rate of higher-grade neutropenia was low This class of agents targets the ubiquitin-proteasome pathway, the com-
(~7 percent). 266,267 plex regulatory system whereby normal and malignant cells eliminate
potentially toxic misfolded proteins and control the intracellular levels
of important regulatory proteins. The importance of this pathway and
275
IBRUTINIB its substrates in diverse aspects of the pathophysiology of human tumors
CLL is a slowly progressive, indolent hematologic malignancy of mature creates opportunities for therapeutic interventions. The multimeric 20S
B lymphocytes. For decades, alkylating agents were the mainstay core particle of the proteasome exhibits three distinct proteolytic activ-
270
for treatment of CLL, with modest benefit for survival. The addition ities, namely chymotryptic, tryptic, and post–glutamyl peptide hydro-
of rituximab, an antibody directed against CD20 on B lymphocytes, lytic-like activities. Both bortezomib (previously known as PS-341)
improves survival in CLL patients. However, subsets of patients and carfilzomib (Fig. 22–8) inhibit the chymotryptic-like activity by
271
with particular deletion, such as 17p13.1, have poor response to this binding to the β5 subunit of the 20S core. Bortezomib, a boronic dipep-
treatment. Furthermore, none of the available therapies are curative. tide, is a reversible inhibitor of the chymotryptic-like activity, while
271
Although no common driver mutation is found in CLL, Bruton tyrosine carfilzomib, an epoxyketone, forms with the β5 subunit an irreversible
276
kinase (BTK), a downstream mediator of the B-cell receptor, appears adduct through two covalent bonds. Bortezomib has potent clinical
277–279
to be critical for B-cell activation, proliferation, and survival. A selec- activity against myeloma and other plasma cell dyscrasias, includ-
280
281
tive BTK inhibitor, ibrutinib, was developed and proved highly active ing amyloidosis and Waldenström macroglobulinemia, and is also
282,283
in high-risk relapsed CLL. It achieved a high rate of overall (88 percent) active in mantle cell lymphoma. Bortezomib induces complex
and progression-free survival (75 percent) at 26 months of followup. molecular sequelae, such as decreased levels of antiapoptotic molecules
272
In a subsequent phase III trial including 391 patients with previously
treated CLL, ibrutinib was compared to ofatumumab (an anti-CD20
antibody approved for relapsed CLL). Ibrutinib achieved a superior CH 3
overall response rate, progression-free and overall survival. Based
273
on these findings, ibrutinib was granted accelerated approval by the N O CH
FDA for this indication. It has also been approved for the treatment of H 3
patients with mantle cell lymphoma. N N N B OH
H
Mechanism of Action O OH
Ibrutinib irreversibly inhibits the BTK active site by forming a covalent
bond with a cysteine residue. Inhibition of the BTK results in disrup- Bortezomib
tion of activation of multiple downstream pathways important for B-cell A
activation, proliferation, and adhesion.

Clinical Pharmacology
Ibrutinib is orally administered once daily. The bioavailability has not O O
been established. The half-life is 4 to 6 hours. Ibrutinib is metabolized O H
in the liver primarily by CYP3A4 and only minimally cleared intact in N N N N N
urine (1 percent). No dose adjustments are required for liver or renal H H H
dysfunction. Dose adjustment may be necessary for patients who have O O O O
more than grade 3 hematologic of nonhematologic adverse effect. Using
whole exome sequencing, distinct resistance mutations were identified
in six patients. In five patients, a cysteine-to-serine mutation (C481S)
274
at the binding site of BTK was found. Interestingly, the resulting pro- Carfilzomib
tein remains sensitive to ibrutinib; however, inhibition in this case is B
reversible. Three other mutations (L845F, R665W, and S707Y) found in
two patients involving a downstream target of BTK, phospholipase γ2 Figure 22–8. Bortezomib and carfilzomib.

Kaushansky_chapter 22_p0313-0352.indd 342 9/18/15 10:26 PM