Pharmacology of Cisplatin

1. Introduction/Overview

Cisplatin, or cis-diamminedichloroplatinum(II), represents a cornerstone of modern chemotherapy and a seminal discovery in oncology. Its serendipitous discovery in the 1960s, arising from observations of inhibited bacterial cell division in the presence of platinum electrodes, ushered in the era of metal-based antineoplastic agents. As a member of the platinum coordination complex family, cisplatin has maintained critical clinical relevance for over five decades due to its potent cytotoxic activity against a spectrum of solid tumors. Its introduction fundamentally altered treatment paradigms and survival outcomes for several malignancies, establishing a prototype upon which subsequent generations of platinum analogs were developed. The drug’s profound efficacy is, however, inextricably linked to a characteristic and often dose-limiting profile of toxicities, necessitating a nuanced understanding of its pharmacology for safe and effective clinical application.

Learning Objectives

Upon completion of this chapter, the reader should be able to:

• Describe the chemical structure of cisplatin and its classification within antineoplastic agents.
• Explain the detailed molecular mechanism of action, including activation, DNA binding, and subsequent cellular consequences.
• Outline the pharmacokinetic profile of cisplatin, emphasizing renal handling and the implications for dosing and toxicity.
• Identify the primary therapeutic indications for cisplatin, both as a single agent and within combination regimens.
• Analyze the spectrum of adverse effects associated with cisplatin, correlating specific toxicities with underlying mechanisms and management strategies.
• Evaluate major drug interactions, contraindications, and special population considerations essential for clinical decision-making.

2. Classification

Cisplatin is systematically categorized within multiple overlapping classification schemas used in pharmacology and oncology.

Chemical and Pharmacotherapeutic Classification

Chemically, cisplatin is an inorganic platinum coordination complex. Its full name, cis-diamminedichloroplatinum(II), precisely describes its square planar molecular geometry: a central platinum (Pt²⁺) ion coordinated by two chloride ligands in the cis configuration and two ammine (NH₃) ligands. The cis stereochemistry is absolutely required for antitumor activity; the trans isomer is therapeutically inert. This specific spatial arrangement facilitates the critical DNA-binding events that underpin its mechanism.

Within pharmacotherapeutic classifications, cisplatin is a member of the alkylating-like agent group, though it does not form traditional carbon-based alkyl bonds. It is more accurately described as a DNA cross-linking agent. It serves as the prototype for the broader class of platinum-based antineoplastic compounds, which includes second- and third-generation analogs such as carboplatin and oxaliplatin. These analogs were developed primarily to alter the toxicity profile while retaining cytotoxic efficacy.

3. Mechanism of Action

The cytotoxic action of cisplatin is a multi-step process initiated by intracellular activation and culminating in the initiation of programmed cell death. Its primary target is nuclear DNA, where it forms covalent adducts that disrupt genomic integrity and inhibit essential cellular processes.

Activation and Cellular Uptake

Cisplatin enters cells primarily via passive diffusion and, to a lesser extent, through copper transport proteins such as CTR1. The extracellular environment, characterized by a high chloride concentration (≈100 mM), maintains cisplatin in its neutral, dichlorinated form, which is membrane-permeable. Once inside the cell, the markedly lower intracellular chloride concentration (≈4-20 mM) promotes a series of aquation reactions. In this process, chloride ligands are sequentially displaced by water molecules, generating positively charged, aquated species: [Pt(NH₃)₂Cl(H₂O)]⁺ and [Pt(NH₃)₂(H₂O)₂]²⁺. These aquated complexes are highly electrophilic and represent the active moieties responsible for binding to nucleophilic sites on biological molecules.

DNA Binding and Adduct Formation

The activated platinum species preferentially target the N7 position of guanine and, to a lesser extent, adenine residues in DNA. This interaction results in the formation of covalent monoadducts. The primary cytotoxic lesions, however, are intra-strand and inter-strand cross-links. The most prevalent adducts (≈90%) are 1,2-intrastrand cross-links between adjacent guanines (d(GpG)) or between adjacent adenine and guanine (d(ApG)). These intrastrand cross-links induce a significant bend and unwinding of the DNA helix, distorting its normal architecture. A smaller proportion of adducts are 1,3-intrastrand cross-links or inter-strand cross-links between guanine residues on opposing DNA strands.

