Medical Pharmacology Chapter 33-34: Anticancer Drugs
Alkylating Agents (Continued):
Overview: Ifosfamide, a cyclophosphamide analog, exhibits clear structural similarity to cyclophosphamide (Cytoxan, Neosar and others.).
Adverse effects related to bladder toxicity represented an early impediment to ifosfamide use.22
Increasing patient hydration and coadministration of mesna (Mesnex) reduces ifosfamide (or cyclophosphamide) bladder toxicity.22
Mesna, an organosulfur compound, interacts with acrolein, a toxic ifosfamide metabolite, reduced toxicity.
With cyclophosphamide, both chloroethyl groups are bound to the exocyclic nitrogen.4
By contrast, one of the two chloroethyl groups of ifosfamide is attached to the primary ring nitrogen.
The plasma elimination t1/2 for ifosfamide is about 1.5 hours following doses of about 4-5 g/m2 with a reduced half-life associated with lower doses.
Pharmacokinetic variability is expected based on a range of hepatic metabolic rates.22
Metabolism: As described earlier, cyclophosphamide is a "prodrug", requiring metabolic activation.4
Ifosfamide is also prodrug, principally activated by the cytochrome P450 microsomal enzyme isoform CYP3A4.
With ifosfamide this activation is slower with increased dechlorinated metabolites and chloroacetaldehyde.
Most likely, these metabolic differences between cyclophosphamide and ifosfamide account for elevated ifosfamide doses needed for "equitoxic" effects.
Furthermore, metabolic differences may also result in greater neurotoxicity with ifosfamide.4
Generally, ifosfamide exhibits a cyclophosphamide-like toxicity profile.
Ifosfamide administration causes increased platelet suppression.
Ifosfamide administration is associated with nephrotoxicity, urothelial pathology and neurotoxicity.
At the higher doses severe neurological toxicity may appear after 12 hours to about a week following initiation of ifosfamide IV administration.
The neurological toxicity may include hallucination, and even death.
The neurotoxicity may be due to an ifosfamide metabolite, chloroacetaldehyde.
More generally ifosfamide administration resulted nausea, vomiting, loss of appetite (anorexia), leukopenia and as noted earlier, nephrotoxicity.
Veno-occulsive disease (VOD) of the liver may also occur.
Example of Ifosphamide clinical use:
Ifosfamide is appropriate for treating patients exhibiting relapsed germ cell testicular cancer.
Ifosfamide is used with other drugs in high-dose chemotherapy protocols with bone marrow/stem cell rescue.
Soft Tissue Sarcoma:
Soft tissue sarcoma is a category of sarcoma developing in connective tissue.17
Sarcoma itself refers to cancer rising from transformed mesenchymal cells.19
Accordingly, malignant tumors of cancellous bone, fat, cartilage, muscle, vascular or hemopoietic tissues are sarcomas.
By contrast, malignant tumors originating from epithelial cells are described as "carcinoma."18
Metastatic soft tissue sarcoma is treated with conventional chemotherapy drugs.
Treatment with these agents has remained principally the same for over 20 years.
Chemosensitivity of tumor to these drugs very based on histologic subtype; furthermore, "higher-grade" tumors appear more responsive to chemotherapy.
Detailed algorithms have been developed that describe treatment approaches for specific sarcoma tumor types (e.g. myxoid liposarcoma, leiomyosarcoma, or angiosarcoma).
These algorithms take into account both tumor subtype sensitivity to particular drugs as well as characteric molecular abnormalities.
Ifosfamide and doxorubicin are the two most active drugs for treating soft tissue sarcoma.16
The single-agent response rate for doxorubicin is about 20%-35%.
Ifosfamide exhibits a comparable single-agent response rate. 16
Optimal responses for ifosfamide may also depend on the infusion duration i.e. 2-3-hour vs. 24-hour infusion.
Combination treatment with high-dose doxorubicin + ifosfamide improves both response rates in progression-free survival with the possibility of improved overall survival.16
Depending on soft tissue sarcoma subtypes a variety of drug and drug combinations may be used including:16
doxorubicin + ifosfamide
doxorubicin + dacarbazine
cyclophosphamide + dacarbazine + dacarbazine,
gemcitabine + docetaxel
Overview: Melphalan (L-phenylalanine mustard)13,22
Melphalan (Evomela) is a nitrogen mustard alkylating agent which has clinical uses in both multiple myeloma and in high-dose treatment prior to bone marrow transplantation.
This agent is an aromatic mustard incorporating the l-isomer of phenylalanine since that the l-amino acids are preferentially transported by specific amino acid carriers.
However, melphalan may enter cells by facilitated diffusion as opposed to active transport.
Melphalan is associated with a lone electron pair which is less reactive compared to the lone electron pair found on aliphatic mustards.
The reduced reactivity was thought to confer both greater likelihood of drug distribution reaching cancer cells and reduction in severity of side effects.
A reduced incidence of nausea and vomiting with melphalan has been noted, compared to that observed with mechlorethamine.
Patients receiving melphalan however can experience myelosuppression.
Melphalan is considered mutagenic in itself and leukemogenic.
Absorption, Distribution, Metabolism, Excretion:
Oral melphalan can be absorbed orally but by this route of administration the absorption appears inconsistent.
Absorption is reduced with food but protocols do not require an empty stomach.
Usually, melphalan (as the hydrochloride salt) is administered by IV infusion; however, this route of administration appears associated with a higher incidence of serious adverse effects.
Melphalan distributes readily in the body water.
Therefore toxicity may be more noted in patients were dehydrated or in patients experiencing renal dysfunction.
In patients with renal disease, dosage adjustments may be made, thus possibly avoiding severe myelosuppression.
Melphalan following oral dosing exhibits variable absorption ranging from about 25% to about 90%.24
Melphalan volume of distribution is estimated at 0.5 L/kg.
This agent exhibits protein binding mainly to albumin (60%-90%, described as moderate to high) and secondarily to α1-acid glycoprotein.
Melphalan is not metabolized actively; rather, the agent spontaneously degrades to mono- and dihydroxy products.
Renal clearance therefore is not a notable route of elimination of the parent agent, accounting for about 10% in the 24 hours following administration.
Melphalan half-life is estimated to be about two hours.24
Melphalan has clinical uses in both multiple myeloma and in high-dose treatment prior to bone marrow transplantation.
In high-dose treatment (myeloablative) prior to hemopoietic cell transplantation, melphalan administration is associated with liver enzyme elevation and acute hepatic injury secondary to sinusoidal obstruction syndrome.
Melphalan may also be used in the palliative setting both in multiple myeloma and in cases of non-resectable epithelial ovarian carcinoma.
Melphalan has also found use in adjuvant treatment of breast cancer.
Melphalan has also been used in palliative treatment of locally recurring or "nonresectable in-transit" metastatic melanoma of the extremities.
Along with prednisone, melphalan may be used in treatment of amyloidosis
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