Pocket Oncology (Pocket Notebook Series), 1st Ed.

SMALL MOLECULE TYROSINE KINASE INHIBITORS

Thu Oanh Dang

Activity of various tyrosine kinase inhibitors (TKIs)

Axitinib (Inlyta)

Dosing/dose adjustments: 5 mg oral every 12 h. No renal dose adjustments recommended. Hepatic: Child-Pugh class B: 50% nl dose, ↑ as tolerated. Child-Pugh class C: Not studied.

PK/PD: Bioavailability 58%, 99% protein bound to albumin, hepatic metabolism via CYP3A4/5, fecal (41%) & urinary (23%) excretion, T1/2 2.5–6 h

Adverse effects: HTN, fatigue, GI, hand-foot syndrome/rash, LFTs & electrolyte abnormalities, ↑ SCr (55%), proteinuria, hematologic

DDI: CYP3A4 inhibitors/inducers (↑/↓ conc. of axitinib), warfarin

Clinical pearls: Available only through specialty pharmacies. Monitor: Hepatic, renal, & thyroid function, U/A (proteinuria), & BP. D/c Rx 24 h prior to surgery (impaired wound healing).

Bosutinib (Bosulif)

Dosing/dose adjustments: 500 mg oral daily. No renal dose adjustments recommended. Hepatic: 200 mg oral daily. Hematologic, hepatic toxicities, grade 3/4 diarrhea: Hold Rx & resume at ↓ dose.

PK/PD: 94% protein bound, hepatic metabolism via CYP3A4, fecal excretion (91%), T1/2 22–27 h

Adverse effects: Edema, diarrhea (82%), ↓ Mg, rash (35%), ↑ LFTs, hematologic

DDI: CYP3A4 inhibitors/inducers (↑/↓ conc. of bosutinib), PPI/H2 blocker/antacid (↓ bosutinib absorption), QTc-prolonging agents, warfarin

Clinical pearls: Take w/food. Diarrhea should resolve after a wk into Rx (tolerance) w/antidiarrheal support. Monitor: CBC weekly first month, LFTs monthly × first 3 mos, EKG baseline & intermittently.

Cabozantinib (Cometriq)

Dosing/dose adjustments: 120 mg oral daily. Renal: CrCl < 30 mL/min: Use caution. No hepatic dose adjustments recommended. Rx-induced toxicities (≥grade 3): Hold dose & restart at ↓ dose (60 mg or 100 mg).

PK/PD: ≥99.7% protein bound, hepatic metabolism via CYP3A4, fecal (54%) & urinary (27%) excretion, T1/2 55 h

Adverse effects: HTN (33%), fatigue, skin toxicities (hand-foot syndrome, alopecia, rash, hair color changes (34%), GI, ↑ LFTs, hematologic

DDI: CYP3A4 inhibitors/inducers (↑/↓ conc. of cabozantinib, ↑ dose by 40 mg w/inducers & ↓ dose by 40 mg w/inhibitors)

Clinical pearls: Take on an empty stomach. Monitor: Proteinuria, BP, renal & hepatic function, electrolytes (Ca, phos, K, & Mg). Distribution is limited to Diplomat Specialty Pharmacy (855-253-3273).

Crizotinib (Xalkori)

Dosing/dose adjustments: 250 mg oral every 12 h. Renal: CrCl < 30 mL/min: No data. Hepatic: Use w/caution in impairment. Rx-related toxicities (heme, effusion/edema, & rash): Hold & restart at ↓ dose.

PK/PD: Bioavailability 43%, 91% protein bound, hepatic metabolism via CYP3A4, fecal excretion (53%), T1/2 42 h

Adverse effects: Edema (28%), fatigue, dizziness, GI (↓ appetite, taste alteration), lymphopenia, ↑ ALT, neuropathy, vision disorders (onset <2 wks: Visual impairment, diplopia, photopsia)

DDI: CYP3A4 inhibitors/inducers (↑/↓ conc. of crizotinib), QTc-prolonging agents, warfarin

Clinical pearls: Available through specialty pharmacies. Monitor: Pneumonitis, ECG, LFTs, ophthalmic evaluation for visual impairment.