Cellular Consequences and Apoptosis

The formation of platinum-DNA adducts presents a formidable block to DNA replication and transcription. Replication forks are arrested upon encountering these bulky lesions, leading to the generation of double-strand breaks. Similarly, RNA polymerases are inhibited, disrupting gene expression. These events are recognized as severe DNA damage by the cellular surveillance machinery. Key proteins involved in the recognition of this damage include the high-mobility group (HMG) domain proteins, which bind to the bent DNA, and nucleotide excision repair (NER) complexes. While NER can remove cisplatin adducts, its activity may contribute to resistance. The persistent, unrepaired damage ultimately triggers robust and sustained activation of signal transduction pathways, including those mediated by p53, ATM, and ATR. This signaling cascade converges on the initiation of mitochondrial-mediated (intrinsic) apoptosis, characterized by cytochrome c release, caspase activation, and programmed cell death. In some cellular contexts, cisplatin may also induce necrosis or autophagy.

4. Pharmacokinetics

The pharmacokinetics of cisplatin are characterized by rapid distribution, extensive tissue binding, and predominant renal elimination, with minimal hepatic metabolism. Its pharmacokinetic profile is complex and significantly influences both its efficacy and toxicity.

Absorption

Cisplatin is not administered orally due to poor and erratic gastrointestinal absorption, as well as significant degradation in the acidic environment of the stomach. It is administered exclusively by intravenous infusion, typically over 1 to 6 hours, to mitigate acute toxicities such as emesis. Following IV administration, plasma concentrations decline in a multiphasic manner.

Distribution

Initial distribution is rapid, with a distribution half-life (t_1/2α) of approximately 20 to 30 minutes. Cisplatin distributes widely into most tissues, including kidneys, liver, intestines, and testes, but penetration into the central nervous system is poor. The drug exhibits high and irreversible binding to plasma proteins, primarily albumin, exceeding 90% within a few hours post-infusion. This protein binding is considered largely inactive, as only the free, unbound platinum is pharmacologically active and subject to renal clearance. The volume of distribution at steady state is moderate, approximating total body water.

Metabolism

Cisplatin undergoes minimal classical hepatic metabolism by cytochrome P450 enzymes. Its primary biotransformation is non-enzymatic and occurs in the systemic circulation and within cells via the aquation reaction described previously. The parent compound and its aquated derivatives can also react with various nucleophiles, including sulfhydryl groups in proteins (e.g., glutathione, metallothionein) and other small molecules. These reactions, particularly with glutathione, represent a significant inactivation pathway and may contribute to cellular resistance mechanisms.

Excretion

Renal excretion is the dominant route of elimination for cisplatin. Clearance is primarily via glomerular filtration, but active tubular secretion and reabsorption also occur. The elimination is biphasic, with an initial terminal half-life (t_1/2β) of 20 to 40 hours for free platinum. However, platinum bound to proteins and tissues is eliminated very slowly, with a prolonged terminal phase (t_1/2γ) lasting days to weeks. This results in cumulative platinum retention in the body. Approximately 15-30% of the administered dose is excreted in the urine within the first 24 hours, with the majority of this being the active, filterable form. Biliary and fecal excretion is minimal. Renal clearance of cisplatin exceeds the glomerular filtration rate, suggesting net tubular secretion.

Dosing Considerations

Dosing is typically based on body surface area (mg/m²). Common regimens include 50-100 mg/m² administered every 3 to 4 weeks, or lower doses (e.g., 20-40 mg/m²) given weekly. Dose calculation must account for renal function, as impaired creatinine clearance necessitates dose reduction to prevent life-threatening accumulative toxicity. Aggressive intravenous hydration with normal saline (e.g., 1-2 liters before and after administration) is a standard component of administration protocols to maintain high urine output and reduce nephrotoxicity. Pharmacokinetic parameters such as area under the curve (AUC) have been correlated with both efficacy (myelosuppression in some contexts) and toxicity (nephrotoxicity, ototoxicity), but therapeutic drug monitoring is not routine clinical practice.

5. Therapeutic Uses/Clinical Applications

Cisplatin possesses a broad spectrum of antitumor activity and serves as a critical component in the curative or palliative treatment of numerous malignancies. It is rarely used as a single agent; its greatest utility lies in combination chemotherapy regimens where it provides synergistic cytotoxicity.

Approved Indications

• Testicular Cancer: Cisplatin, in combination with bleomycin and etoposide (BEP regimen), is the cornerstone of treatment for metastatic germ cell tumors, achieving cure rates exceeding 80%. It represents one of the most notable successes in medical oncology.
• Ovarian Cancer: It is a first-line agent, typically combined with a taxane (paclitaxel) for advanced epithelial ovarian cancer, both in adjuvant and neoadjuvant settings.
• Bladder Cancer: Used as neoadjuvant or adjuvant therapy for muscle-invasive disease, and as first-line therapy for metastatic urothelial carcinoma, often in combination with gemcitabine.
• Head and Neck Squamous Cell Carcinoma: Employed concurrently with radiation therapy for locally advanced disease, or as part of induction chemotherapy regimens (e.g., with 5-fluorouracil and docetaxel).
• Small Cell and Non-Small Cell Lung Cancer (NSCLC): A key component of first-line platinum-doublet chemotherapy for advanced NSCLC (e.g., with etoposide or pemetrexed) and for extensive-stage small cell lung cancer.
• Cervical Cancer: Used concurrently with radiation therapy for locally advanced disease or in combination regimens for metastatic/recurrent cancer.
• Endometrial Cancer and Gastric Cancer: Used in specific advanced or recurrent settings as part of combination therapy.

