HIDRASI CISPLATIN PADA KASUS

ONKOLOGI DI SMF INTERNA

MAGISTER FARMASI KLINIK

FAKULTAS FARMASI
UNIVERSITAS AIRLANGGA
2012-2013
 Dorland's Medical Dictionary for Health
Consumers. © 2007 by Saunders

1. The addition of water to a chemical

molecule without hydrolysis.
2. The process of providing an
adequate amount of liquid to bodily
tissues
 Bertujuan untuk menurunkan
nefrotoksisitas cisplatin
 Cisplatin as an agent chemotherapy for
hematology oncology
Indication Doses Frekuency
CLL or NHL ACE :
Cytarabine 2 mg/m2 Every 12 hour days 1 and 2

Cisplatin 35 mg/m2 Over 4 hours daily day 1

and 2
Etoposide 100 mg/m2 Over 1 hour daily day 1 & 2
Relapsed/ Cisplatin 50 mg/m2 - 75 Every 21 – 28 days
Refractory mg/m2 day 1 (3 – 4 weeks)
acute Temozolomide, 200 mg/m2
leukemia day 1 – 5
Cisplatin 75 mg/m2 - 100
mg/m2 day 1
Temozolomide, 200 mg/m2
day 1 – 7
 Cisplatin in Oncology Cases
Indication Doses Frekuency
Non-Small-Cell lung Fist line, combine with paclitaxel The regimen is repeated every 3
Cancer (NSCLC) Intravenous dosage: Adults: The weeks based on clinical status of
approved regimen consists of patient
cisplatin 75 mg/m2 IV as a
single dose following
administration of paclitaxel
in combination with vinorelbine: Every 6 weeks in combination
Intravenous dosage: with vinorelbine
Adults: Cisplatin 100 mg/m2
IV on days 1 and 29
in combination with gemcitabine:
Intravenous dosage: Adults:
Cisplatin 100 mg/m2 IV
following gemcitabine on day 1 of
a 21-day or 28-day treatment
cycle

Testicular Cisplatin 20mg/m2 IV daily x Repeat cycle every 3 weeks for 2

5 days cycles or more.
with bleomycin and etoposide
(BEP regimen)
 Indication Doses Frekuency
Osteogenic First line :
Sarcoma Doxorubicin and cisplatin primary therapy: The cycle was
Doxorubicin 25 mg/m2 IV on days 1-3 repeated every 21
cisplatin 100 mg/m2 IV on day 1. days

MAP (high-dose methotrexate, cisplatin,

and doxorubicin):
Neoadjuvant setting: High-dose
methotrexate 12 g/m2 IV given over 4h on
weeks 0, 1, 5, 6, 13, 14, 18, 19, 23, 24, 37, and
38, alternating with cisplatin 60 mg/m2 IV
plus doxorubicin 37.5 mg/m2/day IV for 2d
each on weeks 2, 7, 25, and 28
Adjuvant setting: High-dose methotrexate 12
g/m2 IV given over 4h on weeks 3, 4, 8, 9, 13,
14, 18, 19, 23, 24, 37, and 38, alternating with
cisplatin 60 mg/m2 IV plus doxorubicin
37.5 mg/m2/day IV for 2d each on weeks 5,
10, 25, and 28[6] ; 2 cycles are given
preoperatively, and 4 cycles are usually given
postoperatively
Indication Doses Frekuency
Ovarian With paclitaxel; Cisplatin Every 3 weeks
75mg/m2 IV Day 1
With cyclophosphamide: Every 21 days in
Intravenous dosage: Adults: 50—60 combination with
mg/m2 via IV infusion administered cyclophosphamide
as a single dose once
Iv dosage: Adults: 50—70 mg/m2 IV Every 3 – 4 weeks
Bladder a single dose once combination with
other antineoplastic agents.
As part of the MVAC
regimen(methotrexate, vinblastine, Every 28 days (3 weeks)
and doxorubicin), cisplatin is given
as 70 mg/m2 IV on day 2'
Head & neck Cisplatin 75-100 mg/m² IV when Every 4 weeks
squamous cell used with cyclophosphamide
cancer 100 mg/m² IV as single agent
 Cisplatin in Hematology – Oncology
Indication Doses Frekuency
Relapsed or Resistant DHAP :
Diffuse Large B-Cell Dexamethasone, 20 mg twice daily Every 3 weeks
Lymphoma (DLBCL) day 1-4
Cytarabine 2 g/m2 i.v. as 3-hour
For salvage treatment infusion on days 2 in the evening
and 3 in the morning
Cisplatin 35 mg/m2 as 2 hour
infusion on days 1–3

