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

ANTIMICROTUBULAR AGENTS

Mabel Rodriguez

Ixabepilone (Ixempra)

Dosing/dose adjustments: 40 mg/m2 IV over 3 h, BSA capped at 2.2 m2. No renal dose adjustments recommended. AST or ALT > 10× ULN or Tbili > 3× ULN: Avoid use. Adjust dose for toxicities (neutropenia, neuropathy).

PK/PD: Protein bound, hepatic metabolism via CYP3A4

Adverse effects: Leukopenia, fatigue, alopecia, mucositis, myalgia, peripheral neuropathy, N/V (low emetogenic potential)

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

Clinical pearls: Can overpass resistance to taxanes & vinca alkaloids. Premedicate w/H1RA & H2RA.

Eribulin (Halaven)

• Dosing/dose adjustments: 1.4 mg/m2 IV d 1, 8 of 21-d cycle. Renal: CrCl 30–50 mL/min: 1.1 mg/m2/dose. Hepatic: Mild- 1.1 mg/m2, mod. - 0.7 mg/m2, adjust dose for toxicities (myelosuppression).

PK/PD: ∼50% protein bound, insignificant hepatic metabolism, T1/2 40 h

Adverse effects: Fatigue, neutropenia, (nadir 13 d), alopecia, peripheral neuropathy, QTc changes, N/V (low emetogenic potential)

DDI: No significant drug interactions

Cabazitaxel (Jevtana)

Dosing/dose adjustments: 25 mg/m2 IV over 1 h every 3 wks. CrCl < 30 mL/min: Use w/caution. Tbili ≥ ULN or AST/ALT ≥1.5 × ULN: Avoid use. Adjust dose for toxicities (hematologic & GI).

PK/PD: Highly protein bound (>90%), CNS distribution > other taxanes, hepatic metabolism via CYP3A4/5, minor CYP2C8, T1/2 95 h

Adverse effects: Myelosuppression (DLT, nadir 12 d), GI, pain, fatigue, N/V (low emetogenic potential)

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

Clinical pearls: Premedicate w/corticosteroids, H1RA/H2RA prior to administration

Docetaxel (Taxotere)

Dosing/dose adjustments: 60–100 mg/m2 IV over 1 h every 3 wks. Avoid use. No renal dose adjustments recommended. Tbili. > ULN or AST/ALT > 1.5 × ULN-avoid use. Adjust dose for toxicities (neutropenia & GI).

PK/PD: Highly protein bound (>90%), extravascular distribution & tissue binding, hepatic metabolism via CYP3A4, T1/2 11 h

Adverse effects: Myelosuppression (DLT, nadir 7 d), edema (dose-dependent), nail changes, alopecia, neuropathy, rash, N/V (low emetogenic potential)

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

Clinical pearls: Administer corticosteroids × 3 d to ↓ fluid retention. Irritant w/vesicant potential (Elevate extremity & cold compresses).

Paclitaxel (Taxol)

Dosing/dose adjustments: 60–250 mg/m2 IV over 1–24 h weekly or every 3 wks. No renal dose adjustments recommended. Hepatic dose adjustments according to infusion times. Adjust dose for toxicities (sev. peripheral neuropathy or neutropenia: Reduce by 20%)

PK/PD: >90% protein bound, distributed into body fluids & tissues, metabolism via CYP2C8 & CYP3A4, T1/2 (3-h infusion):13–20 h

Adverse effects: Myelosuppression (DLT, nadir 11 d), alopecia, neuropathy, myalgia, HSR, mild GI tox, N/V (low emetogenic potential)

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

Clinical pearls: Premedicate w/corticosteroids, H1RA/H2RA prior to administration. HSR 2° to Cremophor EL solvent. Peripheral neuropathy ↑ w/shorter infusion, myelosuppression ↑ w/longer infusion. Irritant w/vesicant potential (Elevate extremity & cold compresses).

Albumin-Bound Paclitaxel (Abraxane)

Dosing/dose adjustments: 260 mg/m2 IV over 30 min every 3 wks. No renal dose adjustments recommended. Hepatic dose adjustments based on AST/Tbili. Adjust dose for toxicities (neutropenia, neuropathy).

PK/PD: Highly protein bound (>90%), extravascular distribution & tissue binding, hepatic metabolism via CYP2C8 to 6α-hydroxypaclitaxel & CYP3A4, T1/2 27 h

Adverse effects: Myelosuppression (DLT), abnl ECG, alopecia, myalgia, N/V (low emetogenic potential)

DDI: CYP2C8 inhibitors (ethinyl estradiol, tretinoin)/inducers (↑/↓ conc. of albumin-bound paclitaxel)

Clinical pearls: ↓ HSR due to solvent free formulation

Vinblastine (Velban)

Dosing/dose adjustments: 3.7–6 mg/m2 IV every 7 d. No renal dose adjustments recommended. Tbili > 3 mg/dL: 50% of dose.

PK/PD: 99% protein bound, binds extensively to tissues (liver), does not penetrate CNS, hepatic metabolism via CYP3A4, T1/2 25 h

Adverse effects: Myelosuppression (DLT, nadir 5–10 d), constipation, alopecia, HTN, bone/jaw pain, N/V (min. emetogenic potential)

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

Clinical pearls: Implement bowel regimen pre/post dose. Fatal if given intrathecally. Vesicant (elevate extremity & warm compresses).

Vincristine (Oncovin)

Dosing/dose adjustments: 0.5–1.4 mg/m2 IV (dose capping at 2 mg) every 7 d. No renal dose adjustments recommended. Tbili > 3 mg/dL: 50% of dose.

PK/PD: Tightly bound to tissues (>90%), poor CNS penetration, hepatic metabolism via CYP3A4, T1/2 85 h

Adverse effects: Peripheral neuropathy, constipation, alopecia, N/V (min. emetogenic potential)

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

Clinical pearls: Implement bowel regimen pre/post dose. Fatal if given intrathecally. Vesicant (elevate extremity & warm compresses).

Vinorelbine (Navelbine)

Dosing/dose adjustments: 25–30 mg/m2 IV every 7 d. No renal dose adjustments recommended. Tbili 2.1–3 mg/dL: 50% dose, Tbili >3 mg/dL: 25% of dose. Adjust dose for toxicities (neutropenia, neurotoxicity).

PK/PD: Binds to plts & lymphocytes, hepatic metabolism via CYP3A4 to active metabolite, T1/2 28–44 h

Adverse effects: Myelosuppression (DLT, nadir 7–10 d), diarrhea, neuromyopathy, alopecia, N/V (min. emetogenic potential)

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

Clinical pearls: Vesicant (elevate extremity & warm compresses)

Info. based on publicly available drug inserts from Sanofi-Aventis, Bristol-Myers Squibb, Celgene, Bedford Laboratories, Teva Pharmaceuticals, GlaxoSmithKline, Eisai Inc.