Platinum Agents – Cisplatin, Carboplatin, Oxaliplatin, Newer Platins

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Introduction

  • Non-classical, bifunctional alkylating agents
  • Cell cycle nonspecific
  • Cisplatin was first synthesised in 1844 by Peyrone
  • Biological activity first discovered in 1965 by Rosenberg in E.coli
  • Observed that current delivered between platinum electrodes caused inhibition of coli led to development of cisplatin in the 1970s, carboplatin in the1980s, oxaliplatin and satraplatin in the 1990’s

Drug Interactions

Synergistic activity

Mechanism of Resistance

  • altered cellular accumulation of drug – Cu transporters
  • cytosolic inactivation of drug – peptides with sulfhydryl groups covalently bind to platinums
  • increased DNA repair – NER
  • altered apoptotic process – defects in MMR

Cisplatin

cisplatin

  • Non-classical, bifunctional alkylating agent
  • Cell cycle nonspecific
  • Cisplatin was first synthesised in 1844 by Peyrone
  • Biological activity first discovered in 1965 by Rosenberg in E.coli
  • Observed that current delivered between platinum electrodes inhibition of coli
  • Led to development of cisplatin in the 1970s, carboplatin in the1980s, oxaliplatin and satraplatin in the 1990’s

Difference between Cisplatin and Carboplatin

  • Need for an esterase activity to release the carboxylato moiety of the carboplatin molecule.
  • Delayed time frame for the formation of the specific DNA adducts with Carboplatin.
  • Proportion of adducts same as cisplatin.

Difference between Cisplatin and Oxaliplatin

  • The carrier ligand is different for both and that is responsible for the differences.
  • Differences in the rates of formation and repair of oxaliplatin-DNA damage.
  • The proportion of adducts with oxaliplatin are lesser than cisplatin.

Mechanism of Resistance

  • Altered cellular accumulation of drug by Copper transporters
  • Cytosolic inactivation of drug – peptides with sulfhydryl groups covalently bind to platinums
  • Increased DNA repair BY Neucleotide Excision Repair (NER) pathway
  • Altered apoptotic process due to defects in Mismatch Repair (MMR)

Pharmacokinetics and Pharmacodynamics

  • Cisplatin is scientifically CDDP – cis– di chloro diammino platinum
  • > 90% is plasma protein binding (PPB) at 4 hours infusion
  • 25% of the drug is excreted during the first 24 hours
  • Excretion is renal > 90%, and bile < 10%
  • Extensive protein binding which causes accumulation in many tissues
  • The terminal half-life is 1 -5 days

Uses/Indications

Availability and Dosing

  • Supplied as 10 and 50 mg vials
  • Clear, colorless, sterile aqueous solution
  • Dosing – as intravenous injection
      • 40mg/m2 weekly (HNSCC)
      • 20mg/m2 D1-5 Q 3w (GCT)
      • 75mg/m2 Q 3-4 w (ovarian,NSCLC)
      • 120mg/m2 (over3days) Q 3wkly (OS)
  • Intraperitoneal (IP) in ovarian cancer – 100-200 mg/m2

Intraperitoneal Cisplatin

  • Used in ovarian cancer after optimal cytoreductive surgery.
  • A single lumen catheter with a port –  IP access.
  • CDDP mixed in 1 L of NS and warmed to 37°C, infused through the port via gravity drip as rapidly as possible.
  • A 2nd litre of NS to help distribute the drug.
  • Complications – myelosuppression, emesis, neuropathy, abdominal discomfort, etc

Administration

  • Administered in normal saline
  • Rationale – the leaving group
    • In the Intracellular Fluid (ICF), Cl is lysed by H2O to form an aquo ligand which is a better leaving group- so CDDP gets activated in ICF
    • In saline solution, due to high Cl- content the CDDP is maintained in the same form without getting activated
  • Exclude Mg2+, Aluminum needles as they chemically neutralize the compound
  • Administered in 250 ml NS
  • Infusion duration – 1 to 4 hours
  • Potassium and magnesium are always to be added
  • Mannitol in doses > 40 mg/m2

Premedication

  • Aprepitant (ideal)
  • Dexamethasone
  • Palnosetron or Ondansetron
  • Dexamethasone for 2-3 days after administration ( delayed emesis)

Hydration

  • Both pre- and post infusion
  • Atleast 1 litre of NS
  • Essential because 50% reductions in renal clearance may occur in the absence of preinfusion and postinfusion hydration
  • Reductions in renal function are nonoliguric
  • The extent of damage may not be fully reflected by changes in serum creatinine

Toxicity

Nausea and vomiting

Cisplatin is highly emetogenic drug. Adequate antiemetic prophylaxis helps to prevent nausea and vomiting with the drug, in most of the cases.

