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 Torreviejabelen.valenzuela@quiron.es

2

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

3

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

4

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

5

Carrier Solution – Exposure PK Analysis

6

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

once

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tion

(mg/

L)

0 10 20 30 40

0.5

1.0

5.0

Interdisciplinary Coordination in Operating Room Allows Sample Collection

Time (h)

Oxa

lipla

tin C

once

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0.0 0.1 0.2 0.3 0.4 0.5

6070

8090

Time (h)

Oxa

lipla

tin C

once

ntra

tion

(mg/

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

10

Bi-Exponentially Decline of Concentrations Justifies a Two Compartment Disposition Model

0 10 20 30

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, mg/

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ICODEXTRINDEXTROSE

Time, h

Oxa

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, mg/

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Time, h

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0.0 0.2 0.4 0.6 0.8

0.05

0.10

0.50

1.00

Time, h

Oxa

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neal

Nor

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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¡¡¡.