In the name of God

1. In the name of God Platinium compounds Gathered & presented by:F.malek

2. References The Complete Drug Reference Martindale Drugs.com • Principle &practice of pediatric Oncology; P.Pizzo • Drug Interactions in the therapy of • malignant tumors(BAXTER Pub.) • Medscape

3. Introduction • cisplatin, carboplatin, and oxaliplatin are heavy metal coordination complexes which • exert their cytotoxiceffects by platination of DNA a mechanism of action that is analogous to alkylation

4. Pharmacokinetics • The rate of reaction of these platinum analogs with water to form reactive intermediates is an important determinant of the stability of the compounds in solution and influences the drugs' pharmacokinetic • Cisplatinis more reactive than carboplatin and is less stable in aqueous solution • The stability of oxaliplatin is intermediate.

5. Pharmacokinetics • The chemical stability (reactivity) of the • platinum analogs is a critical determinant of their pharmacokinetics. • The reactive intermediates of cisplatin and carboplatin are rapidly and covalently bound to plasma protein and tissue

6. Mechanism of Action • Platinum coordination compound that inhibits DNA synthesis; cross-links and denatures strands of DNA; disrupts DNA function by covalently binding to DNA bases; can also produce DNA intrastrand cross-linking and breakage • Not a true alkylating agent

7. Special pharmacokinetic points about cisplatin • Half-life elimination (terminal): 24hr to 47 days • Protein bound: >90% • Excretion: Urine (90%); feces (10%) • Clearance: 15 L/hr/m² • Vd: 11 L/m²

8. Warnings & precautions • Anaphylactic-like reactions have occurred. Facial edema, bronchoconstriction, tachycardia, and hypotension may occur within minutes of cisplatin administration • Failure to differentiate daily doses from total dose per treatment cycle may result in cisplatin overdose

9. Contraindications • Hypersensitivity to cisplatin, other platinum compounds • Severe myelosuppression, renal impairment, hearing impairment • Pregnancy, lactation

10. cautions • Irritant; injection site reactions may occur during administration; use extravasation precautions • Avoid aluminum needles/equipment • Use with caution in:hearing impairment, neuropathy, neuromuscular disease, with neurotoxic agents, with ototoxic agents, elderly

11. cautions • Risk of cumulative nephrotoxicity (exacerbated by aminoglycoside antibiotics); renal toxicity becomes more prolonged and severe with repeated courses • renal function must return to normal before administering another dose

12. Drug interactions • Patients taking ACE inhibitor with cisplatin are prone to RF 4 times more than other patients • Amphotericin B found to increase the uptake of cisplatin & carboplatin • Anti convulsant drugs one report about lowering plasma level of phenytoin in combination of cisplatin • Bleomycin; as cisplatin dose increased creatinine clearance & bleomycin elimination were decreased

13. Drug interactions • Fludarabinewas shown to enhance the cytotoxicity effect of cisplatin • Irradiation to inner ear developed hearing loss in combination with cisplatin • MTX nephrotoxicity of MTX becomes irreversible in combination with cisplatin • Topotecansevere myelosupression in concomitant use of cisplatin were observed • Rituximabrenal toxicity in concomitant use of cisplatin were observed

14. IV Preparation • Further dilution stability is dependent on chloride ion concentration & should be mixed in solutions of NS (at least 0.3% NaCl) • May administer 12.5-50 g mannitol/L • Standard dilution: dose/250-1000 mL NS, D5W/NS or D5/½NS

15. IV Administration • Perform pretreatment hydration • Do not use aluminum-containing needles or IV administration sets that may come in contact with carboplatin (aluminum can react causing precipitate formation & loss of potency) • Administration rate has varied from a 15-120 min infusion, 1 mg/min infusion, 6-8 hr infusion, 24 hr infusion, or per protocol

16. IV Administration • Maximum rate of infusion: 1 mg/min in patients with CHF • When administered as sequential infusions, taxane derivatives (docetaxel, paclitaxel) should be administered before platinum derivatives to limit myelosuppression & to enhance efficacy

17. Extravasation Management • Large extravasations (>20 mL) of concentrated solutions (>0.5 mg/mL) produce tissue necrosis • Tx is not recommended unless a large amount of highly concentrated solution is extravasated • Mix 4 mL of 10% sodium thiosulfate with 6 mL SWI; inject 1-4 mL through existing IV line cannula; administer 1 mL for each mLextravasated; inject SC if needle is removed

18. Adverse Reaction • Renal side effects have been reported to present during the second week after a dose of cisplatin and become more prolonged and severe with repeated courses of cisplatin therapy. • Nephrotoxicity is the most important dose-limiting side effect of cisplatin, which is dose-related, cumulative, and occurs in 36% of patients after single doses of 50 mg/m2.