Nephrotoxicity

It is 5% with and 25-45% without hydration, so hydration plays a major role in preventing it. Risk factors for it are female gender, older age, smoking, and hypoalbuminemia. It leads to Cation loss (Mg2+ Ca2+)  Recovery usually takes over 2–4 weeks, but rarely it could be protracted or may be irreversible.

Acute toxicity

It is seen in those who have not received adequate hydration. Azotemia and a rising serum creatinine due to early proximal tubular damage (within 1-3 hours) are an indicator of acute nephrotoxicity with cisplatin. Urinary beta-2 microglobulin is a sensitive laboratory indicator.

Chronic toxicity

It is uasually seen in those who have been cured or had a long term remission after CDDP. It is characterised by an irreversible decrease in GFR without changes in serum creatinine. Renal tubular damage is reflected by an increase in urinary excretion of enzymes and loss of Mg+ and potassium.

Methods to Minimise Nephrotoxicity

  • Vigorous intravenous hydration
  • Mannitol to enhance urine flow
  • Amifostine –  detoxifies reactive metabolites and ROS scavenger
  • N-acetyl cysteine

Amifostine use

  • A phase-III trial in ovarian cancer found that amifostine reduced the incidence of nephrotoxicity from 33 to 10 %
  • ASCO in 2002 stated that amifostine could be considered in repeated administrations of CDDP for ovarian/ NSCLC

Not recommended as –

  • Availability of newer regimens that use lower doses of cisplatin or substitute carboplatin for cisplatin
  • Significant toxicity (nausea, vomiting, hypotension)
  • Costs
  • Concerns about interference with the antitumor efficacy

Neurotoxicity

It is a Cumulative toxicity with cisplatin usually seen at doses > 200mg/m2. Incidence of cisplatin induced neurotoxicity is approximately 20-30%. The presence of other known risk factors for CIPN (e.g., alcohol consumption, diabetes, high serum creatinine levels, or age) do not influence the incidence and severity. Peripheral sensory neuropathy is more common than motor neuropathy. Some less common symptoms are visual disturbances, cortical blindness, seizures, papilledema, and retrobulbar neuritis. Although it is reversible in most patients, it can persist for years in around 20% of patients.

Neurotoxicity mechanism

  • Dorsal Root Ganglion (DRG) neuron apoptosis
  • Formation of platinum intra- strand adducts and inter-strand crosslinks and
  • Interaction with mitochondrial DNA leading to oxidative stress, causing increased activity of p53 and mitochondrial release of cytochrome-c pathway.

Ototoxicity

It is a cumulative toxicity of cisplatin, reaching 5% with doses above 100mg/m2. Higher frequencies are affected more commonly (4000 – 8000 Hz). Main mechanism is depletion of glutathione and antioxidant enzymes in the cochlea. At lower doses (50 mg/m2), the inner hair cells and at higher frequencies, outer hair ( 5-fold higher ) cells are lost. The factors that may increase the risk are concurrent use of ototoxic agents, previous cranial irradiation, preexisting renal dysfunction, older age, etc.

Other Side Effects

  • Myelosuppression – In most of the cases, it is trilineage myelosuppression. Seen in around 25-30% cases.
  • Arrythmias, acute ishaemic events, glucose intolerance, pancreatitis, hypersensitivity reactions, leukemia.
  • Acute hypersensitivity reactions are rare and seen after the 6th cycle.

Dose modifications

  • Creatinine clearance 40-60 ml/min, reduce the dose to 50%
  • Contraindicated when CrCl <40 ml/min
  • Contraindicated in history of previous life threatening hypersensitivity reactions
  • Relatively contraindicated in documented hearing impairment
  • Pregnancy – category D and also to be avoided during lactation

Carboplatin

carboplatin

Pharmacokinetics and Pharmacodynamics

  • cis-diammine-cyclobutanedicarboxylato-platinum
  • t1/2 = 12 – 24 min; t1/2 = 1.3 – 1.7 hr; t1/2 = 22 – 40 hr
  • 24% Plasma Protein Binding (PPB) at 4 hours infusion
  • 90% is excreted in the urine in 24 hr

