Carboplatin

Absorption

The Cmax and AUC of carboplatin increase proportionally with increasing doses. A 75 mg/m2 dose reaches a Cmax of 9.06 ± 0.74 μg/mL, with an AUC of 27.18 ± 11.28 h*μg/mL. A 450 mg/m2 dose reaches a Cmax of 55.39 ± 18.30 μg/mL, with an AUC of 224.41 ± 69.07 h*μg/mL.

Toxicity

Patients experiencing an overdose of carboplatin may present with pronounced neutropenia and hepatotoxicity. Treat patients with symptomatic and supportive measures, which may include delaying their next treatment.

Description

Carboplatin is a second generation, platinum-containing antineoplastic agent with significantly reduced nephro-, neuro-, and ototoxicity in comparison to cisplatin. It is effective in the treatment of advanced ovarian carcinoma of epithelial origin and small cell carcinoma of the lung.

Description

Carboplatin, an alkylating agent used to treat ovarian and lung cancers, interferes with the growth of cancer cells by inhibiting DNA synthesis. Carboplatin is less toxic than its predecessor cisplatin, but it can interfere with the growth of healthy cells, including blood cells. Carboplatin''s mechanism of action is not well understood.

Chemical properties

White Crystals

Originator

Johnson Matthey (United Kingdom)

The Uses of Carboplatin

Data on carboplatin production have not been found. Carboplatin is used in chemotherapy to treat cancer, and more particularly to treat cancer of ovary, embryonal carcinoma of the testis, microcellular carcinoma of the lung, neuroblastoma, and squamous cell carcinomas of the head and neck.

The Uses of Carboplatin

Analog of Cisplatin with reduced nephrotoxicity. Antineoplastic

The Uses of Carboplatin

antitumor agent,

What are the applications of Application

Carboplatin is an antitumor agent that binds to DNA leading to apoptosis

Background

Carboplatin is an organoplatinum antineoplastic alkylating agent used in the treatment of advanced ovarian carcinoma. Early clinical studies of carboplatin were performed in 1982. Carboplatin was developed as an analog of cisplatin with reduced nephrotoxicity and vomiting.
Carboplatin was granted FDA approval on 3 March 1989.

Indications

Carboplatin is indicated in combination with an established combination of chemotherapeutic agents for the initial treatment of advanced ovarian carcinoma. Carboplatin is also indicated for the palliative treatment of ovarian carcinoma, recurrent after prior chemotherapy.

Indications

Carboplatin (Paraplatin) is an analogue of cisplatin. Its plasma half-life is 3 to 5 hours, and it has no significant protein binding. Renal excretion is the major route of drug elimination.
Despite its lower chemical reactivity, carboplatin has antitumor activity that is similar to that of cisplatin against ovarian carcinomas, small cell lung cancers, and germ cell cancers of the testis. Most tumors that are resistant to cisplatin are cross-resistant to carboplatin.
The major advantage of carboplatin over cisplatin is a markedly reduced risk of toxicity to the kidneys, peripheral nerves, and hearing; additionally, it produces less nausea and vomiting. It is, however, more myelosuppressive than cisplatin. Other adverse effects include anemia, abnormal liver function tests, and occasional allergic reactions.

Manufacturing Process

cis-Diammine platinum diiodide was reacted with silver sulfate to give cis-diaquodiammine platinum sulfate. This was reacted with the barium salt of 1,1-cyclobutanedicarboxylic acid to yield Carboplatin.

brand name

Paraplatin (Bristol-Myers Squibb).

Therapeutic Function

Antitumor

General Description

Carboplatin is available in 50-, 150-, and 450-mg vials for IVadministration in the treatment of ovarian cancer, bladdercancer, germ cell tumors, head and neck cancers, small celllung cancer, and NSCLC. Activation of the agent occurs byaquation in a manner similar to that seen for cisplatin. Thepresence of the chelating 1,1-cyclobutane-dicarboxylateslows this reaction 100-fold and reduces the toxicity of theagent. The sites of alkylation and mechanisms of resistanceare like those seen for cisplatin, and the two agents showcross-resistance. The agent is widely distributed upon IV administration but, because of its greater stability, it bindsslowly to plasma proteins, requiring 24 hours to reach 90%bound drug compared with 4 hours for cisplatin. The agent iseliminated in the urine with a terminal elimination half-lifeof 2 to 6 hours. Adverse effects include myelosuppression,which is dose limiting. Other adverse effects include renaltoxicity, nausea, vomiting, and peripheral neuropathy, butthese occur much less frequently than with cisplatin.

