Download PLATINUM ANALOGS

OBJECTIVES
PLATINUM ANALOGS
Teresa Slagle, PharmD
Discuss the characteristics of platinum
analogues
Mechanism of Action
Indications
Side Effects
Dosing & Administration
Identify drug specific traits of the
various drugs
Test Your Knowledge
Test Your Knowledge
Cisplatin must be prepared in:
1.
2.
3.
4.
D5W
NS or D5/0.45%NaCl
SWFI
It doesn’t matter
Which requires aggressive hydration?
1.
2.
3.
4.
Oxaliplatin must be prepared in:
1.
2.
3.
4.
D5W
NS or D5/0.45%NaCl
SWFI
It doesn’t matter
Test Your Knowledge
Oxaliplatin
Cisplatin
Carboplatin
All of the above
Platinum’s may require dose reduction if:
1.
2.
3.
4.
Tbili > 3
SrCr > 2.5 mg/dL
K < 3.2
Mg < 1.5
Cell cycle nonspecific
Main target: G1 with some S
Which is known to cause severe
hypomagnesemia?
1.
2.
3.
4.
Oxaliplatin
Cisplatin
Carboplatin
All of the above
Avoid eating or drinking cold foods for 48
hours after:
1.
2.
3.
4.
Oxaliplatin
Cisplatin
Carboplatin
All of the above
www2.mrc-lmb.cam.ac.uk
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DNA BASES
DNA
http://mips.stanford.edu
http://138.192.68.68/bio/Courses/biochem2/GeneIntro/DNAandRNAIntro.html
PLATINUM ANALOGS
HISTORY
CISPLATIN (PLATINOL®, Bristol
Myers Squibb)
CARBOPLATIN (PARAPLATIN®,
Bristol Myers Squibb)
OXALIPLATIN (ELOXATIN®, Sanofi
Aventis)
1845 – Cisplatin first synthesized
1961 – Cisplatin’s cytotoxic effects discovered
by Dr. Barnett Rosenberg during a study on the
effect of electromagnetic radiation on E. Coli
growth
1978 – Cisplatin gains FDA approval for
testicular and ovarian cancers
1988 – Carboplatin gains FDA approval for
palliative treatment of recurrent ovarian
2002 – Oxaliplatin gains FDA approval for
metastatic colorectal 2nd line (2004 gains 1st line
approval for advanced colorectal)
CISPLATIN
CISPLATIN - MOA
Electroneutral molecule that diffuses across the cell
membrane
Lower intracellular chloride concentration leads to
aquation and activation
cis
cis--(NH3)2PtCl2 + H2O ↔ Cl- + Cis
Cis--(NH3)2PtClOH
Once activated, cisplatin forms a covalent bond
preferentially with N7 of GUANINE less with adenine
Can also bind to other nucleophilic proteins
Results in INTRASTRAND,, interstrand, and protein crosscross-linking
of DNA. This leads to apoptosis.
www.ddesignmedia.de
2
CISPLATIN - INDICATIONS
FDA approved for
Metastatic testicular cancer in combination,
adjuvant
Metastatic ovarian cancer in combination,
adjuvant
Transitional cell bladder cancer not amenable
to surgery and/or XRT; single agent; adjuvant
or palliative
CISPLATIN – INDICATIONS
Brain tumor (peds)
Cervical cancer
Germ cell tumors
Head and Neck cancer
Lung cancer, small cell
and nonnon-small cell
Neuroblastoma (peds)
Osteosarcoma (peds)
Esophageal cancer
Wilm’s (peds)
Adrenocortical cancer
Breast cancer
Endometrial cancer
Gastrointestinal cancer
Gynecological sarcoma
Hepatoblastoma
Malignant melanoma
Lymphoma
Thyroid cancer
Skin cancer
CISPLATIN – SIDE EFFECTS
CISPLATIN – SIDE EFFECTS
Nephrotoxicity – Major dose limiting
toxicity
Ototoxicity
Severe and cumulative, noted in 2828-36% of
patients following a single 50mg/m2 dose
Renal function MUST return to normal prior to
next dose
Requires aggressive hydration, ideally 1000ml
IV over 2 to 4 hours prepre- and postpost- cisplatin
Preferably NS + KCl 20meq/L + Mag SO4 1 gm/L
Mannitol 12.512.5-25gm prior to cisplatin
Cumulative effect, more pronounced in children, noted in up to
31% of patients following a single 50mg/m2 dose
Tinnitus and/or loss of high frequency range, rarely deafness;
unilateral or bilateral
