Aspectos Farmacológicos de la Quimioterapia ... fileAspectos Farmacológicos de la Quimioterapia...
Transcript of Aspectos Farmacológicos de la Quimioterapia ... fileAspectos Farmacológicos de la Quimioterapia...
Aspectos FarmacolAspectos Farmacolóógicos de la gicos de la Quimioterapia Quimioterapia IntraperitonealIntraperitoneal con con
Hipertermia: Consideraciones Hipertermia: Consideraciones FarmacocinFarmacocinééticasticas
Dra. Belén Valenzuela JiménezUnidad de Farmacoterapia PersonalizadaPlataforma de Oncología, Hospital Quirón [email protected]
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Outline
• Rational for Intraperitoneal Drug Administration
• Factors Affecting Peritoneal Carcinomatosis Treatment Outcome
• How Can We Optimize HIPEC Treatments by Application of
Pharmacokinetics Principles?
Carrier Solution Effect in Oxaliplatin Exposure
Oxaliplatin Absolute Bioavailability after Intraperitoneal Administration
• Conclusions
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Rational for Intraperitoneal Drug Administration in PC Patients
Hasovits C et al. Clin Pharmacokinet 2012,51:203-224.
MaximalRegional Exposure
MinimalSystemic Exposure
Several Factors Affect Outcome PC treatment
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TemperatureDrugDose
DurationVolumeTonicityCarrier
BIOMETRICSAge
Peritoneal CavityBSA
PHARMACOLOGICALNeoadjuvant Chemotherapy
EPICIntraperitoneal Chemotherapy
TUMORType
Histologic GradeSize
DensityVascularity
SURGICALPeritoneal Cancer Index
Cytoreduction Score
Main Determinants of HIPEC Exposure
• Isotonic solutions are preferred to hyper- or hypo-tonic solutions!
• Several carriers for isotonic solutions have been used but limitedformal equivalence studies have been conducted so far
DrugDoseVolumeDurationTonicityCarrier
PeritoneumPeritoneumInputInput OutputOutput
DrugDoseDurationVolumeTonicityCarrier
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Carrier Solution – Exposure PK Analysis
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Methodological Description
Subject elegibility criteria Inclusion criteria: confirmation of PC without extra abdominal metastasis, PS 0 to 2, anticipated life expectancy of at least 3 months, normal hepatic and renal function, acceptable bone marrow function, negative pregnancy test. Exclusion criteria: active infection, CNS metastases, peripheral neuropathy>grade2,allogenic transplant, prior extensive radiation therapy, prior bone marrow tranasplantation or high dose chemotherapy with bone marrow or stem cell rescue.
Pharmacotherapy treatmentIntraperitoneal oxaliplatin diluted in 4% icodextrin (arm A) or 5% dextrose (arm B) in volumes from 2.5 to 6.0 L, at 42-43ºC, during 36.6 minutes (range 30-60 minutes).
CovariatesAge, sex, body weight, serum creatinine, albumin, serum ALT, serum AST, total bilirubin, hemoglobin, hematocrit, PC index, CCR, and study.
Sample collection and bioanalytical method7
Methodological Description
Subject elegibility criteriaInclusion criteria: confirmation of PC without extra abdominal metastasis, PS 0 to 2, anticipated life expectancy of at least 3 months, normal hepatic and renal function, acceptable bone marrow function, negative pregnancy test. Exclusion criteria: active infection, CNS metastases, peripheral neuropathy>grade2, allogenic transplant, prior extensive radiation therapy, prior bone marrow transplantation or high dose chemotherapy with bone marrow or stem cell rescue.
Pharmacotherapy treatmentIntraperitoneal Oxaliplatin diluted in 4% icodextrin (arm A) or 5% dextrose (arm B) in volumes from 2.5 to 6.0 L, at 42-43ºC, during 36.6 minutes (range 30-60 minutes).
CovariatesAge, sex, body weight, serum creatinine, albumin, serum ALT, serum AST, total bilirubin, hemoglobin, hematocrit, PC index, CCR, and study.