Off-Label and Investigational Uses

Cisplatin may be used off-label in other solid tumors, including esophageal cancer, mesothelioma (often with pemetrexed), and certain pediatric solid tumors like neuroblastoma and osteosarcoma. Its role in intraperitoneal chemotherapy for ovarian cancer and in isolated limb perfusion for melanoma or sarcoma represents specialized regional delivery techniques aimed at maximizing local exposure while minimizing systemic toxicity. Research continues into novel delivery systems, such as liposomal encapsulation, and its use in combination with emerging immunotherapeutic agents.

6. Adverse Effects

The clinical use of cisplatin is constrained by a predictable and often severe profile of toxicities. Management of these adverse effects is integral to treatment protocols.

Common Side Effects

• Nephrotoxicity: Dose-limiting and cumulative. Manifests as acute kidney injury (AKI) from tubular necrosis, primarily in the proximal convoluted tubule. Mechanisms include oxidative stress, inflammation, and apoptosis. Prevented by vigorous hydration and forced diuresis with mannitol, though evidence for mannitol is mixed. Electrolyte disturbances, particularly hypomagnesemia, hypokalemia, and hypocalcemia, are common and persistent due to renal tubular wasting.
• Nausea and Vomiting: Extremely common, severe, and biphasic (acute within 24 hours and delayed for several days). Mediated by release of serotonin and substance P in the gut and brainstem. Requires aggressive prophylactic antiemetic regimens, typically including a 5-HT₃ receptor antagonist (e.g., ondansetron), an NK₁ receptor antagonist (e.g., aprepitant), and dexamethasone.
• Myelosuppression: Neutropenia is common, with nadir occurring around day 18-23. Thrombocytopenia and anemia are also observed but are generally less severe than with some other chemotherapeutic agents.
• Neurotoxicity: A cumulative, dose-limiting toxicity. Presents as a symmetric, sensory peripheral neuropathy characterized by numbness, paresthesias, and loss of proprioception in a stocking-and-glove distribution. Ototoxicity is also common and cumulative, resulting in high-frequency sensorineural hearing loss and tinnitus due to damage to outer hair cells in the organ of Corti.

Serious/Rare Adverse Reactions

• Anaphylactoid Reactions: Can occur during infusion, manifesting as bronchospasm, tachycardia, hypotension, and facial edema.
• Cardiovascular Toxicity: Rare reports of arrhythmias, cardiomyopathy, and myocardial ischemia.
• Vascular Toxicity: Raynaud’s phenomenon and thromboembolic events.
• Ocular Toxicity: Optic neuritis, papilledema, and retinal toxicity.
• Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH): Can occur, leading to hyponatremia.

Black Box Warnings

Cisplatin carries a U.S. Food and Drug Administration (FDA) boxed warning for several life-threatening toxicities:

• Cumulative Nephrotoxicity: Renal function must be monitored, and doses adjusted or withheld based on evidence of toxicity.
• Severe Myelosuppression: Frequent monitoring of blood counts is mandatory.
• Severe and Cumulative Peripheral Neuropathy: May be irreversible.
• Anaphylactic-like Reactions: Can occur within minutes of administration; requires immediate discontinuation and emergency management.
• Nausea and Vomiting: Described as potentially severe.
• Ototoxicity: May be more severe in children and is sometimes irreversible.

7. Drug Interactions

Cisplatin is involved in several clinically significant pharmacokinetic and pharmacodynamic interactions.

Major Drug-Drug Interactions

• Aminoglycoside Antibiotics (e.g., gentamicin), Amphotericin B, and Other Nephrotoxic Agents: Concurrent use produces additive or synergistic nephrotoxicity. Avoidance or extreme caution with intensive monitoring is required.
• Loop Diuretics (e.g., furosemide): May potentiate ototoxicity and should be used cautiously, if at all, during cisplatin therapy. They do not substitute for vigorous hydration with normal saline.
• Phenytoin: Cisplatin may reduce phenytoin levels, potentially leading to loss of seizure control. Therapeutic drug monitoring of phenytoin is advised.
• Antiemetics: While essential, some antiemetics (e.g., metoclopramide) may have additive sedative or extrapyramidal effects. Interactions are generally manageable.
• Myelosuppressive Chemotherapy: Additive bone marrow suppression occurs with other myelosuppressive agents (e.g., paclitaxel, gemcitabine), necessitating careful hematologic monitoring.
• Live Vaccines: Immunization with live vaccines is contraindicated due to the risk of disseminated infection in immunocompromised patients.