Contraindicated in patients with prepre-existing hearing impairment
Myelosuppresion
Occurs in 2525-30% of patients
Nadir at day 18 to 23 (range 7.5 to 45), recovery by day 39
Anemia, including rare Coomb’s positive hemolytic anemia
Neutropenia
Thrombocytopenia
CISPLATIN – SIDE EFFECTS
CISPLATIN – SIDE EFFECTS
Nausea/vomiting
Peripheral neuropathy
~ 100% incidence
Onset 1 to 4 hours post treatment, lasting up to 24 hours for
acute phase
Delayed N/V may persist for up to 1 week
Premedicate with 55-HT3 and dexamethasone plus aprepitant
(Emend®) 125mg PO D1 prior to infusion and 80mg PO QD D2
& D3
Electrolyte abnormalities
↓ Magnesium, calcium, potassium, less often ↓ sodium, phosphate
Likely related to renal tubular damage
Manage with supplemental electrolytes, may require discontinuation
SIADH has also been reported
Usually occurs after prolonged therapy (4 to 7 months), but may
occur after 1st dose
Signs and symptoms may begin 3 to 8 weeks following
completion of therapy – this is quite rare
Discontinue cisplatin when neurotoxicity is first observed
Neuropathy may continue to progress after treatment
discontinuation and may be irreversible
Elderly patients have increased susceptibility
Visual impairment
Infrequent
Improvement and/or total recovery after drug discontinuation
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CISPLATIN - ADMINISTRATION
CISPLATIN – DOSING
Ensure aggressive hydration and
electrolyte replacement
Avoid aluminum containing needles or
administration sets
Must be diluted with a minimum ½ NS
solution, ideally to < 0.5mg/ml
Infuse over 3030-60 minutes
Stable for 24 hours at room temperature
CALL MD IF DOSE > 100mg/m2
Testicular: Cisplatin 20mg/m2 IV daily x 5 days
every 3 weeks (BEP)
Ovarian: Cisplatin 75mg/m2 IV D1 every 3
weeks + paclitaxel
CARBOPLATIN
CARBOPLATIN - MOA
Single agent: Cisplatin 100mg/m2 IV D1 every 4
weeks
IP: Cisplatin 100mg/m2 IP D2 following paclitaxel IV
every 3 weeks, followed by IP paclitaxel D8
Bladder: 5050-70mg/m2 IV every 3 to 4 weeks
(MVAC or RT)
Interstrand, intrastrand, and DNADNA-platinum
adducts
Same as cisplatin
Increased stability compared to cisplatin
Results in low incidence of nephrotoxicity
Slower rate of aquation
commons.wikimedia.org
CARBOPLATIN - INDICATIONS
FDA approved
Advanced ovarian cancer, in combination, 1st line and palliative
Other indications/ongoing trials
Locally advanced NSCLC, inoperable or recurrred
Neuroblastoma (peds)
Transitional cell cancer of the urothelium
Fallopian tube, 1o peritoneal cancer, endometrial cancer
SCLC
Breast cancer
Thyroid cancer
Colon cancer
Wilm’s tumor
Retinoblastoma
CARBOPLATIN – SIDE EFFECTS
Myelosuppression – dose limiting toxicity
Thrombocytopenia – 59% vs 35% cisplatin
Anemia – (<8 g/dL) 8% vs 24% cisplatin
Neutropenia – (<1000) 84% vs 78% cisplatin
Nadir 10 to 14 days
Nausea/vomiting
Moderate risk
Peripheral Neuropathy
Incidence 4% naïve, 6% pretreated
Age > 65 or prior cisplatin = 10% incidence
Lower incidence and reduced severity vs cisplatin
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CARBOPLATIN ADMINISTRATION
No prehydration required
IV infusion over 3030-60 minutes
Avoid aluminum containing needles or
administration sets
Compatible with NaCl 0.9% or D5W
Stable for 24 hours at room temperature
CARBOPLATIN - DOSING
Dose is based on renal function
Renal excretion correlates closely to glomerular filtration rate
(GFR), estimated as creatinine clearance (CrCl)
Calvert formula:
Maximum CrCl for calculation = 135 mg/dL
Carboplatin dose (mg) = (CrCl + 25) x AUC
