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

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 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.

References

  1. 1.
    Witkamp AJ, de Bree E, Van Goethem R, et al. Rationale and techniques of intra-operative hyperthermic intraperitoneal chemotherapy. Cancer Treat Rev 2001; 27: 365–74PubMedCrossRefGoogle Scholar
  2. 2.
    Witkamp AJ, de Bree E, Kaag MM, et al. Extensive cytoreductive surgery followed by intra-operative hyperthermic intraperitoneal chemotherapy with mitomycin-C in patients with peritoneal carcinomatosis of colorectal origin. Eur J Cancer 2001; 37: 979–84PubMedCrossRefGoogle Scholar
  3. 3.
    Witkamp AJ, de Bree E, Kaag MM, et al. Extensive surgical cytoreduction and intraoperative hyperthermic intraperitoneal chemotherapy in patients with pseudomyxoma peritonei. Br J Surg 2001; 88: 458–63PubMedCrossRefGoogle Scholar
  4. 4.
    Storm FK. Clinical hyperthermia and chemotherapy. Radiol Clin North Am 1989; 27: 621–7PubMedGoogle Scholar
  5. 5.
    Rietbroek RC. Hyperthermia in combination with chemotherapy: from laboratory bench to bedside [dissertation]. Amsterdam: University of Amsterdam, 1996Google Scholar
  6. 6.
    Haller DG. Chemotherapy in gastrointestinal malignancies. Semin Oncol 1988; 15: 50–64PubMedGoogle Scholar
  7. 7.
    Panteix G, Guillaumont M, Cherpin L, et al. Study of the pharmacokinetics of mitomycin C in humans during intraperitoneal chemothermia with special mention of the concentration in local tissues. Oncology 1993; 50: 366–70PubMedCrossRefGoogle Scholar
  8. 8.
    Fujimoto S, Shrestha RD, Kokobun M, et al. Pharmacokinetic analysis of mitomycin C for intraperitoneal hyperthermic perfusion in patients with far-advanced or recurrent gastric cancer. Reg Cancer Treat 1989; 2: 198–202Google Scholar
  9. 9.
    Jacquet P, Averbach A, Stephens AD, et al. Heated intraoperative intraperitoneal mitomycin C and early postoperative intraperitoneal 5-fluorouracil: pharmacokinetic studies. Oncology 1998; 55: 130–8PubMedCrossRefGoogle Scholar
  10. 10.
    Fernandez-Trigo V, Stuart OA, Stephens AD, et al. Surgically directed chemotherapy: heated intraperitoneal lavage with mitomycin C. Cancer Treat Res 1996; 81: 51–61PubMedCrossRefGoogle Scholar
  11. 11.
    van Ruth S, Verwaal VJ, Hart AA, et al. Heat penetration in locally applied hyperthermia in the abdomen during intraoperative hyperthermic intraperitoneal chemotherapy. Anti-cancer Research 2003; 23(2B): 1501–8Google Scholar
  12. 12.
    Beal SL, Sheiner LB. NONNEM user’s guide: NONNEM Project Group. San Francisco (CA): University of California, 1992Google Scholar
  13. 13.
    Mandema JW, Danhof M. Electroencephalogram effect measures and relationships between pharmacokinetics and pharmacodynamics of centrally acting drugs. Clin Pharmacokinet 1992; 23(3): 191–215PubMedCrossRefGoogle Scholar
  14. 14.
    Jonsson EN, Karlsson MO. Xpose: an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 1999; 58: 51–64PubMedCrossRefGoogle Scholar
  15. 15.
    Ette EI. Stability and performance of a population pharmacokinetic model. J Clin Pharmacol 1997; 37: 486–95PubMedGoogle Scholar
  16. 16.
    US Department of Health and Human Services, Food and Drug Administration. Guidance for industry: population pharmacokinetics 1999 [online]. Available from URL: http://www.fda.gov/cber/gdlns/popharm.pdf [Accessed 2003 Nov 17]
  17. 17.
    Holford N. Wings for NONMEM. Available online from: http://wfn.sourceforge.net [accessed 2003 Nov 17]
  18. 18.
    National Cancer Institute, Cancer Therapy Evaluation Program. Common toxicity criteria, version 2.0, March 1998. Available from URL: http://ctep.cancer.gov/reporting/CTC-3.html [Accessed 2003 Nov 17]
  19. 19.
    Verweij J, den Hartigh J, Stuurman M, et al. Relationship between clinical parameters and pharmacokinetics of mitomycin C. J Cancer Res Clin Oncol 1987; 113: 91–4PubMedCrossRefGoogle Scholar

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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