Sample collection and bioanalytical method7
Methodological Description
Subject elegibility criteriaInclusion criteria: confirmation of PC without extra abdominal metastasis, PS 0 to 2, anticipated life expectancy of at least 3 months, normal hepatic and renal function, acceptable bone marrow function, negative pregnancy test. Exclusion criteria: active infection, CNS metastases, peripheral neuropathy>grade2, allogenic transplant, prior extensive radiation therapy, prior bone marrow transplantation or high dose chemotherapy with bone marrow or stem cell rescue.
Pharmacotherapy treatmentIntraperitoneal Oxaliplatin diluted in 4% icodextrin (arm A) or 5% dextrose (arm B) in volumes from 2.5 to 6.0 L, at 42-43ºC, during 36.6 minutes (range 30-60 minutes).
CovariatesAge, sex, body weight, serum creatinine, albumin, serum ALT, serum AST, total bilirubin, hemoglobin, hematocrit, PC index, CCR, and study.
Sample collection and bioanalytical method7
Methodological Description
Subject elegibility criteriaInclusion criteria: confirmation of PC without extra abdominal metastasis, PS 0 to 2, anticipated life expectancy of at least 3 months, normal hepatic and renal function, acceptable bone marrow function, negative pregnancy test. Exclusion criteria: active infection, CNS metastases, peripheral neuropathy>grade2, allogenic transplant, prior extensive radiation therapy, prior bone marrow transplantation or high dose chemotherapy with bone marrow or stem cell rescue.
Pharmacotherapy treatmentIntraperitoneal Oxaliplatin diluted in 4% icodextrin (arm A) or 5% dextrose (arm B) in volumes from 2.5 to 6.0 L, at 42-43ºC, during 36.6 minutes (range 30-60 minutes).
CovariatesAge, sex, body weight, serum creatinine, albumin, serum ALT, serum AST, total bilirubin, hemoglobin, hematocrit, PC index, CCR, and study.
Sample collection and bioanalytical method7
Time (h)
Oxa
lipla
tin C
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tion
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L)
0 10 20 30 40
0.5
1.0
5.0
Interdisciplinary Coordination in Operating Room Allows Sample Collection
Time (h)
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0.0 0.1 0.2 0.3 0.4 0.5
6070
8090
Time (h)
Oxa
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tin C
once
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L)
0.0 0.5 1.0 1.5
0.8
1.0
2.0
3.0
8
33.8 (5.1)3.6 (0.6)
399.5 (94.7)92.37.7
11.0 (10.8)15.484.6
261 (127)4.6 (3.5)11.8 (1.1)79.7 (34.0)
6238
69.1 (12.7) 58.2 (12.8)
Dextrose 5%(N = 13)Patient Characteristics Icodextrin 4%
(N = 36) P value
Age (y) 57.7 (11.6) 0.89Body Weight (kg) 69.3 (12.1) 0.95 Sex (%)
Male 39 0.98Female 61
Creatinine Clearance (mL·min-1) 80.5 (29.2) 0.95Haemoglobin (g·dL-1) 11.6 (2.0) 0.71Neutrophil (x109·L-1 ) 4.7 (3.6) 0.92Platelets (x109·L-1 ) 286 (155) 0.61Liver metastases
Yes (%) 86.1 0.84No (%) 13.9
Peritoneal Carcinomatosis Index 12.3 (12.3) 0.73Complete Cytoreduction
Yes (%) 27.8 0.14No (%) 72.2
Oxaliplatin Dose (mg·m-2) 364.5 (32.4) 0.59Volume Carrier Solution (L) 3.9 (0.8) 0.20Duration Oxaliplatin Perfusion (min) 37.6 (8.3) 0.13
Patient Characteristics at BaselineStratified by Carrier Solution
Continuous variables are expressed as mean (standard deviation), whereas categorical variables are expressed as percentage (%).9
