PharmacologyGroup I presentation

Topic: Cisplatin

Drug background

• was first synthesized in 1845 • Alkylating agent • an inorganic complex formed by an atom of plati

num surrounded by chlorine and ammonia atoms in the cis position of a horizontal plane

Drug usage

• This medication is used to treat: – metastatic testicular tumors – metastatic ovarian tumors – advanced bladder carcinoma – also used to treat other kinds of cancer

Clinical trials

Clinical trials which cisplatin have been involved in include:

Type of CancerType of Cancer Cisplatin in coCisplatin in combination with:mbination with:

PhasePhase Carried out Carried out by:by:

ResultResult

NSCLC Mitomycin C, Vinorelbine

Two Keon et al., 2002

Active against advanced NSCLC

Vinorelbine One & Two

Hotta et a., 2001

Promising anti-tumour activity

Advanced Ovarian Cancer

Gemcitabine Two Bauknecht et al., 2003

Feasible as a first-line treatment

Advanced Hepatocellular carcinoma

Topotecan Two Lee et al., 2003

Not effective when used in dose and schedule tested

Clinical trials

• Cisplatin has also been involved in clinical trials to determine its toxicity.

– Omidvari et al., 2004 concluded their study by advising that cisplatin should be added to a list of agents causing hypokalemic paralysis. However clinical trials which have regulated the dose of cisplatin between 75 – 80mg/m² have shown that this helps minimise toxicity

• Future clinical trials involving Cisplatin: – Cancer research in the UK are currently recruiting people for cli

nical trials involving cisplatin. These include: 1. Irinotecan & cisplatin for the treatment of ca of the penis2. Cisplatin & temozolomide for children diagnosed with glioma3. Cisplatin & 5-fluorouracil to prevent recurrence of anal cancer

Pharmacokinetics

• Vd = 0.17-1.47 L/kg • Route of Entry

– Mainly by intravenous

• Distribution organ– Kidney– Also high concentration of drug can be found in liver, intestine

• Target – DNA synthesis– Little effect on protein and RNA synthesis

• Elimination– By renal clearance

• 15 to 30% of drugs will eliminate at first 2-4 hr• 20 to 80% of drugs will recoverd at the first 24hr

Pharmacodynamics

CisplatinCisplatin

The chloride is replaced by H2O

The chloride is replaced by H2O

Bind to DNABind to DNA

Formation of positive Charge Pt complex

Formation of positive Charge Pt complex

Toxic to cellToxic to cell

At the guanine bases At the guanine bases Form intrastrand and interstrand cross links Form intrastrand and interstrand cross links

Inhibit DNA, RNA, synthesis

Inhibit DNA, RNA, synthesis

Cause mutationCause mutation

Pass cell membrane Pass cell membrane

Cell deathCell death

Factor affecting kinetics

• Chemical factors– Lipophilicity

• water soluble

– Chirality• cis isomer provided relief and inhibited several forms of

cancer• trans isomer is inactive• slowly changes from the cis to the trans form in aqueous

solution

– Protein binding capacity• rapidly bound to tissue and plasma proteins• protein-bound drug (nonfilterable): elimination rate declines

rapidly, prolonged excretory phase

Factors affecting kinetics

• Biological factors– Dose

• saturation of plasma-protein binding sites may lead to significance rise in the plasma concentration of free compound

• increase toxicity

– Age• Children are more sensitive to the effects of cisplatin

– Disease• terminal half life of total platinum

– 8.1 to 49 minutes (normal renal function)– 1 to 240 hours (patient with severe renal failure)

Contraindications

• A factor that renders the administration of a drug or the carrying out of a medical procedure inadvisable:

• A previous allergic reaction to penicillin is a contraindication to the future use of that drug.

• Because cisplatin is used to treat life-threatening malignancies,contraindications to its use are only relative and must be placed in the context of the patient's overall well-being.

Contraindications

• Include:1. Renal failure

2. Severe bone marrow suppression

3. Peripheral neuropathy

4. Pregnancy

5. Hearing disorders

6. Allergic or anaphylactic-like reactions to platinum containing compounds.

Toxicology Data

• The principal target organ for cisplatin toxicity is the kidney:

• This toxicity is manifested by reduced renal function and leads to serum electrolyte changes and pathological changes in the urine analysis.

• Doses of cisplatin which produce changes in renal function may cause no histopathological changes.

• Higher doses of the drug lead to interstitial nephritis. • Nephrotoxicity characterised by oliguria, azotaemia, renal tubular ac

idosis and acute renal failure may occur.• Electrolyte disturbances, particularly hypomagnesaemia and hypoca

lcaemia, may occur as a result of renal toxicity Cisplatin also causes bone marrow hypoplasia and is oto

toxic. Bone marrow depression may be severe, with decreased leucocyte and platelet counts.

Toxicology Data

• Neurotoxicity is also commonly seen with cisplatin:• Neurotoxicity includes peripheral neuropathy with numbness,tingling

and decreased vibratory sensation.Autonomic neuropathy may also occur with gait difficulties, involuntary movements and loss of deep tendon reflexes.

• Central nervous system toxicity includes confusion, extrapyramidal effects and focal convulsions progressing to grand mal convulsions.

• Other reported effects of cisplatin neurotoxicity include tachycardia, acute respiratory failure, metabolic acidosis, transient elevation of alkaline phosphatase, and serum bilirubin

• Prevention of cisplatin toxicity:• Hydration is considered important for the prevention of cisplatin toxi

city. • Severe nausea and vomiting may be managed with antiemetics

Reference

• IPCSINTOX-Data bank– http://www.intox.org/databank/documents/pha

rm/cisplat/ukpid21.htm

• BC Cancer Agency– http://www.bccancer.bc.ca/HPI/DrugDatabase

/DrugIndexPro/Cisplatin.htm