PFIZER DAUNORUBICIN

Indications

• Acute myelogenous leukemia
• Acute lymphocytic leukemia
• Advanced AIDS-related Kaposi's sarcoma (liposomal formulation)

Dosage

Adults: The adult dosage of daunorubicin should be determined according to specific product literature, typically given by intravenous infusion. Cardiac monitoring is essential during treatment. Dose adjustments may be necessary based on serum bilirubin

Mechanism of action

Daunorubicin has antimitotic and cytotoxic activity through several mechanisms. It forms complexes with DNA by intercalating between base pairs and inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex. This action prevents the religation process that topoisomerase II catalyzes, resulting in single-strand and double-strand breaks in DNA. Additionally, daunorubicin may inhibit polymerase activity, affect gene expression regulation, and contribute to free radical damage to DNA. While it is most cytotoxic in the S phase of the cell cycle, it is not cycle-phase specific.

Pharmacodynamics

As an anthracycline antibiotic, daunorubicin inhibits cellular reproduction by interfering with DNA replication and induces cell death by increasing oxidative stress through the generation of reactive oxygen species and free radicals. Its significant toxicities include cytopenias, hepatotoxicity, and extravasation reactions. The drug's cardiotoxic potential is proportional to the cumulative dose over time, necessitating careful dose management.

Pharmacokinetics

Daunorubicin is administered intravenously and undergoes extensive hepatic metabolism, with its active metabolite, daunorubicinol, contributing to its pharmacological effects. The drug is primarily eliminated via biliary excretion. In patients with hepatic impairment, dose adjustments may be necessary due to altered metabolism and clearance rates. Monitoring of liver function is essential during treatment.

Contra-indications

• Myocardial insufficiency
• Previous treatment with maximum cumulative doses of daunorubicin or other anthracyclines
• Recent myocardial infarction
• Severe arrhythmia

Adverse effects

• Abdominal pain
• Alopecia
• Amenorrhea
• Anaemia
• Arrhythmias
• Ascites
• Atrioventricular block
• Azoospermia
• Bone marrow disorders
• Cardiac inflammation
• Cardiomyopathy
• Chills
• Congestive heart failure
• Cyanosis
• Death
• Dehydration
• Diarrhea
• Dyspnoea
• Extravasation necrosis
• Fever
• Flushing
• Gastrointestinal disorders
• Haemorrhage
• Hepatomegaly
• Hyperpyrexia
• Hyperuricemia
• Hypoxia
• Infection
• Ischaemic heart disease
• Leucopenia
• Mucositis
• Myocardial infarction
• Nail discolouration
• Nausea

Interactions

• Ciclosporin: Unknown (increases concentration)
• Leflunomide: Unknown (increases exposure)
• Teriflunomide: Unknown (increases exposure)

Precautions

• Caution in handling due to irritant properties
• Cardiac monitoring essential during treatment
• Caution in hepatic impairment; avoid in severe impairment
• Caution in renal impairment; consult product literature for specific recommendations

Pregnancy

Daunorubicin is not recommended during pregnancy due to potential risks to the fetus.

Breast-feeding

Discontinue breastfeeding during treatment with daunorubicin.

Storage

Store at room temperature, protected from light. Do not freeze.

Formulations

• Daunorubicin (as daunorubicin hydrochloride) 20 mg powder for solution for infusion vials

Mechanism of action

Daunorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action: Daunorubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. Daunorubicin is an antineoplastic antibiotic. Daunorubicin has antimitotic and cytotoxic activity. Daunorubicin forms a complex with DNA by intercalation between base pairs. By stabilizing the complex between DNA and topoisomerase II, daunorubicin inhibits the activity of this enzyme, resulting in single-strand and double-strand breaks in DNA. Daunorubicin also may inhibit polymerase activity, affect regulation of gene expression, and be involved in free radical damage to DNA. Although daunorubicin is maximally cytotoxic in the S phase, the drug is not cycle-phase specific. Daunorubicin also has antibacterial and immunosuppressive properties. Anthracyclines are an important reagent in many chemotherapy regimes for treating a wide range of tumors. One of the primary mechanisms of anthracycline action involves DNA damage caused by inhibition of topoisomerase II. Enzymatic detoxification of anthracycline is a major critical factor that determines anthracycline resistance. Natural product, daunorubicin a toxic analogue of anthracycline is reduced to less toxic daunorubicinol by the AKR1B10, enzyme, which is overexpressed in most cases of smoking associate squamous cell carcinoma (SCC) and adenocarcinoma. In addition, AKR1B10 was discovered as an enzyme overexpressed in human liver, cervical and endometrial cancer cases in samples from uterine cancer patients. Also, the expression of AKR1B10 was associated with tumor recurrence after surgery and keratinization of squamous cell carcinoma in cervical cancer and estimated to have the potential as a tumor intervention target colorectal cancer cells (HCT-8) and diagnostic marker for non-small-cell lung cancer. This article presents the mechanism of daunorubicin action and a method to improve the effectiveness of daunorubicin by modulating the activity of AKR1B10. ... In the present study using the ATP depleting agents cyanide, azide, or dinitrophenol to inhibit energy dependent transport processes, /investigators/ observed even larger increases in daunorubicin accumulation than were seen with CsA. Similar patterns were seen in a wide range of P-gp negative human cancer cell lines. Also the observed cyanide effect did not correlate with the expression of mRNA for multidrug resistance-associated protein (MRP), the only other member of the ABC family of membrane transporters that is known to be capable of effluxing daunorubicin. Thse results suggest that daunorubicin accumulation in many cases of AML is modulated by one or more novel energy-dependent processes that are distinct from P-gp or MRP. /The authors/ speculate that this novel drug transport mechanism(s) may influence the response of AML patients to daunorubicin and other therapeutic agents. Inhibits DNA synthesis and blocks DNA-directed RNA polymerase. It can prevent cell division in doses that do not interfere with nucleic acid synthesis.

Pharmacodynamics

Daunorubicin is an anthracycline antibiotic and antineoplastic agent. It acts by inhibiting cellular reproduction through interference with DNA replication although it may contribute to the induction of cell death by increasing oxidative stress through the generation of reactive oxygen species and free radicals. As an antineoplastic agent, daunorubicin carries significant toxicities including cytopenias, hepatotoxicity, and extravasation reactions. Like other anthracyclines, daunorubicin also exhibits cardiotoxicity in proportion with the cumulative dose received over time.