Uses/Indications

  • Ovarian cancer
  • Germ cell tumors
  • Head and neck cancer
  • Small cell and non–small cell lung cancer
  • Bladder cancer
  • Relapsed and refractory lymphoma
  • Endometrial cancer
  • Cervical cancer

Cisplatin vs Carboplatin

  • Carboplatin can replace cisplatin in the treatment of ovarian cancer and lung cancer
  • Carboplatin is inferior to cisplatin in germ cell, head and neck, gastric and esophageal cancers
  • Not known whether it has equivalent efficacy to cisplatin in bladder, cervical, and endometrial cancers

Availability and Dosing

  • Available as 50, 150, 450 mg vials
  • Dosing of carboplatin is calculated based on glomerular filtration rate. The formula used for it is called as Calvert’s Formula.
  • The AUC dose is calculated using the Calvert formula
      • Carboplatin dose = target AUC * (GFR + 25)

Why AUC is used to calculate dosing?

  • A close relationship of changes in platelet counts, response and neutropenia to AUC.
  • AUC is related to the renal function.
  • AUC of 5-7 is used as response increases with the increase in the AUC upto this level, and plateaus beyond this dose.
  • Unit – mg/ ml/ min.
  • The value of 25 ml/min is a constant that used to correct for the nonrenal clearance of irreversibly tissue-bound carboplatin.

Administration

  • In NS or 5% Dextrose
  • Duration of administration is usually 1 to 4 hours.
  • The 1-hour time frame is the most common.
  • Much less renal toxicity than cisplatin, hence no need for vigorous hydration or forced diuresis.

Toxicity

Dose-limiting

  • Myelosuppression
  • Increases with reduced creatinine clearance levels and with subsequent cycles

Common

  • Nausea and vomiting (less severe than with cisplatin, resolves in 24 hrs ),
  • Pain at injection site

Occasional

  • Abnormal LFTs,
  • Azotemia;
  • Neurotoxicity (5%) with dose > 600 mg/m2, features similar to cisplatin,
  • Hypersensitivity reactions ( > 6 cycles ),
  • Disorders in fertility

Oxaliplatin

oxaliplatin

Pharmacokinetics and Pharmacodynamics

  • 1,2-diamminocyclohexaneoxalato-platinum
  • Levels decrease in a triphasic fashion
    Terminal t1/2 = 27.3 hr
  • 85% Plasma Protein Binding (PPB) at 2-5 hours
  • Renal elimination predominantly, >50% of the drug is excreted through kidneys
  • No dose adjustment with a creatinine clearance > 20 ml/min

Uses/Indications

Cisplatin vs Oxaliplatin

  • FDA approved for colorectal cancer. Not been extensively studied in other malignancies
  • Cisplatin is effective in upper GI malignancy where as oxaliplatin is more effective in colorectal cancer
  • This difference is due to 1,2-diaminocyclohexane carrier ligand, which inhibits replicative bypass of platinum DNA adducts

Availability and Dosing

  • Available as 50- and 100-mg vials
  • It is a white crystalline powder
  • Administer in a 5% dextrose IV
  • Dosing – 85 mg/m2 q2weeks; 130 mg/m2 q3weeks
  • Although infusion can be done in 2 to 6 hours, 2 hours is most commonly used

Administration

  • Reconstituted by adding 10 mL (for the 50 mg vial) or 20 mL (for the 100 mg vial) of water for Injection or 5% Dextrose
  • Further diluted in 250-500 mL of 5% Dextrose
  • RECONSTITUTION MUST NEVER BE DONE WITH NS / CHLORIDE-CONTAINING SOLUTIONS.
  • Reconstitution in normal saline leads to rapid inactivation to reactive compounds mono- and dichloroplatinum,
  • Diaquoplatinum also reacts with tissues causing neurotoxicity

Toxicity

Dose-Limiting

  • Peripheral sensory neuropathy- seen in 65%
  • In all DACH containing compounds
      • Acute dysesthesias – may be ameliorated by prolonging the infusion to 6 hours
      • Persistent peripheral neuropathy
  • Grade 2 or worse neuropathy seen in 40–50% , grade 3 neuropathy in 10–20% of patients

Oxaliplatin-Induced Neurotoxicity

Acute Neurotoxicity

  • Common (90% of patients)
  • May appear at first treatment cycle
  • Onset during or within hours to days
  • Transient, short lived, < 2 weeks
  • Cold-triggered or cold-aggravated
  • Dysesthesias and paresthesias of distal extremities, perioral, oral, and pharyngolaryngeal areas
  • Associated symptoms of muscular hyperactivity including jaw tightness, cramps, and fasciculations
  • Depending on dosing schedule (infusion rate)

