Pharmacology Group I presentation Topic: Cisplatin

Drug background was first synthesized in 1845 Alkylating agent an inorganic complex formed by an atom of platinum 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 which cisplatin have been involved in include: Type of Cancer Cisplatin in combination with: Phase Carried out by: Result 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 Bauknecht et al., 2003 Feasible as a first-line treatment Advanced Hepatocellular carcinoma Topotecan 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 clinical trials involving cisplatin. These include: Irinotecan & cisplatin for the treatment of ca of the penis Cisplatin & temozolomide for children diagnosed with glioma Cisplatin & 5-fluorouracil to prevent recurrence of anal cancer

Pharmacokinetics Vd = 0.17-1.47 L/kg Route of Entry Distribution organ 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

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: Renal failure Severe bone marrow suppression Peripheral neuropathy Pregnancy Hearing disorders 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 acidosis and acute renal failure may occur. Electrolyte disturbances, particularly hypomagnesaemia and hypocalcaemia, may occur as a result of renal toxicity Cisplatin also causes bone marrow hypoplasia and is ototoxic. 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 toxicity. Severe nausea and vomiting may be managed with antiemetics

Reference IPCSINTOX-Data bank BC Cancer Agency http://www.intox.org/databank/documents/pharm/cisplat/ukpid21.htm BC Cancer Agency http://www.bccancer.bc.ca/HPI/DrugDatabase/DrugIndexPro/Cisplatin.htm