Common carboplatin doses
Weekly administration = AUC 2
Every 3 weeks = AUC 4 to 7.5
AUC correlates to toxicity
OXALIPLATIN
AUC 4 to 5 = grade 3/4 ↓ Plt 16%, ↓ WBC 13%
AUC 6 to 7 = grade 3/4 ↓ Plt 33%, ↓ WBC 34%
OXALIPLATIN - MOA
Interstrand, intrastrand, and DNADNA-platinum
adducts
Same as cisplatin
Exhibits activity in cisplatincisplatin-resistant tumors
Mismatch repair (MMR) complex does not
recognize oxaliplatinoxaliplatin-DNA adducts
Larger carrier ligand, diaminocyclohexane
(DACH), produces a bulkier adduct
May defeat repair mechanisms
May induce apoptosis more readily
www.pharmazeutische-zeitung.de
OXALIPLATIN - INDICATIONS
FDA approved in Colorectal cancer; in
combination; first line in metastatic,
adjuvant in Stage III
OXALIPLATIN - INDICATIONS
Ongoing studies
Advanced nasopharyngeal cancer with concurrent
radiation
Gastrointestinal cancer
Pancreatic cancer
Cholangiocarcinoma
NHL
Germ Cell tumor
Ovarian cancer
Breast cancer
NSCLC
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OXALIPLATIN PHARMACOKINETICS
Metabolism
OXALIPLATIN – SIDE EFFECTS
Neuropathy
Frequency: 92% (all grades) 13% (grade 3)
Improves over time
Acute, reversible, primarily peripheral, sensory neuropathy
Rapid nonnon-enzymatic biotransformation
Distribution
Freq at 18 months followfollow-up: 20.7% (all grades) 0.5% (grade 3)
Occurs within hours or 11-2 days of dosing
Resolves within 14 days
Recurs frequently with further dosing
Occurred in ~ 56% of study patients
Exacerbated by cold – avoid ice
α = 1212-25 mins, β = 1515-16 hours, γ = 27 hours
Elimination
Renal
Persistent (>14 days), primarily peripheral, sensory neuropathy
Characterized by parethesias, dysesthesias, hypoesthesias, may
also include deficits in proprioception that interferes with ADL’s
Occurred in ~48% of study patients
OXALIPLATIN ADMINISTRATION
OXALIPLATIN – SIDE EFFECTS
Pulmonary toxicity
Rare (<1%), but potentially fatal pulmonary fibrosis
Hepatotoxicity
↑ LFT’s and alk phos twice as likely in studies
Nausea/Vomiting
Pretreatment with 55-HT3 antagonist and dexamethasone
Myelosuppression
Alone vs combo w/ 55-FU/LV:
Anemia (64% vs 81%, grade 3/4 2%)
Neutropenia (7% vs 73%, grade 3/4 44%)
Thrombocytopenia (30% vs 64%, grade 3/4 4%)
OXALIPLATIN - DOSING
No prehydration required
Do not allow to come in contact with
aluminum
Compatible with D5W only – never dilute
with NaCl or other Cl containing solutions
Flush line with D5W prior to administering
any other medication, especially 55-FU
Stable for 6 hours room temperature and
24 hours refrigerated
PHARMACOKINETICS
FOLFOX 6
Day 1 Oxaliplatin 100mg/m2 IV over 2 hours + Leucovorin
400mg/m2 over 2 hours, followed by bolus 55-FU 400mg/m2,
followed by CIVI 55-FU 2400mg/m2 over 46 hours
Administer every 2 weeks x 12 cycles
mFOLFOX 6 uses Oxaliplatin 85mg/m2
XELOX
Day 1 Oxaliplatin 130mg/m2 + Capecitabine 1000mg/m2 PO
BID x 14 days every 3 weeks x 8 cycles
Efficacy data not yet available – Phase III study ongoing
Dose modification
Consider dose reduction for grade 2 neuropathy, grade 3/4 GI
toxicities or thrombocytopenia, grade 4 neutropenia
Consider discontinuing for grade 3 neuropathy
Cisplatin
Carboplatin
Oxaliplatin
t1/2 α (min)
1414-49
1212-98
26
t1/2 β (hour)
0.7
0.7--4.6
1.3
1.3--1.7
_
t1/2 γ (hour)
2424-127
8.2
8.2--40
3838-47
Protein
binding
> 90%
2424-50%
85%
Urinary
excretion
2323-50%
5454-82%
> 50%
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SATRAPLATIN
SATRAPLATIN
3rd generation, orally available platinum analog
Ongoing studies
SPARC (phase III) satraplatin + prednisone vs.