Chronic Neurotoxicity

  • 10% to 15% – cumulative dose of 750 to 850 mg/m2
  • Not schedule-dependent
  • Symmetric dysesthesias , paresthesias persist between cycles
  • Progressive functional impairment: loss of fine sensorimotor coordination, sensory ataxia
  • Spares motor neurons (like cisplatin)
  • Lasts > 2 weeks
  • Partially reversible in about 80% and completely in about 40% at 6–8 months

Neurotoxicity – Mechanism

  • Acute neurotoxicity
      • Altering the current of voltage-gated Na(+) channels in response to oxalate
      • Oxalate may also interact indirectly with the voltage-gated Na(+) channels through chelation Ca and Mg
  • Chronic neurotoxicity
      • Dose-dependent accumulation of platinums in the DRG neuronal atrophy and apoptosis

Prevention

  • A stop-and-go approach with intermittent oxaliplatin dosing
  • Dose modification
  • The concurrent use of neuromodulatory agents
      • Calcium and magnesium infusions have been tried on the basis that they may bind to oxalate
      • Glutathione
      • N-acetyl cysteine
      • Glutamine
      • Oxcarbamazapine, carbamazapine
      • Xaliproden, gabapentin, pregabalin

Treatment

  • Venlafaxine tried in the treatment of acute OXIN
      • A randomized trial in patients with acute OXIN receiving FOLFOX for adjuvant or palliative treatment of colon cancer demonstrated a reduction in acute OXIN from 31.3% in the placebo arm vs 5.3% in the venlafaxine arm (P = 0.03)
      • Also there was a reduction in the incidence of chronic OXIN that was grade >2 from 33% in the placebo  vs 0% in the venlafaxine arm
  • Amitriptyline – nonsignificant trend to improvement

Supportive care

  • Prolonging the infusion time
  • Avoid cold temperatures
  • If exposure to cold temperatures cannot be avoided, such as use of the refrigerator, wear gloves during the exposure
  • Use face masks in cold weather
  • Use cotton socks, pot holders, rubber gloves for dish washing
  • Assess the water temperature in the home
  • Use moisturizer

Other Toxicities

  • Nausea and vomiting
  • Diarrhea
  • Myelosuppression

Satraplatin

satraplatin

  • Bis-(acetate)-ammine dichloro-(cyclohexylamine) platinum

Uses/Indications

Pharmacokinetics

  • Comparable antitumor activity to and no cross-resistance relative to cisplatin
  • Half life – 100 hrs, renal excretion

Dose and Availability

  • Oral route
  • 10 and 50 mg capsules
  • Max dose – 80 mg/m2

Adverse Effects

  • Toxicological profile similar to carboplatin
  • Most common – noncumulative myelosuppression, trilineage
  • Nausea, vomiting and diarrhea
  • Not associated with neurotoxicity, ototoxicity and nephrotoxicity

Lipoplatin

  • Liposomal Cisplatin/Nanoplatin
  • Nanoparticle of 110nm composed of lipids and cisplatin
  • Superior to cisplatin with paclitaxel in NSCLC – adenocarinoma
  • 150 mg vials
  • Organ drug status by EMEA in 2007 in pancreatic Ca
  • Also approved in 2009 by EMEA as 1st line in NSCLC
  • Lesser nephrotoxicity than cisplatin

Nedaplatin

  • cis-diammine- glycolatoplatinum
  • A cisplatin analog, developed to decrease the toxicities of CCDP , such as nephrotoxicity and GI toxicity
  • Half -life – 1.1–4.4 hours
  • Off-white crystalline powder, 10mg vials
  • Dose – 80–100 mg/m2
  • Non-small cell lung cancer, esophageal cancer, cervical cancer, H&N cancer, urothelial cancer
  • Moderate emetic risk
  • Dose-limiting toxicity – myelosuppression – primarily thrombocytopenia

Lobaplatin

  • A platinum complex in which the leaving group is lactate and the stable amine ligand is the 1,2 bis(aminomethyl) cyclobutane
  • Stable amine ligand may convey some non-cross resistance compared to cisplatin or carboplatin
  • Uses – breast cancer, small cell-lung cancer and chronic myeloid leukaemia
  • Approved only in China, not in the USA or Europe

 

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