Platinum Coordinates: Cisplatin, Carboplatin and Oxaliplatin

Mechanism

Pharmacological Class and Group

Non-classical cytotoxic agents, heavy coordination metals that act as inducers of DNA adducts.

Mechanism of Action

After entering the cell by active transport (CTR1 channel) or passive diffusion, the molecules lose their chlorine or carboxylate ligands due to the low concentration of intracellular chloride (4 mM versus 100 mM extracellular), hydrolyzing to form the reactive platinum aquo cationic complex.

Platinum Adduct Formation: Intrastrand and Interstrand

1. Aquation of Platinum: The displacement of the chlorine atoms (Cisplatinum) or the dicarboxylate portion (Carboplatinum) by water molecules activates the central metal atom of platinum (II).

2. Pairing with Guanine: The reactive complex forms stable coordinate covalent bonds with the nitrogen 7 atom (N7) of two adjacent purine residues on the same DNA strand.

Cisplatin-Aquo + N7-Guanine Intrastrand Adducts 1,2-d(GpG) (90%) Double Helix Distortion

3. DNA Repair Blockade: This structural distortion of the double helix diverts HMG (High Mobility Group) domain proteins and inhibits nucleotide excision repair (NER) mechanisms, irreversibly stopping the activity of the polymerase and inducing apoptosis.

Pharmacokinetics

High Resolution Pharmacokinetics

• Protein Distribution and Binding: Free plasma cisplatin decays rapidly due to an irreversible binding to plasma proteins (mainly albumin) of greater than 90% within the first hours of infusion. Oxaliplatin irreversibly binds to erythrocytes and peripheral stromal proteins.
• Metabolism: They are not metabolized by hepatic phase I or phase II cytochrome CYP450 enzymes. They undergo non-enzymatic deactivation by spontaneous intracellular conjugation with sulfhydryl groups of glutathione.
• Elimination: They are cleared through renal excretion. Carboplatin clearance correlates with glomerular filtration, allowing accurate dose calculation using creatinine clearance.

Indicators and dose

Clinical Indications and Frequent Regimens

• Cisplatin: Non-small cell lung cancer (combined with Gemcitabine or Pemetrexed), advanced epithelial ovarian cancer, cervical cancer (as a weekly radiosensitizer at a dose of 40 mg/m²), testicular germ cell tumors (BEP Regimen).
• Carboplatin: Ovarian cancer, small cell lung cancer, head and neck tumors refractory to cisplatin or in patients with significant renal comorbidity.
• Oxaliplatin (FOLFOX Scheme): Adjuvant or metastatic colon and rectal cancer, combined with 5-Fluorouracil and Leucovorin.

Dosage of Carboplatin using the Calvert Formula

The dose of Carboplatin is not usually calculated by body surface area, but rather by the desired systemic exposure target using the Area Under the Curve (AUC) via renal clearance:

Total dose (mg) = Target AUC (mg · min/mL) × ( GFR (mL/min) + 25 )

Where the GFR (glomerular filtration rate) is estimated by Cockcroft-Gault. A GFR upper limit of 125 mL/min is applied to prevent severe hematologic toxicity in patients with supranormal clearance.

Dosage and Clinical Adjustment

• Cisplatin: 50 - 100 mg/m² IV as a single infusion every 21 days.
• Carboplatin: Dose calculated by Calvert (usually with AUC targets of 4 to 6).
• Oxaliplatin: 85 - 130 mg/m² IV as a 2-hour infusion every 14 or 21 days.
• Clinical Adjustments: If renal clearance drops below 50 mL/min, suspend or replace cisplatin; Carboplatin dose is automatically recalculated by formula. For oxaliplatin, if there is neuropathy with persistent grade 2 pain, a 20% dose reduction is suggested.

Security

Absolute and Relative Contraindications

Contraindications of Cisplatin

• Moderate to severe renal dysfunction (Cl_Cr < 50-60 mL/min).
• Clinically significant pre-existing sensorineural hearing loss.
• Pre-existing peripheral neuropathy of grade 2 or higher.
• Decompensated heart failure.

Oxaliplatin contraindications

• Pre-existing peripheral sensory neuropathy with persistent baseline functional impairment.
• Confirmed hypersensitivity to platinum metals.
• Unrecovered profound myelosuppression.

Adverse Effects (ADR) and Specific Toxicity

• Cisplatin: Limiting acute tubular nephrotoxicity (necrosis of epithelial cells of the proximal convoluted tubule), irreversible cumulative bilateral ototoxicity, extreme emetogenic potential.
• Carboplatin: Profound dose-dependent myelosuppression, mainly affecting the platelet line (late nadir thrombocytopenia at 14-21 days).
• Oxaliplatin: Acute and chronic peripheral neuropathy. The acute form presents with transient paresthesias in the extremities and perioral region, typically exacerbated or triggered by exposure to low temperatures (cold drinks, air conditioning).

Management of Cisplatin Nephrotoxicity: Hydration and Ions

Tubular damage by cisplatin is linked to the uptake of free platinum by proximal tubular cells through OCT2 transporters. It causes necrosis of the villi and massive loss of electrolytes (magnesium, potassium and calcium):

Platinum Infiltration in OCT2 Proximal Tubular Necrosis Massive Loss of Mg²⁺ and K⁺

It is essential to institute aggressive pre- and post-infusion intravenous isotonic saline hydration (minimum of 1 to 2 liters of 0.9% saline solution) supplemented with 20 mEq of potassium chloride and 10-20 mEq of magnesium sulfate per liter to force an alkaline diuresis and reduce the intratubular half-life of the free cation.