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Bi-Exponentially Decline of Concentrations Justifies a Two Compartment Disposition Model
0 10 20 30
0.00
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0.00
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ntra
tions
, mg/
L
ICODEXTRINDEXTROSE
Time, h
Oxa
lipla
tin P
lasm
a N
orm
aliz
ed C
once
ntra
tions
, mg/
L
ICODEXTRINDEXTROSE
Time, h
Oxa
lipla
tin P
lasm
a N
orm
aliz
ed C
once
ntra
tions
, mg/
L
ICODEXTRINDEXTROSE
Time, h
Oxa
lipla
tin P
lasm
a N
orm
aliz
ed C
once
ntra
tions
, mg/
L
ICODEXTRINDEXTROSE
Time, h
Oxa
lipla
tin P
lasm
a N
orm
aliz
ed C
once
ntra
tions
, mg/
L
ICODEXTRINDEXTROSE
Time, h
Oxa
lipla
tin P
lasm
a N
orm
aliz
ed C
once
ntra
tions
, mg/
L
ICODEXTRINDEXTROSE
Time, h
Oxa
lipla
tin P
lasm
a N
orm
aliz
ed C
once
ntra
tions
, mg/
L
ICODEXTRINDEXTROSE
Time, h
Oxa
lipla
tin P
lasm
a N
orm
aliz
ed C
once
ntra
tions
, mg/
L
ICODEXTRINDEXTROSE
Time, h
Oxa
lipla
tin P
lasm
a N
orm
aliz
ed C
once
ntra
tions
, mg/
L
ICODEXTRINDEXTROSE
Time, h
Oxa
lipla
tin P
lasm
a N
orm
aliz
ed C
once
ntra
tions
, mg/
L
ICODEXTRINDEXTROSE
Time, h
Oxa
lipla
tin P
lasm
a N
orm
aliz
ed C
once
ntra
tions
, mg/
L
ICODEXTRINDEXTROSE
Time, h
Oxa
lipla
tin P
lasm
a N
orm
aliz
ed C
once
ntra
tions
, mg/
L
ICODEXTRINDEXTROSE
0.0 0.2 0.4 0.6 0.8
0.05
0.10
0.50
1.00
Time, h
Oxa
lipla
tin P
erito
neal
Nor
mal
ized
Con
cent
ratio
ns, m
g/L ICODEXTRIN
DEXTROSE
CentralCompartment
Vc =19.7 L
PeripheralCompartment
Vp = 57.3 LDOSE
Q=34.9 L/h
PeritonealCompartment
Va= 3.9 LVa=3.1 L
Cla=2.03 L/h Clp=1.71 L/h
Goodness of Fit and Model Validations Techniques Confirms the Absence of Systematic Bias
11
PLASMAPERITONEUM
Carrier Solution EquivalenceAnalysis Results
0.849 (0.742-0.971)
0.955 (0.857-1.060)
Ratio (90% CI)
0.93 (0.80-1.05)
1.08 (0.95-1.22)
1.05 (0.93-1.17)
0.89 (0.80-1.02)
1.13 (1.0-1.23)
1.03 (0.93-1.13)
Ratio (90% CI)
0.47Cmax (mg·L-1)
0.18AUC0-tlast (mg·h·L-1)
Sampling Site
Non-compartmental Parameters* P value
Peritoneum
Cmax (mg·L-1) 0.71
t1/2 (h) 0.28
Plasma AUC0-tlast (mg·h·L-1) 0.34
t1/2 (h) 0.36Sampling
Site Compartmental Parameters P value
PeritoneumCla (L·h-1) 0.73
Va (L) 0.02*Ratio Dextrose /Icodextrin (Reference).* Data were normalized and log-transformed prior to the equivalence study.
• Grade 4 neutropenia lasting 5 days was 15% higher for 5% dex.vs 4% icodex.
• For HIO 30 min, one additional case of G4N for every 67 patients treated.12
Oxaliplatin Absolute Bioavailability after Intraperitoneal Administration
13
• Absolute bioavailability compares the bioavailability of a drug in systemic circulation following non-intravenous administration with the bioavailability of the same drug following intravenous administration.
DAUCClF 0
.v.i
.p.i·
D AUC· ClD AUC· Cl
Fabs 100
Poster nº56. Oxaliplatin bioavailability after intraperitoneal administration in peritoneal carcinomatosis patients.
Conclusions
• Isotonic icodextrin and dextrose carrier solutions can be consideredequivalent for HIPEC of short duration.
• Pharmacokinetic principles are helpful to characterize and to modulatethe dosing regimens in order to maximize periotoneal exposure andminimize toxicity folllowing HIPEC treatment in PC patients.
14
Time is ripe: quit guessing and startmeasuring¡¡¡.