19. Adverse Reaction • Renal function should return to baseline before subsequent doses are administered. Cisplatin-induced renal tubule damage can result in clinically significant hypomagnesemia and hypokalemia as well as hypocalcemia, hyponatremia, hypophosphatemia, and hyperuricemia

20. Adverse Reaction • The risk of renal toxicity may be decreased with appropriate monitoring of renal function tests as well as aggressive hydration with chloride-containing fluids and appropriate electrolyte replacement. • Amifostine, a thiolchemoprotectant, is approved to reduce cisplatinnephrotoxicity and does not interfere with antitumor activity

21. Adverse Reaction • As a result of its nephrotoxic effects, cisplatin can alter its own elimination rate and that of other drugs, such as methotrexate • renal clearance of ultrafilterable platinum fell from almost 500mL/min with the first course to 150 mL/min by the fourth course in patients receiving repeated doses

22. Adverse Reaction • Gastrointestinal • Acute cisplatin-induced emesis occurs one to four hours after cisplatin administration and is primarily serotonin mediated. • A serotonin-receptor antagonist in combination with a steroid controls this emesis effectively • Delayed emesis occurs two to seven days after cisplatin administration and is more difficult to control. Oral steroid therapy, if tolerated, with or without metoclopramide may be useful in the prevention of delayed emesis.

23. Nervous system • Nervous system side effects can be dose limiting for patients receiving cisplatin. • The most common form of nerve damage from cisplatin is a sensory polyneuropathy. • Other forms of nerve damage from cisplatin include autonomic neuropathies, seizures, encephalopathy, myasthenic syndrome, cortical blindness, Lhermitte's sign, and dorsal column myelopathy

24. Nervous system • Symptoms of the sensory polyneuropathy typically begin in toes and feet and, later, affect the fingers and hands in a stocking-and-glove distribution. • The neuropathies typically occur after prolonged therapy (4 to 7 months) • Cisplatinneuropathies generally occur with higher dosage regimens and may be irreversible

25. Nervous system • at cumulative doses of 300 to 600 mg/m2. Lhermitre's sign is common at high cumulative doses of cisplatin • Symptoms may progress after discontinuation of cisplatin

26. Ototoxicity • Tinnitus and/or high-frequency (4000 to 8000 Hz) hearing loss occurs first, is unilateral or bilateral and may appear 3 to 4 days after initial treatment; • however, deafness after the initial dose of cisplatin is rare

27. Ototoxicity • Cisplatin-induced ototoxicity is related to the loss of outer hair cells in the cochlea. Ototoxicity is associated with both high cisplatin doses and high cumulative doses. • Hearing impairment is generally irreversible; however, hearing aids may help

28. Hematologic • Cisplatincauses moderate and transient myelosuppression in 25% to 30% of patients. • Coombs' positive hemolytic anemia has also been reported • Myelosuppressionis a dose-related effect and usually occurs with doses greater than 50 mg/m2.

29. Hematologic • Treatment of anemia with recombinant erythropoietin is generally helpful.The nadirs in circulating erythrocytes, platelets, and leukocytes occur between days 18 to 23 (range 7.5 to 45), with most patients recovering by day 39 (range 13 to 62). Leukocytes usually recover after 14 to 21 days. Most patients are able to be retreated at 21 day intervals

30. Hypersensitivity • Hypersensitivity side effects including anaphylactic-like reactions have been occasionally reported in patients previously exposed to cisplatin. • The reactions consist of facial edema, wheezing, tachycardia, and hypotension within a few minutes of drug administration. • Reactions may be treated with intravenous epinephrine, corticosteroids and/or antihistamines

31. pharmacokinetics of Carboplatin • Absorption • Peak Plasma Time: 2-4 hr • Distribution • Protein Bound: 87% (platinum) • Vd: 16 L • Elimination • Clearance: 4.4 L/hr • Excretion: Urine (70% as carboplatin) • Half-life • Carboplatin: 3-6 hr