Erlotinib (Tarceva)

Dosing/dose adjustments: 100–150 mg oral daily. No renal dose adjustments recommended. Hepatic: TBili >3 × ULN and/or ↑ ALT/AST >5 × ULN: ↓ dose.

PK/PD: Absorption 100% (w/food), 60% (w/o food), hepatic metabolism via CYP3A4, fecal (83%) & urinary (8%) excretion, T1/2 24–36 h

Adverse effects: Rash (up to 75% - DLT), GI (N/V/D), pyrexia, fatigue

DDI: CYP3A4 inhibitors/inducers (↑/↓ conc. of erlotinib), PPI/H2 blocker/antacid (↓ erlotinib absorption)

Clinical pearls: Take on empty stomach. Monitor: Skin toxicities (possible exfoliative rash)

Dasatinib (Sprycel)

Dosing/dose adjustments: 100–140 mg oral daily. No renal or hepatic dose adjustments recommended. Adjust dose for Rx-related toxicities.

PK/PD: Hepatic metabolism via CYP3A4, fecal excretion (85%), T1/2 3–5 h

Adverse effects: Skin toxicities, edema (peripheral & pulm), hematologic, electrolyte disturbances, hepatotoxicities, GI

DDI: CYP3A4 inhibitors/inducers (↑/↓ conc. of dasatinib), PPI/H2 blocker/antacid (↓ dasatinib absorption), QTc-prolonging agents, warfarin (↑/↓ warfarin effects)

Clinical pearls: Monitor: Pulm edema (CXR if indicated)

Gefitinib (Iressa)

Dosing/dose adjustments: 250 mg oral daily. No renal or hepatic dose adjustments recommended. Adjust dose for Rx-induced toxicities.

PK/PD: Bioavailability 60%, 90% protein bound to α-acid glycoprotein, hepatic metabolism via CYP3A4, fecal excretion (86%), T1/2 41 h

Adverse effects: Skin toxicities (rash, acne, dry skin), GI (N/V/D)

DDI: CYP3A4 inhibitors/inducers (↑/↓ conc. of gefitinib), PPI/H2 blocker/antacid (↓ gefitinib absorption), warfarin

Clinical pearls: Distribution is limited through Iressa Access program. Monitor: Skin toxicities, worsening pulm function, & diarrhea.

Imatinib (Gleevec)

Dosing/dose adjustments: 400–800 mg oral daily. Renal: CrCl 40–59 mL/min: Max 600 mg; 20–39 mL/min: Max 400 mg; <20 mL/min: 100 mg daily. Sev. hepatic impairment: ↓ dose 25%. Rx-related toxicities: Adjust dose.

PK/PD: Bioavailability 98%, hepatic metabolism via CYP3A4, fecal (68%) & urinary (13%) excretion, T1/2 18 h

Adverse effects: Edema (periorbital edema, pulm, peripheral), fatigue, skin toxicities, hematologic, GI, ↑ LFTs

DDI: CYP3A4 inhibitors/inducers (↑/↓ conc. of imatinib), PPI/H2 blocker/antacid (↓ imatinib absorption), QTc-prolonging agents, warfarin (↑/↓ warfarin effects)

Clinical pearls: 800 mg dose should be split twice daily for better tolerance

Lapatinib (Tykerb)

Dosing/dose adjustments: 1000–1500 mg oral daily. No renal dose adjustments recommended. Pre-existing hepatic impairment (Child-Pugh class C): ↓ 1000 mg to 750 mg w/capecitabine & ↓ 1500 mg to 1000 mg w/letrozole.

PK/PD: Incomplete, variable absorption, hepatic metabolism via CYP3A4/5, fecal excretion (27%), T1/2 25 h

Adverse effects: Hand-foot syndrome (w/capecitabine 53%), rash, fatigue, hematologic, ↑ LFTs, LVEF dysfunction

DDI: CYP3A4 inhibitors/inducers (↑/↓ conc. of lapatinib), PPI/H2 blocker/antacid (↓ lapatinib absorption), QTc-prolonging agents, warfarin (↑/↓ warfarin effects)

Clinical pearls: Take on empty stomach. Monitor: QTc, electrolytes, LVEF baseline & periodic. Distribution is limited through Tykerb CARES.

