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338 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 339

TABLE 22–5. Tyrosine Kinase Inhibitors in Treatment of Chronic Myelogenous Leukemia
Unique Mechanism Drug
Targets Pharmacokinetics of Clearance Half-Life Dosing Interactions Toxicity
Imatinib BCR-ABL, c-Kit, 98 percent Hepatic; 18 hours Once daily at CYP3A4 inducers Dose-related fluid
platelet-de- bioavailability; dose adjust- 400–800 mg (dexamethasone, retention, heart
rived growth transport via OCT-1 ments for phenytoin, car- failure, hepatotox-
factor receptor severe bamazepine, etc.) icity, nausea and
(PDGFR) hepatic CYP3A4 inhibi- vomiting, diarrhea,
and renal tors (aprepitant, abdominal pain,
impairment clarithromycin, skin reactions,
itraconazole, etc.) myelosuppression
Dasatinib BCR-ABL, c-Kit, pH-dependent Hepatic 3–5 hours Once daily CYP3A4 inducers Fluid retention
PDGFR, Src absorption at 100 mg or (dexamethasone, (>20%) including
family kinases twice daily at phenytoin, car- pleural and pericar-
70 mg bamazepine, etc.) dial effusions, heart
CYP3A4 inhibi- failure, hepatotox-
tors (aprepitant, icity, nausea and
clarithromycin, vomiting, diarrhea,
itraconazole, etc.) abdominal pain,
Antacids, H skin reactions, mye-
losuppression, QT
2
blockers, proton prolongation (in
pump inhibitors vitro), hypocalcemia,
hypophosphatemia
Nilotinib BCR-ABL, c-Kit, Increased bioavail- Hepatic 17 hours Twice daily at CYP3A4 inducers Fluid retention, heart
PDGFR ability if taken with 400 mg (dexamethasone, failure, hepatotox-
food phenytoin, car- icity, nausea and
bamazepine, etc.) vomiting, diarrhea,
CYP3A4 inhibi- abdominal pain, skin
tors (aprepitant, reactions, myelosup-
clarithromycin, pression, QT prolon-
itraconazole, etc.) gation, hypocalcemia,
Drugs that hypophosphatemia,
elevated serum lipase
prolong the QT and amylase
interval
Bosutinib BCR-ABL, SRC, Absorption may be Hepatic; 22 hours Once daily at CYP3A4 inducers Myelosuppression,
LYN, HCK affected by magne- dose adjust- 500–600 mg (dexamethasone, skin reactions,
sium intake ments for phenytoin, car- QT prolongation,
severe bamazepine, etc.) Fluid retention,
hepatic CYP3A4 inhibi- diarrhea, hypoph-
and renal tors (aprepitant, osphatemia, hyper-/
impairment clarithromycin, hypomagnesemia
itraconazole, etc.)
Antacids, H
2
blockers, proton
pump inhibitors
Ponatinib BCR-ABL pH-dependent Hepatic 24 hours Once daily at CYP3A4 inducers Arterial thrombo-
(including absorption 30–45 mg (dexamethasone, sis, hepatotoxicity,
T315I), VEGFR, phenytoin, car- gastrointestinal
PDGFR, FGFR, bamazepine, etc.) perforation, wound
SRC, KIT, RET, CYP3A4 inhibi- healing complica-
TIE-2, FLT-3 tors (aprepitant, tions, hemorrhage,
clarithromycin, myelosuppression,
itraconazole, etc.) cardiac arrhythmias,
Ponatinib is pancreatitis
an inhibitor
of ABCG2 and
P-glycoprotein

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