32. IV Preparation • Reconstitute powder to yield a final concentration of 10 mg/mL which is stable for 5 days at room temp (25°C) • IV Administration • Administer as IV over 15 min or continuous infusion over 24 hr • May also be administered intraperitoneally

33. Drug Interactions • VP16 clearance was lower when given with high dose carboplatin • Amifostine is potential inactivator of cisplatin & carboplatin

34. Adverse Reactions • dose-limiting toxicity of carboplatin is hematological toxicity, • primarily thrombocytopenia, and the nonhematological toxicities observed with cisplatin are only seen at doses of carboplatin • exceeding 800 mg/m2

35. Adverse Reactions • Carboplarin'smyelosuppressive effects are delayed, affecting the frequency by which the drug can be administered • Plateletnadirs are typically seen up to 3 weeks after the dose and milder granulocyte nadirs are observed 3 to 4 weeks after carboplatinadministration

36. Adverse Reactions • carboplatin are associated with a small drop in glomerular filtration rate and serum magnesium, not clinically significant. • Hypersensitivity reactions to carboplatinare relatively common and the risk increases after • multiple cycles of therapy

37. oxaliplatin (Rx) - Eloxatin • Pharmacokinetics • Peak Plasma Time: 2 hr • Concentration: 1.21 mcg/mL • Protein Bound: >90%; • Vd: 440 L • Clearance: 10.1 L/hr • Excretion: Urine(54%); feces (2%) • Dialyzable: no

38. Drug interactions • A cholinergic syndrome were evaluated in a patient whom received oxaliplatin in combination of amphotricin

39. Recommended Laboratory Tests • Standard monitoring of the white blood cell count with differential, hemoglobin, platelet count, and blood chemistries (including ALT, AST, bilirubin and creatinine) is recommended before each Oxaliplatin cycle • There have been reports while on study of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received Oxaliplatin plus 5-fluorouracil/leucovorinwhile on anticoagulants

40. Nervous system • Acute neuropathy is reversible and primarily of a peripheral sensory nature. • The onset occurs within hours to 2 days of dosing. • It generally resolves within 2 weeks and frequently recurs with repeat doses. • Exposure to cold temperature or cold objects may precipitate or exacerbate symptoms. • Symptoms may include transient paresthesia, dysesthesia, and hypoesthesia in the hands, feet, perioral area, or throat

41. Grade Definition • Grade 0 No change or none • Grade 1 Mild paresthesias, loss of deep tendon reflexes • Grade 2 Mild or moderate objective sensory loss, moderate paresthesias • Grade 3 Severe objective sensory loss or paresthesias that interfere with function Grade 4 Not applicable

42. Nervous system • Persistent neuropathy may occur with no prior neuropathy event. • Eighty percent of patients who developed Grade 3 persistent neuropathy progressed from Grade 1 or 2 • Persistent neuropathy generally lasts for more than 2 weeks and is also primarily of a peripheral sensory nature.

43. Nervous system • Jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and chest pressure have also been reported. • Ice should be avoided for mucositis prophylaxis. • Acute pharyngolaryngealdysesthesiawith sensations of dysphagia and dyspnea but no laryngospasm or bronchospasm has been reported in 1% to 2% of patients.

44. Treatment • The symptoms may improve in some patients when oxaliplatin is discontinued. • Treatment measures include calcium and magnesium solutions, gabapentin, and alpha-lipoic acid

45. Hepatotoxicity • Hepatotoxicity as evidenced in the adjuvant study, by increase in transaminases(57% vs. 34%) and alkaline phosphatase(42% vs. 20%) was observed more commonly in the Oxaliplatin combination arm than in the control arm. • The incidence of increased bilirubin was similar on both arms.

46. Hypersensitivity • Hypersensitivity reactions of an anaphylactoid and anaphylactic nature with symptoms of rash, urticaria, erythema, pruritus, and rarely, bronchospasm, and hypotension have been reported. • Anaphylactic shock has also been reported

47. Hypersensitivity • Patients who develop mild to moderate hypersensitivity to oxaliplatin may be pretreated with steroids as well as type 1 and type 2 histamine receptor antagonists. • However, patients who develop severe reactions are unlikely to tolerate further therapy

48. Thank you