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Medical Pharmacology Chapter 33-34: Anticancer Drugs
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Natural Products: Microtubule Antagonists
Taxanes
Cabazitaxel (Jetana)
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Carbazitaxel
was approved in 2010 (FDA) for treatment of metastatic
castration-resistant prostate cancer (CRPC) in patients having received
other chemotherapeutic agents earlier, including those treated with
docetaxel-containing protocols.
Some
patients may experience resistance to treatment and for those
patients with hormone-refractory metastatic prostate cancer
carbazitaxel may be an appropriate agent given that it is a poor
substrate for Pgp (P-glycoprotein 1 a.k.a. multidrug-resistant
protein one (MDR1).1,8
For patients with metastatic CRPC failing docetaxel treatment, I phase III study suggested an improvement in overall median survival on carbazitaxel when compared to mitoxantrone.8
Pharmacokinetics and Metabolism:
Carbazitaxel is administered by IV infusion along with daily oral prednisone and premedication prior to infusion to reduce likelihood of hypersensitivity reactions.8
Carbazitaxel is metabolized by the liver microsomal drug metabolizing system a.k.a. the cytochrome P450 system.10
The primary isoforms responsible for hepatic metabolism are CYP3A4 and CYP3A5 and to a lesser extent CYP3A8.
Liver metabolism results in seven plasma metabolites identified along with 20 metabolites including those excreted.
Most (80%) of carbazitaxel is excreted within about two weeks of administration mainly in the feces (about 80%).
Renal excretion accounts for about 4% with half that is the unchanged agent.10
Given
carbazitaxel dependency on the liver for metabolism, patients
with hepatic dysfunction may require drug dosage adjustment
along lines described for paclitaxel.
Reduced dose thus may be appropriate in individuals exhibiting mild to moderate reduction in liver function; however, with severe liver dysfunction carbazitaxel administration would be contraindicated.
By contrast, given the limited dependency on the kidney for drug excretion (about 4%), dosage adjustment in the presence of renal dysfunction is likely unnecessary.9
Principal toxicities (common) as a result of carbazitaxel administration are typically hematologic (90%) including:
Neutropenia
Leukopenia
Anemia.
Other, nonhematologic adverse reactions would most commonly be diarrhea, asthenia and fatigue.
Compared to docetaxel, carbazitaxel induces less peripheral neuropathy, alopecia and nail disorders.
Carbazitaxel
-induced high rate of grade ≥ 3 neutropenia requires aggressive
management.
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