Nilotinib (Tasigna)

Dosing/dose adjustments: 300–400 mg oral every 12 h. No renal dose adjustments recommended. Mild-mod hepatic impairment: Start at 200–300 mg every 12 h, ↑ as tolerated. Dose adjust for Rx-induced toxicities (hepatic, hematologic, QTc, amylase/lipase).

PK/PD: Bioavailability 50%, hepatic metabolism via CYP3A4, fecal excretion (96%), T1/2 15–17 h

Adverse effects: Peripheral edema, HTN, QTc prolongation, fatigue, rash, alopecia, muscular/skeletal, hematologic

DDI: CYP3A4 inhibitors/inducers (↑/↓ conc. of nilotinib), PPI/H2 blocker/antacid (↓ nilotinib absorption), QTc-prolonging agents, warfarin (↑/↓ warfarin effects)

Clinical pearls: Take on empty stomach. Monitor: QTc at baseline & periodic

Pazopanib (Votrient)

Dosing/dose adjustments: 800 mg oral daily. No renal dose adjustments recommended. Hepatic: TBili > 1.5–3 × ULN: 200 mg daily; Tbili > 3 × ULN: Use not recommended. Adjust dose for Rx-induced toxicities.

PK/PD: Bioavailability ↑ w/food, ≥ 99% protein bound, hepatic metabolism via CYP3A4, fecal excretion, T1/2 31 h

Adverse effects: HTN, edema, fatigue, hair color change, alopecia, hyperglycemia, hepatic, hematologic, GI

DDI: Statin (↑ hepatotoxicity of pazopanib), QTc-prolonging agents, CYP3A4 inhibitors/inducers (↑/↓ conc. of pazopanib), warfarin (↑/↓ warfarin effects)

Clinical pearls: Take on empty stomach. Monitor: LFTs, LVEF, BP, thyroid, & ECG.

Ponatinib (Iclusig)

Dosing/dose adjustments: 45 mg oral daily. No renal or hepatic dose adjustments recommended. Concomitant strong CYP3A4 inhibitor: 30 mg daily. Adjust dose for Rx-induced toxicities.

PK/PD: Hepatic metabolism via CYP3A4, fecal excretion (87%), T1/2 24 h

Adverse effects: Pancreatitis (DLT), ↑ LFTs, rash, CV (HTN, HF, peripheral edema, thromboembolism), fatigue, hematologic, GI, hyperglycemia

DDI: CYP3A4 inhibitors/inducers (↑/↓ conc. of ponatinib), PPI/H2 blocker/antacid (↓ ponatinib absorption), QTc-prolonging agents, warfarin (↑/↓ warfarin effects)

Clinical pearls: Distribution only through the ARIAD PASS program. Monitor: Pancreatic enzymes, LFTs, GI perforation, HF, & edema

Regorafenib (Stivarga)

Dosing/dose adjustments: 160 mg oral daily. No renal or hepatic dose adjustments recommended. Adjust dose for Rx-induced tox.

PK/PD: Bioavailability 69%, metabolism via CYP3A4 & UGT1A9, fecal excretion (71%), T1/2 28 h

Adverse effects: HTN, skin toxicities, fatigue, electrolyte imbalances, hematologic, hepatic, GI, proteinuria

DDI: CYP3A4 inhibitors/inducers (↑/↓ conc. of regorafenib), warfarin (↑/↓ warfarin effects)

Clinical pearls: Take w/low-fat breakfast. Monitor: Cardiac, rash, LFTs, electrolytes. Available only through the REACH support program.

Ruxolitinib (Jakafi)

Dosing/dose adjustments: 15–20 mg oral every 12 h based on plt count. Renal: CrCl 15–59 mL/min & plts > 100 K: 10 mg oral every 12 h. ESRD on dialysis & plts > 100 K: 15 mg post dialysis. Hepatic impairment & plts > 100 K: 10 mg bid; plts <100 K, avoid use. Dose adjustments based on response & toxicities.

