Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Alkylating Agents

  • Classification: Platinum Analogs:

    • Carboplatin (Paraplatin): Overview

      • Carboplatin (Paraplatin)

      • Carboplatin (Paraplatin) is classified as a second-generation platinum drug that exhibits the same cytotoxic mechanisms, resistance mechanisms and general clinical pharmacology as has been described for cisplatin.³ 

        • Carboplatin also shows activity against many types of solid tumors.

        • One major difference compared to cisplatin is that carboplatin is associated with notably reduced gastrointestinal and kidney toxicity.

        • The primary dose-limiting toxic reaction to carboplatin is myelosuppression.³ 

          • Accordingly, carboplatin has been used in management of refractory blood cancers as part of transplant protocols.

          • Because of reduced renal toxicity potential, carboplatin does not require the aggressive intravenous hydration previously described for cisplatin and is therefore more easily administered to patients.

            • In a number of combination chemotherapy protocols carboplatin has replaced cisplatin.³

    • Mechanism of Action:

      • Cisplatin (Platinol), as well as carboplatin and oxaliplatin initiate their cytotoxic activity by first entering cells by means of a high affinity Cu²⁺ CTR1 transporter.¹ 

         

        • All-Atom Model (orange) with Superimposition of the Electron Density Map of CTR1¹⁰

          Attribution:  "Superimposition of the electron density map of the cryoelectron microscopy structure of the CTR1 with the all-atom model (orange wire line).  The 'edge' points of the cytoplasmic loop model have the cotrresponding maximums of the electron density." Tsigelny IF Sarikov Y Greenberg JP Miller MA Kouznetsova VL Larson CA Howell SB An All-Atom  Model of the Structure of Human Copper Transporter 1 Cell Biochemistry and Biophysics 63(3) (2012):  223-234. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590913/

        • Degraded transporter activity is associated with transporting these agents.

      • The compounds are extruded from cells by other copper transporters, in this case exporters.¹ 

        • These "exporters" are ATP7A and ATP7B.

        • Clinical resistance to the action of these platinum-based antineoplastic drugs depends in part on the expression level of these transporters.

      • Once inside the cell, specific ligands associated with the platinum drugs are displaced by water which results in a positively charged molecule, highly reactive with DNA and proteins.¹

        • Cisplatin is perhaps the most prominent organoplatinum anticancer agent.

          •  As such, this drug has an electron-deficient metal atom (platinum) which is attractive for electron-rich DNA nucleophiles..⁷ 

          • As noted earlier, organoplatinum antineoplastic drugs exhibit bifunctionality given that they can accept electrons from to DNA nucleophiles.

          • Cross-linking with interstrand is most likely between adjacent guanine residues (diguanosine dinucleotides, about 60% in frequency) or between adenine in guanine adjacent residues (about 27% in frequency).

            • Cross-linking between DNA strands (interstrand) occurs much less frequently than intrastrand cross-linking.⁷

      • Cisplatin aquation is more likely to occur intracellularly and in urine due to low chloride concentration.¹ 

        • By contrast, high concentrations of chloride tend to stabilize the drug, finding consistent with the observation that cisplatin-induced nephrotoxicity is prevented by chloride diuresis.

      • As noted earlier, formation of DNA-platinum adducts inhibit both transcription and replication.¹ 

        • These adducts induce single-and double-stranded breaks as well as miscoding.

        • If the adducts in DNA are so recognized by p53 and other checkpoint proteins, programmed cell death or apoptosis is induced.

      • Various platinum analogues are different with respect to adduct configuration and adduct effects on DNA structure and function.¹ 

        • For example, carboplatin (Paraplatin) and oxaliplatin (Eloxatin) form adducts more slowly compared to cisplatin.

    • Absorption, distribution, Metabolism Excretion: Carboplatin

      • Primary differences in pharmacokinetics comparing cisplatin and carboplatin is based on relatively slower conversion of carboplatin to reactive forms.⁸ 

        • This relative carboplatin stability is responsible for substantially reduced nephrotoxicity, compared to cisplatin,.⁸ 

        • Following infusion, carboplatin is readily available to tissues and exhibits plasma stability.

        • About 25% of an administered carboplatin dose was plasma protein associated at the four hour mark following infusion.

        • Disappearance of platinum (i.e. carboplatin) from plasma following infusion is described by a biphasic or triphasic curve. ⁸

          • t_1/2 for the first phase is in the range of 10-100 min..

          • t_1/2 for the second phase has been estimated at 1.3 to 1.7 hours.

          • Terminal phase half-time is about 10-40 hours.⁸ 

        • Carboplatin is mainly excreted by the kidney and exhibits a urinary excretion percentage of about 50% to 80%, primarily as parent drug, carboplatin.

        • About 4% appears as platinum within 1-4 days.

          • Carboplatin renal clearance is closely correlated with the glomerular filtration rate (GFR). Carboplatin-dosing, therefore, can be individualized, based on the patient's GFR.⁸

        • Carboplatin volume of distribution (VD) is about 16L.⁹ 

          • Carboplatin itself is not associated with protein binding; however, platinum derived from carboplatin binds irreversibly to plasma protein.

        • Carboplatin is metabolized by the liver to a very limited extent to aquated and hydroxylated derivatives.⁹

    • Clinical Uses:

      • Carboplatin and cisplatin have been judged comparably effective in treating certain patients such as those with:¹

        • Suboptimally surgically debulked ovarian cancer

        • Extensive, high-stage small cell lung cancer and

        • Non-small cell lung cancer (NSCLC).¹ 

           

          • "First-Line Carboplatin and Pemetrexed with Pembrolizumab for NSCLS"

            Attribution: Gandhi L First-Line Carboplatin and Pemetrexed with Pembrolizumab for NSCLS https://www.youtube.com/watch?v=ExqqMB4VssA Targeted Oncology Youtube Channel:  https://www.youtube.com/channel/UCE-5JpR_HFBQXgG0dH5DYPg

      • Cisplatin is more likely to be effective compared to carboplatin in those patients with esophageal cancer, head and neck cancer and germ cell cancer.¹ 

      • Some patients are not able to tolerate cisplatin due to renal toxicity, refractory nausea, neuropathy or ototoxicity.

        • In these patients, carboplatin represents a reasonable alternative for responsive tumors.

      • Carboplatin may be employed in high-dose treatment associated with bone marrow or peripheral stem cell rescue.¹

    • Adverse Effects:

      • Carboplatin exhibits a dose-limiting toxicity of myelosuppression expressed mainly as thrombocytopenia.

        • Carboplatin administration may also induce a hypersensitivity reaction which may be manageable either by premedication, management of drug dosing or lengthening infusion which may promote desensitization.

      • Adverse effects associated with carboplatin, as monotherapy, clinically observed >10% of the time include:⁹

        • Pain (CNS)⁹

        • Endocrine and metabolic effects (hyponatremia, hypomagnesemia, hypokalemia, hypocalcemia)

        • Gastrointestinal effects (vomiting, abdominal pain, nausea)

        • Hematologic and oncologic (bone marrow depression, anemia, leukopenia, neutropenia, thrombocytopenia)

        • Hepatic (elevated serum alkaline phosphatase)⁹