Contraindications

Absolute contraindications to cisplatin therapy include a history of severe hypersensitivity reactions to cisplatin or other platinum compounds, pre-existing severe renal impairment (unless the indication is life-threatening and no alternative exists), severe myelosuppression, and pre-existing significant hearing impairment when the risk outweighs the potential benefit. Pregnancy is a strong contraindication due to teratogenic and embryotoxic effects.

8. Special Considerations

Pregnancy and Lactation

Cisplatin is classified as FDA Pregnancy Category D, indicating positive evidence of human fetal risk. It is teratogenic and embryotoxic in animal studies, and human data, though limited, suggest a high risk of major congenital malformations. It should not be used during pregnancy unless the potential benefit to the mother justifies the clear risk to the fetus. Effective contraception is required for patients of reproductive potential during and for several months after therapy. Cisplatin is excreted in breast milk, and breastfeeding is contraindicated during treatment.

Pediatric Considerations

Children are particularly susceptible to cisplatin-induced ototoxicity, which may be more severe and have profound implications for speech and language development. Baseline and serial audiometric testing are mandatory. Nephrotoxicity and electrolyte wasting also occur and require vigilant monitoring. Dosing is typically based on body surface area, similar to adults, with adjustments for renal function.

Geriatric Considerations

Elderly patients often have reduced renal function, decreased bone marrow reserve, and increased comorbidities. These factors increase the risk of severe nephrotoxicity, myelosuppression, and neurotoxicity. A comprehensive assessment of renal function (using measured creatinine clearance rather than serum creatinine alone), performance status, and comorbidity burden is essential before initiating therapy. Dose reductions and enhanced supportive care are frequently necessary.

Renal and Hepatic Impairment

Renal Impairment: Dose adjustment is mandatory. Cisplatin is contraindicated in severe renal impairment. For mild to moderate impairment, doses are reduced, often guided by calculated creatinine clearance (e.g., Cockcroft-Gault formula). Vigorous hydration protocols remain critical. Hepatic Impairment: Cisplatin is not primarily metabolized by the liver, so dose adjustment for hepatic dysfunction is not routinely required. However, caution is warranted in severe impairment due to potential alterations in protein binding and general metabolic reserve. Pre-existing liver disease may also affect the metabolism of concomitant medications.

9. Summary/Key Points

• Cisplatin is an inorganic platinum complex and a prototype alkylating-like agent whose cis stereochemistry is essential for forming cytotoxic DNA intra-strand and inter-strand cross-links, ultimately triggering apoptosis.
• Its pharmacokinetics are characterized by rapid distribution, extensive irreversible protein binding, minimal hepatic metabolism, and predominant renal excretion, which is the basis for its dose-limiting nephrotoxicity.
• It is a cornerstone of curative and palliative therapy for testicular, ovarian, bladder, head and neck, lung, and cervical cancers, almost always used in combination regimens.
• The adverse effect profile is significant and includes cumulative nephrotoxicity (managed by hydration), severe emesis (requiring aggressive antiemetics), dose-limiting peripheral neuropathy, ototoxicity (especially in children), and myelosuppression.
• Major drug interactions involve additive toxicity with other nephrotoxic or ototoxic agents and enhanced myelosuppression with other chemotherapeutics.
• Special population management is critical: contraindication in pregnancy, heightened ototoxicity monitoring in pediatrics, careful renal dose adjustment in the elderly and renally impaired, and no routine dose adjustment for hepatic impairment.

Clinical Pearls

• Aggressive hydration with normal saline before, during, and after cisplatin infusion is the single most important intervention to prevent acute nephrotoxicity.
• Prophylaxis for nausea and vomiting must be aggressive and multi-modal, incorporating agents from different drug classes (5-HT₃ antagonist, NK₁ antagonist, corticosteroid).
• Electrolyte levels, particularly magnesium and potassium, should be monitored closely before each cycle and replaced proactively, as deficiencies can be profound and persistent.
• Neurological and audiometric assessments at baseline and periodically during treatment are essential to detect cumulative neurotoxicity and ototoxicity early.
• Renal function must be assessed using calculated creatinine clearance, not just serum creatinine, to guide appropriate dosing and minimize toxicity risk.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
3. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
4. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
5. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
6. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
7. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
8. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.