ESHAP :
Etoposide, 40 mg/m2,
days 1–4
Methylprednisolone, 500 mg, days
1–5
High-dose Cytarabine, 2 g/m2,
day 5
Cisplatin, 25 mg/m2, days 1–4
 Indication Doses Frekuency
Relapsed or DICE (IVPD) :
refractory Dexamethasone,40 mg i.v. daily for 4 all administered every 3
intermediate and days weeks for 3 cycles.
high grade advanced Cisplatin 30mg/m2 IV weekly, followed
NHL by
Etoposide 100mg/m2 IV + ifosfamide
1,200mg/m2 IV (plus mesna) +
cisplatin 33mg/m2 IV, day 1 – 3
Days 1–4: Dexamethasone 40mg IV or
orally.

In patients with poor GEM-P : Every 28 days (4 weeks)

prognostic primary Gemcitabine, 1000 mg/m2 was delivered
progressive or as i.v. infusion over 30 min on day 1, 8
multiply relapsed and 15
Hodgkin’s and non- Cisplatin, 100 mg/m2 was given over 4
Hodgkin’s lymphoma hour on day 15 only. Cisplatin was
started 4 h after the gemcitabine infusion
Methylprednisolone, 1 g either orally or
intravenously
on day 1–5
 Indication Doses Frekuency

In relapsed or GEPD :
refractory non- Gemcitabine, 700 mg/m2 as a The cycle was
Hodgkin's continuous iv infusion over 70 repeated every 21
lymphoma min on days 1 and 8. Etoposide, days
40 mg/m2 as an iv infusion over
30 min on days 1-4.
Cisplatin, 60 mg/m2 was given
over 1 hour on day 1.
Dexamethasone, 40 mg
intravenously on days 1-4.
 Cases
(July 2013)

No Profile Diagnose Protocol Drug Therapy

Patient
1. Mr. S (M) / 31 y Osteosarcoma regio Cisplatin- Doxorubicin 20 mg
Hospitalized: iliaca D Doxorubicin (d 1-4)
chondroblastik type Doxorubicin 25 mg Cisplatin 100 mg
(d 1-3) (d 6)
Cisplatin 100 mg
(d5)

2. Mrs. S (F) / 57 y Cutaneus T cell ESHAP Etoposide 40 mg

Hospitalized : Etoposide : Cisplatin 20 mg
1/7 40mg/m2 (d1-4)
Methylprednisolone
500 mg (d1-5) :
Citarabine : 2 g/m2
(d5)
Cisplatin 25mg/m2
(d1-4)
Cisplatin : efek samping

BC Cancer Agency, 2008)

 Risk Factor for Cisplatin
Nephrotoxicity

Vincent et al, Prevention of cisplatin nephrotoxicity: state of the art and recommendations from the European
Society of Clinical Pharmacy Special Interest Group on Cancer Care, Cancer Chemo Pharmacol, 2008
 Kerusakan mtDNA

Kerusakan Mitokondria

MEKANISME
Produksi energi untuk membuka kanal Na, K, Mg ↓ KERUSAKAN GINJAL

Reabsorpsi Na, air, K, Mg ↓

Vasokonstriksi arteri renalis

↓ RBF, ↑ Filtration Pressure

Reversibel (recovery
setelah 2 – 4 minggu)
↓ GFR
Ireversibel

(Townsend et al, 2003 ; Miller et al, 2010)

