Clinical Pharmacokinetics

, Volume 43, Issue 2, pp 131–143 | Cite as

Population Pharmacokinetics and Pharmacodynamics of Mitomycin During Intraoperative Hyperthermic Intraperitoneal Chemotherapy

  • Serge van Ruth
  • Ron A. A. Mathôt
  • Rolf W. Sparidans
  • Jos H. Beijnen
  • Vic J. Verwaal
  • Frans A. N. Zoetmulder
Original Research Article


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.

Conclusion: 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.


Body Surface Area Mitomycin Haematological Toxicity Plasma Exposure Population Pharmacokinetic Model 



The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this study.


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Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Serge van Ruth
    • 1
  • Ron A. A. Mathôt
    • 2
  • Rolf W. Sparidans
    • 3
  • Jos H. Beijnen
    • 4
  • Vic J. Verwaal
    • 1
  • Frans A. N. Zoetmulder
    • 1
  1. 1.Department of Surgical OncologyThe Netherlands Cancer Institute/Antoni van Leeuwenhoek HospitalAmsterdamThe Netherlands
  2. 2.Department of Clinical Pharmacy and Clinical PharmacologyErasmus University Medical CentreRotterdamThe Netherlands
  3. 3.Division of Drug Toxicology, Department of Biomedical Analysis, Faculty of Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
  4. 4.Department of Pharmacy and PharmacologySlotervaart Hospital and Antoni van Leeuwenhoek HospitalAmsterdamThe Netherlands

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