Pharmacokinetics and the effect of heat on intraperitoneal pemetrexed using a murine model

Badrudin, David; Perrault-Mercier, Camille; Bouchard‐Fortier, Antoine; Hubert, Julien; Leblond, François; Sidéris, Lucas; Dubé, Pierre

doi:10.1016/j.suronc.2016.05.014

Cited by 8 publications

(8 citation statements)

References 16 publications

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“…In animal model, hyperthermia increased the drug absorption by the tumour cells [106]. It has been used in postoperative bidirectional chemotherapy after cytoreductive surgery and HIPEC for malignant peritoneal mesothelioma [29].…”

Section: Premetrexedmentioning

confidence: 99%

Pharmacological principles of intraperitoneal and bidirectional chemotherapy

Bree

Michelakis

Stamatiou

et al. 2017

Pleura and Peritoneum

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Intraperitoneal chemotherapy is associated with a significant pharmacokinetic and pharmacodynamic benefit and can, alone or in combination with systemic chemotherapy (bidirectional chemotherapy), be used for treating primary and secondary peritoneal surface malignancies. Due to the peritoneal-plasma barrier, high intraperitoneal drug concentration can be achieved by intraperitoneal chemotherapy, whereas systemic concentration remains low. Bidirectional chemotherapy may provide in addition adequate drug concentrations from the side of the subperitoneal space to the peritoneal tumour nodules. Major pharmacological problems of intraperitoneal chemotherapy are limited tissue penetration and poor homogeneity of drug distribution to the entire seroperitoneal surface. Significant pharmacological determinants of intraperitoneal chemotherapy are choice of drug, drug dosage, solution volume, carrier solution, intra-abdominal pressure, temperature, duration, mode of administration, extent of peritonectomy and interindividual variability. Drugs most commonly applied for intraperitoneal chemotherapy include mitomycin C, cisplatin, carboplatin, oxaliplatin, irinotecan, 5-fluoruracil, gemcitabine, paclitaxel, docetaxel, doxorubicin, premetrexed and melphalan. The drugs and their doses that are used vary widely among centres. While the adequate drug choice for intraperitoneal and bidirectional chemotherapy is essential, randomized clinical trials to determine the most optimal drug or drug combination are lacking, and only eight retrospective comparative clinical studies are available. Further clinical pharmacological studies are required to determine the most effective drug regimen for intraperitoneal and bidirectional chemotherapy in various indications. In the future, reliable drug sensitivity testing and genetic profiling of peritoneal metastases will be needed for enabling patient-specific therapy.

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Section: Premetrexedmentioning

confidence: 99%

Pharmacological principles of intraperitoneal and bidirectional chemotherapy

Bree

Michelakis

Stamatiou

et al. 2017

Pleura and Peritoneum

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“…Since its discovery, pemetrexed has become one of the most effective systemic agent against malignant mesothelioma . More recently, the use of local therapies such as CRS/HIPEC has been associated with significant survival benefits in the treatment of MPM and pemetrexed is thus an appealing agent to use in this context . However, the optimal technique for its IP delivery remains undefined.…”

Section: Discussionmentioning

confidence: 99%

“…The reasons behind this seemingly opposite effect of HIPEC delivery technique on absorption of the two drugs are unclear. Their pharmacokinetic profiles when used in HIPEC are in fact very different . An additional hypothesis to explain these results would imply a decreased elimination of plasmatic pemetrexed with the use of the open technique.…”

Section: Discussionmentioning

confidence: 99%

“…Regarding the temperature of IP perfusion, experimental studies have shown enhancement of pemetrexed cytotoxic effect when administered in hyperthermia. However, for temperatures above 40°C, this effect reached a plateau . Thus, we chose not to exceed 40°C, especially as we previously demonstrated that perfusion temperatures exceeding 43°C were associated with mortality rates above 50% in a murine model…”

Section: Methodsmentioning

confidence: 99%

“…By achieving high concentrations of cytotoxic drugs locally and minimizing systemic absorption, thus limiting potential side effects, HIPEC offers an important pharmacokinetic advantage over systemic treatment. Consequently, pemetrexed is an appealing agent to use for CRS with HIPEC for the treatment of MPM …”

Section: Introductionmentioning

confidence: 99%

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Comparison of open and closed abdomen techniques for the delivery of intraperitoneal pemetrexed using a murine model

Badrudin

Sidéris

Perrault-Mercier

et al. 2018

Journal of Surgical Oncology

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A comparative in vivo study of hyperthermic intraperitoneal chemotherapy with cisplatin versus doxorubicin versus cisplatin plus doxorubicin for the treatment of intra‐abdominally disseminated alveolar rhabdomyosarcoma in mice

Martynov,

Gesche,

Dhaka

et al. 2024

Pediatric Blood & Cancer

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BackgroundTreatment options for advanced intra‐abdominal pediatric rhabdomyosarcoma (RMS) with peritoneal sarcomatosis (PS) include cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). However, optimal dosages and combination regimens of drugs used for HIPEC are underexplored. We aimed to evaluate the efficacy of HIPEC with cisplatin, doxorubicin, and their combination in vivo.MethodsWe established PS/RMS mouse model by intraperitoneally injecting RH30 cells into NOD/LtSz‐scid IL2Rγ‐null mice. Two weeks post xenotransplantation, mice underwent a single HIPEC procedure at 42°C for 60 minutes. Treatment groups received cisplatin (50, 100, and 150 mg/m2) and doxorubicin (30, 45, and 60 mg/m2), administered alone or combined. The control group underwent an intraperitoneal lavage with isotonic saline. Peritoneal cancer index (PCI) was used to quantify the extent of peritoneal tumor spread. Tissue samples were evaluated regarding proliferation (Ki‐67) and apoptosis (caspase 3).ResultsMice treated with cisplatin at 100 mg/m2 (PCI of 3.875, p = .007) and 150 mg/m2 (PCI of 4.556, p = .026), and doxorubicin at 30 mg/m2 (PCI of 2.875, p < .001) and 45 mg/m2 (PCI of 4.143, p = .021) showed reduced PCI, with the combination of cisplatin 50 mg/m2 and doxorubicin 30 mg/m2 showing the most prominent effect (PCI of 3.333, p < .001) compared to the control group (PCI of 8.615). Histologically, there was no difference in Ki‐67 or caspase 3 expression among the groups.ConclusionsThe cisplatin‐ and doxorubicin‐based HIPEC significantly reduces peritoneal tumor dissemination in vivo. Further investigations are needed to explore the underlying molecular responses to optimize therapeutic strategies.

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Pharmacokinetics and the effect of heat on intraperitoneal pemetrexed using a murine model

Cited by 8 publications

References 16 publications

Pharmacological principles of intraperitoneal and bidirectional chemotherapy

Pharmacological principles of intraperitoneal and bidirectional chemotherapy

Comparison of open and closed abdomen techniques for the delivery of intraperitoneal pemetrexed using a murine model

A comparative in vivo study of hyperthermic intraperitoneal chemotherapy with cisplatin versus doxorubicin versus cisplatin plus doxorubicin for the treatment of intra‐abdominally disseminated alveolar rhabdomyosarcoma in mice

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