In the name of God Platinium - PowerPoint Presentation

Slide1

In the name of God

Platinium

compounds

Gathered & presented

by:F.malek

Slide2

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

References

Slide3

cisplatin

,

carboplatin, and oxaliplatin are heavy metal coordination complexes which exert their cytotoxic effects by platination of DNA a mechanism of action that is analogous to alkylation

Introduction

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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' pharmacokineticCisplatin is more reactive than carboplatin and is less stable in aqueous solution The stability of oxaliplatin is intermediate.

Pharmacokinetics

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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 tissuePharmacokinetics

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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 breakageNot a true alkylating agentMechanism of Action

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Half-life elimination (terminal): 24hr to 47 days

Protein bound: >90%

Excretion: Urine (90%); feces (10%)Clearance: 15 L/hr/m²Vd: 11 L/m²Special pharmacokinetic points about cisplatin

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The drug should be administered under the supervision of an experienced cancer chemotherapy physician

Severe

nephrotoxicity, myelosuppression, and nausea and vomiting are dose related Significant ototoxicity, manifested by tinnitus and occasionally deafness, reported in children Warnings & precautions

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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 overdoseWarnings & precautions

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Hypersensitivity to cisplatin

, other platinum compounds

Severe myelosuppression, renal impairment, hearing impairmentPregnancy, lactationContraindications

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Irritant; injection site reactions may occur during administration; use

extravasation

precautionsAvoid aluminum needles/equipmentUse with caution in: hearing impairment, neuropathy, neuromuscular disease, with neurotoxic agents, with ototoxic agents, elderly

cautions

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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 cautions

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Patients taking

ACE

inhibitor with cisplatin are prone to RF 4 times more than other patientsAmphotericin 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

Drug interactions

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Fludarabine

was shown to enhance the cytotoxicity effect of cisplatinIrradiation to inner ear developed hearing loss in combination with cisplatinMTX nephrotoxicity of MTX becomes irreversible in combination with

cisplatin

Topotecan

severe

myelosupression

in concomitant use of

cisplatin

were observed

Rituximab

renal toxicity in concomitant use of

cisplatin

were observed

Drug interactions

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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/LStandard dilution: dose/250-1000 mL NS, D5W/NS or D5/½NSIV Preparation

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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 protocolIV Administration

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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 efficacyIV Administration

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Large extravasations (>20

mL

) of concentrated solutions (>0.5 mg/mL) produce tissue necrosisTx is not recommended unless a large amount of highly concentrated solution is extravasatedMix 4 mL of 10% sodium

thiosulfate

with 6

mL

SWI

; inject 1-4

mL

through existing IV line

cannula

; administer 1

mL

for each

mL

extravasated

; inject SC if needle is removed

Extravasation

Management

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Renal

A study of 12 patients who received recommended doses of

cisplatin incurred moderate loss of renal function 12 and 24 months after therapy was discontinued. The renal dysfunction was not progressive. Other studies have shown moderate and permanent reduction in GFR up to 52 months after cisplatin therapy.Adverse Reaction

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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.

Adverse Reaction

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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

Adverse Reaction

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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 thiol chemoprotectant, is approved to reduce cisplatin nephrotoxicity and does not interfere with antitumor activity

Adverse Reaction

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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

Adverse Reaction

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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.

Adverse Reaction

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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

Nervous system

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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)Cisplatin neuropathies generally occur with higher dosage regimens and may be irreversible

Nervous system

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As methods to prevent

nephrotoxicity

have allowedthe administration of higher single and cumulative doses ototoxicity and peripheral neuropathy have becomemore prorminent. Cisplatin causes a reversible sensoryperipheral neuropathy (i.e., numbness, tingling, and parasthesias

)

Adverse reactions

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at cumulative doses of

300 to 600 mg/m2

. Lhermitre's sign is common at high cumulative doses of cisplatinSymptoms may progress after discontinuation of cisplatinNervous system

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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 rareOtotoxicity

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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

O

totoxicity

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Cisplatin

causes moderate and transient myelosuppression in 25% to 30% of patients. Coombs' positive hemolytic anemia has also been reportedMyelosuppression is a dose-related effect and usually occurs with doses greater than 50 mg/m2.

Hematologic

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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

Hematologic

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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

Hypersensitivity

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Absorption

Peak Plasma Time: 2-4 hr

DistributionProtein Bound: 87% (platinum)Vd: 16 L EliminationClearance: 4.4 L/hr Excretion: Urine (70% as carboplatin) Half-lifeCarboplatin

: 3-6 hr

pharmacokinetics of

Carboplatin

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Reconstitute powder to yield a final concentration of 10 mg/

mL

which is stable for 5 days at room temp (25°C)IV AdministrationAdminister as IV over 15 min or continuous infusion over 24 hrMay also be administered intraperitoneallyIV Preparation

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VP16

clearance was lower when given with high dose

carboplatinAmifostine is potential inactivator of cisplatin & carboplatinDrug Interactions

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dose-limiting toxicity of

carboplatin

is hematological toxicity,primarily thrombocytopenia, and the nonhematological toxicities observed with cisplatin are only seen at doses of carboplatinexceeding 800 mg/m2Adverse Reactions

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Carboplarin's

myelosuppressive effects are delayed, affecting the frequency by which the drug can be administeredPlatelet nadirs are typically seen up to 3 weeks after the dose and milder granulocyte nadirs are observed 3 to 4 weeks after

carboplatin

administration

Adverse Reactions

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carboplatin

are associated with a small drop in

glomerular filtration rate and serum magnesium, not clinically significant. Hypersensitivity reactions to carboplatin are relatively common and the risk increases aftermultiple cycles of therapy

Adverse Reactions

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Pharmacokinetics

Peak Plasma Time: 2 hr

Concentration: 1.21 mcg/mLProtein Bound: >90%; Vd: 440 LClearance: 10.1 L/hrExcretion: Urine(54%); feces (2%)Dialyzable: no

oxaliplatin

(Rx) -

Eloxatin

Slide41

A cholinergic syndrome were evaluated in a patient whom received

oxaliplatin

in combination of amphotricinDrug interactions

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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 cycleThere have been reports while on study of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received Oxaliplatin

plus 5-fluorouracil/

leucovorin

while on anticoagulants

Recommended Laboratory Tests

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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

Nervous system

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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 applicableGrade Definition

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Persistent neuropathy may occur with no prior neuropathy event

.

Eighty percent of patients who developed Grade 3 persistent neuropathy progressed from Grade 1 or 2Persistent neuropathy generally lasts for more than 2 weeks and is also primarily of a peripheral sensory nature.

Nervous system

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Jaw spasm, abnormal tongue sensation,

dysarthria

, eye pain, and chest pressure have also been reported. Ice should be avoided for mucositis prophylaxis. Acute pharyngolaryngeal dysesthesia with sensations of dysphagia

and

dyspnea

but no

laryngospasm

or

bronchospasm

has been reported in 1% to 2% of patients.

Nervous system

Slide47

The symptoms may improve in some patients when

oxaliplatin

is discontinued.Treatment measures include calcium and magnesium solutions, gabapentin, and alpha-lipoic acidTreatment

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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.

Hepatotoxicity

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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 reportedHypersensitivity

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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 therapyHypersensitivity

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Thank you