Pharmaceutical Applications

Carboplatin, cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II), is a second-generation platinum drug. Its structure is based on cisplatin with the difference that the chloride ligands are exchanged for a bidentate chelating ligand. A consequence is that carboplatin is less reactive than cisplatin and therefore is less nephrotoxic and orthotoxic than the parent compound. Unfortunately, it is more myelosuppressive than cisplatin, which reduces the patients’ white blood cell count and makes them susceptible to infections. Carboplatin was licensed by the FDA in 1989 under the brand name Paraplatin and has since then gained worldwide recognition. Carboplatin on its own or in combination with other anticancer agents is used in the treatment of a variety of cancer types including head and neck, ovarian, small-cell lung, testicular cancer and others.
Carboplatin is a pale-white solid showing good aqueous solubility. The synthesis starts with potassium tetrachloroplatinate, which is reacted to the orange [PtI₄]^2- anion.

Biological Activity

Antitumor agent that forms platinum-DNA adducts. Causes intra- and interstrand DNA crosslinks blocking DNA replication and transcription. Enhances radiation-induced single-strand DNA breakage and displays lower nephrotoxicity than analog cisplatin (cis-Diaminodichloroplatinum ).

Biochem/physiol Actions

Carboplatin is a platinum-based antineoplastic drug that damages DNA by forming intrastrand cross-links with neighboring guanine residues. Tumors acquire resistance to these drugs through the loss of DNA-mismatch repair (MMR) activity and the resultant decrease in the induction of programmed cell death.

Mechanism of action

Carboplatin, another square planar Pt(II) complex, forms the same cytotoxic hydrated intermediate as cisplatin but does so at a slower rate, making it a less potent chemotherapeutic agent.

Pharmacokinetics

Carboplatin is an organoplatinum antineoplastic alkylating agent used in the treatment of advanced ovarian carcinoma. Carboplatin has a long duration of action as it is given every 4 weeks, and a narrow therapeutic index. Patients should be counselled regarding bone marrow suppression and anemia.

Clinical Use

This drug induces fewer nonhematological toxicities (e.g., emesis, nephrotoxicity, and ototoxicity) compared to cisplatin, and it is approved for use only in the treatment of ovarian cancer. Unlabeled uses include combination therapy in lung, testicular, and head and neck cancers.

Side Effects

The ultimate damage done to cells as a result of carboplatin use, however, approaches that of cisplatin. The plasma half-life of carboplatin is 3 hours, and the drug is less extensively bound to serum proteins. Excretion is predominantly renal, and doses must be reduced in patients with kidney disease. Suppression of platelets and white blood cells is the most significant toxic reaction of carboplatin use.

Synthesis

Carboplatin, cis-diamino-(1,1-cyclobutandicarboxylate)platinum(II), is made from cisplatin by reacting it with a solution of silver nitrate, and then with cyclobutan-1,1-dicarboxylic acid to form the desired carboplatin (30.2.5.2).

Veterinary Drugs and Treatments

Like cisplatin, carboplatin may be useful in a variety of veterinary neoplastic diseases including squamous cell carcinomas, ovarian carcinomas, mediastinal carcinomas, pleural adenocarcinomas, nasal carcinomas and thyroid adenocarcinomas. Carboplatin’s primary use currently in small animal medicine is in the adjunctive treatment (post amputation) of osteogenic sarcomas. Its effectiveness in treating transitional cell carcinoma of the bladder has been disappointing; however, carboplatin may have more efficacy against melanomas than does cisplatin.
Carboplatin, unlike cisplatin, appears to be relatively safe to use in cats.
Carboplatin may be considered for intralesional use in conditions such as equine sarcoids or in treating adenocarcinoma in birds.
Whether carboplatin is more efficacious than cisplatin for certain cancers does not appear to be decided at this point, but the drug does appear to have fewer adverse effects (less renal toxicity and reduced vomiting) in dogs.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: increased risk of nephrotoxicity and possibly ototoxicity with aminoglycosides, capreomycin, polymyxins or vancomycin.
Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.

Metabolism

Carboplatin is predominantly eliminated as the unchanged parent compound.

Metabolism

There is little, if any, true metabolism of carboplatin. Excretion is primarily by glomerular filtration in the urine, with 70% of the drug excreted within 24 hours, most of it in the first 6 hours. Approximately 32% of the dose is excreted unchanged. Platinum from carboplatin slowly becomes protein bound, and is subsequently excreted with a terminal halflife of 5 days or more.

storage

+4°C

References

[1]. banerji u, sain n, sharp sy, et al. an in vitro and in vivo study of the combination of the heat shock protein inhibitor 17-allylamino-17-demethoxygeldanamycin and carboplatin in human ovarian cancer models. cancer chemother pharmacol, 2008, 62(5): 769-778.
[2]. fiebiger w, olszewski u, ulsperger e, et al. in vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines. clin transl oncol, 2011, 13(1): 43-49.
[3]. smith ie, evans bd. carboplatin (jm8) as a single agent and in combination in the treatment of small cell lung cancer. cancer treat rev, 1985, 12 suppl a: 73-75.