(Miller et al, 2010)
Vacher et al, 2008
 Creatinine
Urine output
Serum
Reevaluation Renal
Function After
Treatment With
Cisplatin

BUN Electrolit
 Kesimpulan:
Prehidrasi Cisplatin dosis
tinggi dapat
menggunakan D5 1/2NS.
Setelah diuresis
dihentikan, total cairan
keluar digantikan tiap 2
jam sampai pagi
berikutnya.
 Kesimpulan:
Hidrasi yang paling sering digunakan adalah larutan NS,
ataupun yang dikombinasi dengan mannitol atau
furosemid untuk meningkatkan urine output.
Tezcan et al, 2013
Suplementasi Mg, Ca, K
 Kesimpulan :
Gangguan elektrolit seperti hipomagnesia, hipokalsemia, hipofosfatemia
dan hipokalemia sering terjadi pada terapi cisplatin.
Hipokalsemia dan hipokalemia berat dapat terjadi setelah
hipomagnesemia berat.
Katzung et al., 2011
Comparison of Serum & Urine Levels, before&after
treatment of Cisplatin
 DAFTAR PUSTAKA
 Florea A, M., Büsselberg D, 2011. Cisplatin as an Anti-Tumor Drug: Cellular
Mechanisms of Activity, Drug Resistance and Induced Side Effects , MDPI, Basel,
Switzerland
 Hanigan M.H., Prasad Devarajan, 2003. Review Article, Cisplatin nephrotoxicity:
molecular mechanisms, Cancer Therapy Vol 1, 47-61,
 Lacy, C.F., Amstrong, L.L., Goldman, N.P., Lance, L.L. (Ed.), 2009. Drug Information
Handbook 18th edition. APhA : Lexi-Comp
 Marcello Tiseo, Olga Martelli, Andrea Mancuso, Maria Pia Sormani, Paolo Bruzzi,
Roberto Di Salvia , Filippo De Marinis, and Andrea Ardizzoni1 , 2007. Short
Hydration Regimen And Nephrotoxicity of Intermediate to High-dose Cisplatin-
based Chemotherapy for Outpatient Treatment in Lung Cancer and Mesothelioma,
University Hospital of Parma, Via Gramsci 14, 43100 Parma, Italy.
 Miguel A. Fuertes, Carlos Alonso, Jose´. M. Pe´rez, 2002. Chemical Reviews ;Volume
103, Number 3, Biochemical Modulation of Cisplatin Mechanisms of Action:
Enhancement of Antitumor Activity and Circumvention of Drug Resistance,
American Chemical Society
 Miller, R. P. et al. 2010. Mechanism of Cisplatin Toxicity. Toxins (2) : 2490 – 2518
 Pabla, N and Dong, Z. 2008. Cisplatin nephrotoxicity: Mechanisms and
renoprotective strategies. International Society of Nephrology
 Songül Tezcan1, Fikret Vehbi Izzettin, Mesut Sancar, Perran Fulden Yumuk, Serdar
Turhal, 2013. Nephrotoxicity Evaluation in Outpatients Treated with Cisplatin-Based
Chemotherapy Using a Short Hydration Method, Pharmacology & Pharmacy, 4, 296-
302.
 Takashi Taguchia, Mohammed S. Razzaque, 2005. Cisplatin-Associated
Nephrotoxicity and Pathological Events, Razzaque MS, Taguchi T (eds): Cellular
Stress Responses in Renal Diseases.Contrib Nephrol. Basel, Karger, vol 148, pp 106–
120
 Townsend, D. M. et al. 2003. Metabolism of Cisplatin to a Nephrotoxin in Proximal
Tubule Cells. J Am Soc Nephrol 14
 Xin Yao, Md; Kessarin Panichpisal, Md; Neil Kurtzman, Md; Kenneth Nugent, Md
2007. Cisplatin Nephrotoxicity: A Review, [Am J Med Sci 334(2):115–124.]
Slide cadangan
 PHARMACOKINETIC