PK/PD: Hepatic metabolism via CYP3A4, urinary excretion (74%), T1/2 3 h

Adverse effects: Edema, dizziness, HA, insomnia, ↑ cholesterol, GI, ↑ LFTs, dyspnea, zoster reactivation

DDI: CYP3A4 inhibitors/inducers (↑/↓ conc. of ruxolitinib)

Clinical pearls: Available through specialty/network pharmacies only. Monitor: Hepatic & renal function, CBC every 2–4 wks until stable dose.

Sorafenib (Nexavar)

Dosing/dose adjustments: 400 mg oral every 12 h. Renal: CrCl 20–39 mL/min: 200 mg every 12 h; CrCl < 20 mL/min: No data. Hepatic: TBili 1.5–3 × ULN: 200 mg every 12 h; TBili> 3–10 × ULN: 200 mg q3d (regimen not tolerated), albumin <2.5 g/dL (any TBili & AST): 200 mg daily. Adjust dose for toxicities.

PK/PD: Bioavailability 38–49%, hepatic metabolism via CYP3A4, fecal (77%) & urinary 19%), T1/2 25–48 h

Adverse effects: Sensory neuropathy, HTN, skin toxicities, hepatic, hematologic, GI, alopecia

DDI: APAP (↑ hepatotoxicity), CYP3A4 inhibitors/inducers (↑/↓ conc. of sorafenib), warfarin (↑/↓ warfarin effects)

Clinical pearls: Take on empty stomach. Monitor: Amylase/lipase, LFTs, BP, skin toxicities.

Sunitinib (Sutent)

Dosing/dose adjustments: 37.5–50 mg oral daily. Use caution in sev. renal or hepatic impairment. Adjust dose for Rx-related toxicities.

PK/PD: Hepatic metabolism via CYP3A4, fecal excretion (61%), T1/2 40–60 h

Adverse effects: HTN, hepatic, edema, hypothyroidism, fatigue, skin toxicities (discoloration, rash), hyperglycemia, GI, hematologic, ↑ SCr, ONJ

DDI: CYP3A4 inhibitors/inducers (↑/↓ conc. of sunitinib), P-gp inhibitors (↑ conc. of sunitinib), QTc-prolonging agents, warfarin (↑/↓ warfarin effects)

Clinical pearls: Monitor: LVEF, ECG, BP, oral exam prior to tx (ONJ risk)

Vandetanib (Caprelsa)

Dosing/dose adjustments: 300 mg oral daily. Renal: CrCl < 50 mL/min: 200 mg daily. Mod.-sev. hepatic: Use not recommended. Adjust dose for toxicities.

PK/PD: Hepatic metabolism via CYP3A4, fecal (44%) & urinary (25%) excretion, T1/2 19 d

Adverse effects: HTN, QTc prolongation, skin toxicities, insomnia (13%), fatigue, GI, hematologic, corneal abnormalities, hepatic, ↑ SCr

DDI: CYP3A4 inhibitors/inducers (↑/↓ conc. of vandetanib), P-gp inhibitors (↑ conc. of vandetanib), QTc-prolonging agents, warfarin (↑/↓ warfarin effects)

Clinical pearls: QTc > 450 msec: Withhold Rx. Monitor: Electrolytes, TSH, ECG, renal & hepatic function, BP, signs/sx HF. Distribution restriction: REMS Program (1-800-236-9933)

Vemurafenib (Zelboraf)

Dosing/dose adjustments: 960 mg oral every 12 h. No renal or hepatic dosing. Adjust dose for toxicities.

PK/PD: Fecal excretion (94%), T1/2 57 h

Adverse effects: Edema, fatigue, fevers, skin tox (alopecia, photosensitivity, rash), GI, ↑ GGT, cough, NM, skeletal

DDI: CYP3A4 inhibitors/inducers (↑/↓ conc. of vemurafenib), P-gp inhibitors (↑ conc. of vemurafenib), QTc-prolonging agents, warfarin (↑/↓ warfarin effects)

Clinical pearls: Available through specialty pharmacies. Monitor: LFTs, electrolytes, skin tox, sign & sx of uveitis

Info. based on publicly available drug inserts from: Pfizer, Exelixis, Genetech, Bristol-Myers Squibb, Astrazeneca, Novartis, GSK, Ariad, Bayer, & Incyte. Accessed 2/17/13.