Population Pharmacokinetics and Pharmacodynamics of Mitomycin During Intraoperative Hyperthermic Intraperitoneal Chemotherapy
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.
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