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.


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.
van Ruth
Serge
S
Department of Surgical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Mathôt
Ron A A
RA
Sparidans
Rolf W
RW
Beijnen
Jos H
JH
Verwaal
Vic J
VJ
Zoetmulder
Frans A N
FA
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001499:Bayes Theorem; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000601:surgery*; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced / Q000295:instrumentation / Q000379:methods*; D007432:Intraoperative Period; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D016685:Mitomycin