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Pharmacological Aspects of Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Pharmacodynamic Considerations
III Congreso Nacional SEOQ y V Reunion GECOP Alicante, 4 de Octubre de 2013
Juan Jose Pérez Ruixo, PhD
PKPD knowledge of HIPEC treatments is critical to select dosing regimens that maximize efficacy & minimize toxicity
DrugDoseVolumeTonicityCarrier Duration
PeritonealCarcinomatosis
PeritonealCarcinomatosis
InputInput OutputOutput
Tumor BiologyPatient SensitivitySurgery Effect
SafetyEfficacy
III Congreso Nacional SEOQ y V Reunion GECOP, Alicante, 2013
• Oxaliplatin maximum tolerated exposure in peritoneum is 240 mg∙h/L and exposures >120 mg∙h/L require G-CSF support.• Absolute neutrophil counts after CRS & oxaliplatin potency to induced neutropenia were higher than expected
III Congreso Nacional SEOQ y V Reunion GECOP, Alicante, 2013
III Congreso Nacional SEOQ y V Reunion GECOP, Alicante, 2013
Time course of ANC following CRS + HIPECA
bsol
ute
Neu
trop
hil C
ount
s x
109
Cells
/L
Time, Days
III Congreso Nacional SEOQ y V Reunion GECOP, Alicante, 2013
Mitotic Phase Postmitotic PhaseMature
neutrophils released into
the circulation3 to 9 days 5 to 7 days
Homeostasis
Surgery
3 to 9 days 1 day
Surgery effect on granulopoiesis
III Congreso Nacional SEOQ y V Reunion GECOP, Alicante, 2013
Study Design
Cytoreductive Surgery HIPEC Oxaliplatin (Icodextrin 4%)Cytoreductive Surgery HIPEC Oxaliplatin (Icodextrin 4%)Cohort A
Cytoreductive Surgery HIPEC Oxaliplatin (Dextrose 5%)Cytoreductive Surgery HIPEC Oxaliplatin (Dextrose 5%)Cohort B
Cytoreductive SurgeryCytoreductive SurgeryCohort C
III Congreso Nacional SEOQ y V Reunion GECOP, Alicante, 2013
III Congreso Nacional SEOQ y V Reunion GECOP, Alicante, 2013
Neutrophil dynamics model for HIPEC
III Congreso Nacional SEOQ y V Reunion GECOP, Alicante, 2013
Neutrophil dynamics model predictionsModel PredictionsANC Observations
0 5 10 15 20
34
56
7
Time, Days
Abs
olut
e Neu
troph
il Cou
nts,
x 1
0̂9
Cel
ls/L
0 5 10 15 20 25 30
34
57
9
Time, Days
Abs
olut
e Neu
troph
il Cou
nts,
x 1
0̂9
Cel
ls/L
0 5 10 15 20 25
1020
40Time, Days
Abs
olut
e Neu
troph
il Cou
nts,
x 1
0̂9
Cel
ls/L
0 5 10 15 20 25 30
0.5
1.0
5.0
Time, Days
Abs
olut
e Neu
troph
il Cou
nts,
x 1
0̂9
Cel
ls/L
0 10 20 30
510
1525
Time, Days
Abs
olut
e Neu
troph
il Cou
nts,
x 1
0̂9
Cel
ls/L
0 10 20 30
57
920
Time, Days
Abs
olut
e Neu
troph
il Cou
nts,
x 1
0̂9
Cel
ls/L
0 5 10 15 20
34
56
78
Time, Days
Abs
olut
e Neu
troph
il Cou
nts,
x 1
0̂9
Cel
ls/L
0 10 20 30 40
0.1
0.5
5.0
Time, Days
Abs
olut
e Neu
troph
il Cou
nts,
x 1
0̂9
Cel
ls/L
0 5 10 15 20 25
34
57
9Time, Days
Abs
olut
e Neu
troph
il Cou
nts,
x 1
0̂9
Cel
ls/L
Cohort A: CRS + HIO Icodextrin 4% Cohort B: CRS + HIO Dextrose 5% Cohort C: CRS
Time (days)
III Congreso Nacional SEOQ y V Reunion GECOP, Alicante, 2013
Effect of surgery, oxaliplatin dose and vehicle on the ANC time course
Time, days
III Congreso Nacional SEOQ y V Reunion GECOP, Alicante, 2013
What’s the maximum tolerated exposure of oxaliplatin in HIPEC?
• PKPD knowledge of HIPEC treatments is critical to select dosingregimens that maximize efficacy & minimize toxicity.
• Cytoreductive surgery affect the neutrophil dynamics by stimulating the proliferation of precursor cells and reducing the maturation time
• Although several Ph1 clinical studies have established the oxaliplatin MTD, our exposure response analysis indicates that higher doses or extended duration might be feasible and should be tested in the context of clinical studies.
III Congreso Nacional SEOQ y V Reunion GECOP, Alicante, 2013
Conclusions
