Population pharmacokinetics and pharmacodynamics of mitomycin during intraoperative hyperthermic intraperitoneal chemotherapy
(2004) In Clinical Pharmacokinetics 43(2). p.43-131- Abstract
BACKGROUND: During recent years, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin has been used for various malignancies.
OBJECTIVE: To characterise the population pharmacokinetics and pharmacodynamics of mitomycin during HIPEC.
METHODS: Forty-seven patients received mitomycin 35 mg/m2 intraperitoneally as a perfusion over 90 minutes. Mitomycin concentrations were determined in both the peritoneal perfusate and plasma. The observed concentration-time profiles were used to develop a population pharmacokinetic model using nonlinear mixed-effect modelling (NONMEM). The area under the plasma concentration-time curve (AUC) was related to the haematological... (More)
BACKGROUND: During recent years, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin has been used for various malignancies.
OBJECTIVE: To characterise the population pharmacokinetics and pharmacodynamics of mitomycin during HIPEC.
METHODS: Forty-seven patients received mitomycin 35 mg/m2 intraperitoneally as a perfusion over 90 minutes. Mitomycin concentrations were determined in both the peritoneal perfusate and plasma. The observed concentration-time profiles were used to develop a population pharmacokinetic model using nonlinear mixed-effect modelling (NONMEM). The area under the plasma concentration-time curve (AUC) was related to the haematological toxicity.
RESULTS: Concentration-time profiles of mitomycin in perfusate and plasma were adequately described with one- and two-compartment models, respectively. The average volume of distribution of the perfusate compartment (V1) and rate constant from the perfusate to the systemic circulation (k12) were 4.5 +/- 1.1L and 0.014 +/- 0.003 min(-1), respectively (mean +/- SD, n = 47). The average volume of distribution of the central plasma compartment (V2), clearance from the central compartment (CL) and volume of distribution of the peripheral plasma compartment (V3) were 28 +/- 16L, 0.55 +/- 0.18 L/min and 36 +/- 8L, respectively. The relationship between the AUC in plasma and degree of leucopenia was described with a sigmoidal maximum-effect (Emax) model.
CONCLUSIONS: The pharmacokinetics of mitomycin during HIPEC could be fitted successfully to a multicompartment model. Relationships between plasma exposure and haematological toxicity were quantified. The developed pharmacokinetic-pharmacodynamic model can be used to simulate different dosage schemes in order to optimise mitomycin administration during HIPEC.
(Less)
- author
- van Ruth, Serge ; Mathôt, Ron A A ; Sparidans, Rolf W ; Beijnen, Jos H ; Verwaal, Vic J LU and Zoetmulder, Frans A N
- publishing date
- 2004
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Antibiotics, Antineoplastic/administration & dosage, Area Under Curve, Bayes Theorem, Colorectal Neoplasms/drug therapy, Female, Humans, Hyperthermia, Induced/instrumentation, Intraoperative Period, Leukopenia/chemically induced, Male, Metabolic Clearance Rate, Middle Aged, Mitomycin/administration & dosage, Tissue Distribution
- in
- Clinical Pharmacokinetics
- volume
- 43
- issue
- 2
- pages
- 43 - 131
- publisher
- Adis International
- external identifiers
-
- pmid:14748621
- scopus:1442308464
- ISSN
- 0312-5963
- DOI
- 10.2165/00003088-200443020-00005
- language
- English
- LU publication?
- no
- id
- 9e563b1d-f0a7-4311-b00b-c419a70d2e58
- date added to LUP
- 2022-04-12 10:51:20
- date last changed
- 2024-02-07 13:46:57
@article{9e563b1d-f0a7-4311-b00b-c419a70d2e58,
abstract = {{<p>BACKGROUND: During recent years, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin has been used for various malignancies.</p><p>OBJECTIVE: To characterise the population pharmacokinetics and pharmacodynamics of mitomycin during HIPEC.</p><p>METHODS: Forty-seven patients received mitomycin 35 mg/m2 intraperitoneally as a perfusion over 90 minutes. Mitomycin concentrations were determined in both the peritoneal perfusate and plasma. The observed concentration-time profiles were used to develop a population pharmacokinetic model using nonlinear mixed-effect modelling (NONMEM). The area under the plasma concentration-time curve (AUC) was related to the haematological toxicity.</p><p>RESULTS: Concentration-time profiles of mitomycin in perfusate and plasma were adequately described with one- and two-compartment models, respectively. The average volume of distribution of the perfusate compartment (V1) and rate constant from the perfusate to the systemic circulation (k12) were 4.5 +/- 1.1L and 0.014 +/- 0.003 min(-1), respectively (mean +/- SD, n = 47). The average volume of distribution of the central plasma compartment (V2), clearance from the central compartment (CL) and volume of distribution of the peripheral plasma compartment (V3) were 28 +/- 16L, 0.55 +/- 0.18 L/min and 36 +/- 8L, respectively. The relationship between the AUC in plasma and degree of leucopenia was described with a sigmoidal maximum-effect (Emax) model.</p><p>CONCLUSIONS: The pharmacokinetics of mitomycin during HIPEC could be fitted successfully to a multicompartment model. Relationships between plasma exposure and haematological toxicity were quantified. The developed pharmacokinetic-pharmacodynamic model can be used to simulate different dosage schemes in order to optimise mitomycin administration during HIPEC.</p>}},
author = {{van Ruth, Serge and Mathôt, Ron A A and Sparidans, Rolf W and Beijnen, Jos H and Verwaal, Vic J and Zoetmulder, Frans A N}},
issn = {{0312-5963}},
keywords = {{Antibiotics, Antineoplastic/administration & dosage; Area Under Curve; Bayes Theorem; Colorectal Neoplasms/drug therapy; Female; Humans; Hyperthermia, Induced/instrumentation; Intraoperative Period; Leukopenia/chemically induced; Male; Metabolic Clearance Rate; Middle Aged; Mitomycin/administration & dosage; Tissue Distribution}},
language = {{eng}},
number = {{2}},
pages = {{43--131}},
publisher = {{Adis International}},
series = {{Clinical Pharmacokinetics}},
title = {{Population pharmacokinetics and pharmacodynamics of mitomycin during intraoperative hyperthermic intraperitoneal chemotherapy}},
url = {{http://dx.doi.org/10.2165/00003088-200443020-00005}},
doi = {{10.2165/00003088-200443020-00005}},
volume = {{43}},
year = {{2004}},
}