NAMA DISTR PROT T1/2 METABOLISME EKSKRESI

OBAT BIND
CISPLATIN IV : cepat > 90 % 20-30’ Non enzimatik, Urin > 90 %
ke jar, diinaktifkan oleh Feses > 10%
terkonsen ulfhidril, ikatan
trasi tinggi kovalen oleh
di ginjal, gluthation dan
hati, thiosulfat
uterus,
ovarium,
paru
MANITOL OOA : 1-3 1,1-1,6 Minimally hepatic Unchanged
jam jam to glycogen drugs
DOA : 1.5 terutama di
– 6 jam urin
Tidak
terpenetra
si di BBB
 PHARMACOKINETIC

DRUG DISTR BIND T1/2 METABOLISM EXCRETION

PROT
FUROSE OOA: > 98% Normal Minimally Urine (Oral:
MIDE Diuresis: renal hepatic 50%, I.V.:
IV : 5 function: 80%) within 24
minutes 0.5-1.1 hours; feces (as
IV : 2 hours hours; unchanged
ESRD : 9 drug);
hours nonrenal
clearance
prolonged in
renal
impairment
 Sodium, water and
potassium
Michael D. Penney, Clinical Biochemistry2008
 Perbedaan Komposisi D51/2NS & D5NS

D5NS D5 1/2NS
Na 77 mEq/L
Cl 77 mEq/L
Dextrose 50 g/L 50 g/L
NaCl 9 g/L 4,5 g/L
WFI 1L 1L
Osmolaritas 560 mOsm/L 432 mOsm/L
low-dose Cisplatin, 5-Fluorouracil and Interferon alpha: report on
several cases and review of the literature [ISRCTN62866759]
Katrin Hoffmann*†1, Angela Marten†1, Katja Lindel2, Stefan Fritz1,2,
Dirk Jager2, Markus W Buchler1 and Jan Schmidt1, Published: 10 May 2006
BMC Cancer 2006, 6:128 doi:10.1186/1471-2407-6-128
Mannitol
8 Interactions Found
Significant - Monitor Closely
doxorubicin + cyclophosphamide
 doxorubicin increases toxcity of cyclophosphamide by unspecified
interaction mechanism. Significant - Monitor Closely. Increased risk of
hemorrhagic cystitis.
furosemide + cisplatin
 furosemide, cisplatin. Either increases toxcity of the other by
pharmacodynamic synergism. Significant - Monitor Closely. Additive
ototoxicity.
potassium chloride + furosemide
 potassium chloride increases and furosemide decreases serum
potassium. Effect of interaction is not clear, use caution. Significant -
Monitor Closely.
cisplatin + cyclophosphamide
 cisplatin, cyclophosphamide. Either increases toxcity of the other by
pharmacodynamic synergism. Significant - Monitor Closely. Additive
myelosuppression.
Minor
prednisone + vincristine
 prednisone will decrease the level or effect of vincristine by
affecting hepatic/intestinal enzyme CYP3A4 metabolism.
Minor or non-significant interaction.
dextrose + magnesium sulfate
 dextrose decreases levels of magnesium sulfate by
increasing renal clearance. Minor or non-significant
interaction.
prednisone + furosemide
 prednisone, furosemide. Mechanism: pharmacodynamic
synergism. Minor or non-significant interaction. Risk of
hypokalemia, especially with strong glucocorticoid activity.
furosemide + magnesium sulfate
 furosemide decreases levels of magnesium sulfate by
increasing renal clearance. Minor or non-significant
interaction.
Interaksi obat-obat