placebo + prednisone, 2nd line treatment, hormonehormonerefractory prostate cancer
↓ relative risk of disease progression by 33% (26% vs 46%),
46%),
median TTP 16 vs 6 weeks, but no OS benefit
Pre--specified subset analyses underway
Pre
Phase II trials for inoperable advanced NSCLC
Satraplatin + erlotinib, 1st line, age > 70
Satraplatin + paclitaxel, 1st line
www.chemblink.com
Test Your Knowledge
MECHANISMS OF RESISTANCE
May be intrinsic or acquired
Two major mechanisms
Limited formation of DNADNA-platinum adducts
↓ drug accumulation (↑ efflux and/or ↓ uptake)
↑ drug inactivation by thiols
Prevention of apoptosis in the presence of
DNA--platinum adducts
DNA
↑ DNADNA-platinum adduct repair
↓’d in testicular cancer
↑ tolerance of DNADNA-platinum damage
Cisplatin must be prepared in:
1.
2.
3.
4.
Oxaliplatin must be prepared in:
1.
2.
3.
4.
Test Your Knowledge
Cisplatin must be prepared in:
1.
2.
3.
4.
D5W
NS or D5/0.45%NaCl
SWFI
It doesn’t matter
Oxaliplatin must be prepared in:
1.
2.
3.
4.
D5W
NS or D5/0.45%NaCl
SWFI
It doesn’t matter
D5W
NS or D5/0.45%NaCl
SWFI
It doesn’t matter
D5W
NS or D5/0.45%NaCl
SWFI
It doesn’t matter
Test Your Knowledge
Cisplatin must be prepared in:
1.
2.
3.
4.
D5W
NS or D5/0.45%NaCl
SWFI
It doesn’t matter
Oxaliplatin must be prepared in:
1.
2.
3.
4.
D5W
NS or D5/0.45%NaCl
SWFI
It doesn’t matter
7
Test Your Knowledge
Test Your Knowledge
Which requires aggressive hydration?
1.
2.
3.
4.
Oxaliplatin
Cisplatin
Carboplatin
All of the above
Which requires aggressive hydration?
1.
2.
3.
4.
Platinum’s may require dose reduction if:
1.
2.
3.
4.
Tbili > 3
SrCr > 2.5 mg/dL
K < 3.2
Mg < 1.5
Platinum’s may require dose reduction if:
1.
2.
3.
4.
Test Your Knowledge
2.
3.
4.
Oxaliplatin
Cisplatin
Carboplatin
All of the above
Which is known to cause severe
hypomagnesemia?
1.
2.
3.
4.
Platinum’s may require dose reduction if:
1.
2.
3.
4.
Tbili > 3
SrCr > 2.5 mg/dL
K < 3.2
Mg < 1.5
Tbili > 3
SrCr > 2.5 mg/dL
K < 3.2
Mg < 1.5
Test Your Knowledge
Which requires aggressive hydration?
1.
Oxaliplatin
Cisplatin
Carboplatin
All of the above
Oxaliplatin
Cisplatin
Carboplatin
All of the above
Avoid eating or drinking cold foods with:
1.
2.
3.
4.
Oxaliplatin
Cisplatin
Carboplatin
All of the above
REFERENCES
Cisplatin Package Insert. Bedford Labs, June 2004.
DeVita VT (2004) CANCER: PRINCIPLES & PRACTICE.
PRACTICE. LWW (344(344-356).
AHFS Drug Information (2007)
www.cancer.gov
Oxaliplatin Package Insert. SanofiSanofi-Aventis, Nov 2006.
Schmoll H et al. Phase III trial of capecitabine plus oxaliplatin as adjunctive therapy
for stage III colon cancer: a planned safety analysis in 1,864 patients. JCO
2007;25:102.
Cvitkovic E. Ongoing and unsaid on oxaliplatin: the hope. Br J Cancer. 1998 Jun;77
Suppl:8--11. Abstract.
Suppl:8
www.gpc--biotech.com/en/anticancer_programs/satraplatin/index.html
www.gpc
Warmerdam LJC et al. The use of the Calvert formula to determine the optimal
carboplatin dosage. Journal of Cancer Research and Clinical Oncology. 1995
Aug;121:478--486. Abstract.
Aug;121:478
Carboplatin (Paraplatin®) Package Insert. BMS, Jan 2004.
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