Tatro, 2009
Cyclophosphamide-Ondansetron
Furosemide-Cisplatin
 Penambahan diuretika tidak mempengaruhi
kadar platinum dalam plasma dan ginjal,
maupun derajat sel yang mengalami nekrosis
(BCCA, 2008).
 Besarnya jumlah hidrasi, diuretika, maupun
dosis elektrolit yang diberikan bergantung pada
besarnya dosis cisplatin (mg/m2) yang diterima
pasien (BCCA, 2008).
 FDA merekomendasikan regimentasi hidrasi
sebagai pre-treatment sebesar 1-2 L cairan yang
diinfuskan selama 8-12 jam (BCCA, 2008; Tiseo
et al., 2007).
 Menurut tinjauan yang ditulis Miller et al.,
hidrasi dengan infus NS dalam jumlah besar
 Hidrasi yang cukup pada saat pemberian
cisplatin (hingga 12 jam setelahnya) akan
menginduksi diuresis sedikitnya 100 mL/jam.
 Bila dalam periode 3 jam produksi urin tidak
mencapai 300 mL, maka pemberian cairan
hidrasi ditingkatkan menjadi 300 mL/jam
selama 3 jam, dan apabila produksi urin tetap
kurang dari 300 mL pada periode 3 jam
berikutnya, maka perlu ditambahkan diuretika
furosemide (1 x 20 mg) untuk menginduksi
terjadinya diuresis.
 Evaluasi fungsi ginjal pasien dilakukan secara
rutin sebelum kemoterapi cisplatin siklus
selanjutnya melalui pemeriksaan laboratoris
Dari data tersebut dapat diperkirakan nilai GFR
dan ClCr lewat rumus MDRD atau Cockroft-Gault
yang digunakan sebagai perhitungan modifikasi
dosis atau terapi jika ditemukan tanda-tanda
gangguan ginjal. SCr dapat diperiksa pada hari
ke-3 hingga 5 setelah pemberian cisplatin untuk
mengetahui peningkatan SCr secara akut (Vacher
et al., 2008).
 Mengacu pada protokol dari BC Cancer Agency, hidrasi yang
disarankan untuk pemberian kemoterapi cisplatin tunggal
dosis 40-60 mg/m2 adalah dengan menggunakan 1000 mL NS
selama 1 jam yang disertai dengan penambahan KCl 10 mEq
dan MgSO4 0,5 g (BCCA, 2008).
 Keberhasilan hidrasi dinilai dari produksi urin tampung 100
mL/jam yang diharapkan dapat menurunkan risiko
nefrotoksisitas.
 Sampai saat ini, upaya pemberian hidrasi yang dilakukan di
SMF Obstetrik-Ginekologi RSUD Dr. Soetomo masih belum
dievaluasi secara mendalam.
 Penelitian ini merupakan studi observasi prospektif guna
melihat efektivitas hidrasi NS terhadap risiko nefrotoksisitas
pada pasien kanker serviks yang menerima kemoterapi
cisplatin dosis 50 mg/m2.
 Evaluasi terhadap fungsi ginjal dilakukan melalui pengamatan
kadar serum elektrolit dalam darah pre- dan post-hidrasi
kemoterapi.
 Jenis Kerusakan Sel Akibat Cisplatin

• Dosis rendah  apoptosis

• Dosis tinggi  nekrosis
(Pabla and Dong, 2008)
Slide ini dimasukkan cadangan dulu aja mbak,soalnya q blm nemu
berapa dosis tepatnya
General Administration for Cisplatin in Regimen
Chemoterapy

Cisplatin Administration
For single dose of cisplatin or any combination, especially for cisplatin was
mixed in normal or half-normal saline prior to administration. Individual doses
greater than 25 mg/m2 were usually accompanied by mannitol (250 ml of a
20% solution) plus at least an additional 750 ml of intravenous (i.v.) fluids,
with the entire hydration and cisplatin administration procedure requiring
a minimum of 1.5 h (most often as an outpatient).
Patients were also encouraged to drink a minimum of six to eight glasses of
fluid per day at home in the 2±3 days following treatment, although the
amount of oral hydration was not monitored or recorded.
Patients who were receiving a cisplatin dose of £ 75 mg/m2 per course
divided over 3 or more days (i.e. £ 25 mg/m2 per day) were in some cases
treated without mannitol and with only 300±550 ml total i.v. fluids per day.
On the other hand, a small proportion of the patients receiving cisplatin
100±120 mg/m2 as an inpatient received several litres of i.v. fluids
Stewart; 1996