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Pharmacokinetics of cisplatin during hyperthermic intraperitoneal treatment of peritoneal carcinomatosis

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Cisplatin during hyperthermic intraperitoneal chemotherapy (HIPEC) has not previously been measured with a selective technique. The primary aims were to examine the pharmacokinetics of active cisplatin and its monohydrated complex (MHC) during HIPEC using a specific measuring technique, to compare cisplatin’s systemic absorption with oxaliplatin, and to compare active cisplatin levels to that of total platinum.

Methods

Ten patients treated with cytoreductive surgery and HIPEC (cisplatin 50 mg/m2,doxorubicin 15 mg/m2) were recruited. Blood and perfusate samples were drawn during and after HIPEC. Cisplatin analysis was conducted using liquid chromatography (LC) with post-column derivatization with diethyldithiocarbamate and compared with inductively coupled plasma-mass spectrometry (ICP-MS).

Results

The mean half-life (t1/2) of perfusate cisplatin was 18.4 min, with area under the time-concentration curve (AUC) 0–90 min of 2.87 mM·min and estimated 0–60 min of 2.45 mM·min. The absorption t1/2 was 9.0 min for cisplatin and 18.2 min for oxaliplatin. The ratio of total platinum to active cisplatin increased in a linear manner by time of perfusion.

Conclusions

Cisplatin is absorbed quicker than oxaliplatin. Lowering the perfusion time to 60 min does not significantly change the pharmacokinetics of cisplatin, and is therefore to be considered. As the HIPEC perfusion progresses, the ICP-MS technique does not adequately reflect active cisplatin levels in the perfusate.

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Abbreviations

AAS:

Flameless atomic absorption spectrophotometry

AUC:

Area under the time-concentration curve

BMI:

Body mass index

BSA:

Body surface area

CC:

Completeness of cytoreduction

CRS:

Cytoreductive surgery

HIPEC:

Hypthermic intraperitoneal chemotherapy

ICP-MS:

Inductively coupled plasma mass spectrometry

IV:

Intravenous(ly)

MHC:

Monohydrated complex of cisplatin

PCI:

Peritoneal cancer index

PMP:

Pseudomyxoma peritonei

UF:

Ultrafiltrate

References

  1. Yang X-J, Huang C-Q, Suo T et al (2011) Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a phase III randomized clinical trial. Ann Surg Oncol 18:1575–1581

    Article  PubMed  Google Scholar 

  2. Deraco M, Kusamura S, Virzì S et al (2011) Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as upfront therapy for advanced epithelial ovarian cancer: Multi-institutional phase-II trial. Gynecol Oncol 122:215–220

    Article  PubMed  Google Scholar 

  3. Bancroft D, Lepre C, Lippard S (1990) (195)PT NMR kinetic and mechanistic studies of cis-and trans-diamminedichloroplatinum (II) binding to DNA. J Am Chem Soc 112:6860–6871

    Article  CAS  Google Scholar 

  4. Segal E, Le Pecq JB (1985) Role of ligand exchange processes in the reaction kinetics of the antitumor drug cis-diamminedichloroplatinum(II) with its targets. Cancer Res 45:492–498

    PubMed  CAS  Google Scholar 

  5. Sherman S, Lippard S (1987) Structural aspects of platinum anticancer drug interactions with DNA. Chem Rev 87:1153–1181

    Article  CAS  Google Scholar 

  6. Elias D, Bonnay M, Puizillou JM et al (2002) Heated intra-operative intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis: Pharmacokinetics and tissue distribution. Ann Oncol 13:267–272

    Article  PubMed  CAS  Google Scholar 

  7. Ceelen WP, Van Nieuwenhove Y, Van Belle S, Denys H, Pattyn P (2009) Cytoreduction and hyperthermic intraperitoneal chemoperfusion in women with heavily pretreated recurrent ovarian cancer. Ann Surg Oncol. doi:10.1245/s10434-009-0878-6

  8. Mahteme H, Wallin I, Glimelius B, Påhlman L, Ehrsson H (2008) Systemic exposure of the parent drug oxaliplatin during hyperthermic intraperitoneal perfusion. Eur J Clin Pharmacol 64:907–911

    Article  PubMed  CAS  Google Scholar 

  9. Royer B, Guardiola E, Polycarpe E et al (2005) Serum and intraperitoneal pharmacokinetics of cisplatin within intraoperative intraperitoneal chemotherapy: Influence of protein binding. Anticancer Drugs 16:1009–1016

    Article  PubMed  CAS  Google Scholar 

  10. Kern W, Braess J, Kotschofsky M et al (2002) Application of cisplatin as intraoperative hyperthermic peritoneal lavage (IHPL) in patients with locally advanced gastric cancer: Analysis of pharmacokinetics and of nephrotoxicity. Anticancer Res 22:3099–3102

    PubMed  CAS  Google Scholar 

  11. Stephens AD, Belliveau JF, Sugarbaker PH (1996) Intraoperative hyperthermic lavage with cisplatin for peritoneal carcinomatosis and sarcomatosis. Cancer Treat Res 81:15–30

    Article  PubMed  CAS  Google Scholar 

  12. Chatelut E, de Forni M, Canal P et al (1991) Teniposide and cisplatin given by intraperitoneal administration: preclinical and phase I/pharmacokinetic studies. Ann Oncol 2:217–221

    PubMed  CAS  Google Scholar 

  13. Jones MM, Basinger MA, Beaty JA, Holscher MA (1991) The relative nephrotoxicity of cisplatin, cis-[Pt(NH3)2(guanosine)2]2+, and the hydrolysis product of cisplatin in the rat. Cancer Chemother Pharmacol 29:29–32

    Article  PubMed  CAS  Google Scholar 

  14. Andersson A, Fagerberg J, Lewensohn R, Ehrsson H (1996) Pharmacokinetics of cisplatin and its monohydrated complex in humans. J Pharm Sci 85:824–827

    Article  PubMed  CAS  Google Scholar 

  15. Mahmood I, Duan J (2009) Population pharmacokinetics with a very small sample size. Drug Metabol Drug Interact 24:259–74

    PubMed  CAS  Google Scholar 

  16. Sugarbaker PH (1995) Peritonectomy procedures. Ann Surg 221:29–42

    Article  PubMed  CAS  Google Scholar 

  17. Sugarbaker P (1998) Management of peritoneal surface malignancy using intraperitoneal chemotherapy and cytoreductive surgery. A manual for physicians and nurses, 3rd edn. The Ludann Company, Grand Rapids, MI

    Google Scholar 

  18. Andersson A, Ehrsson H (1995) Stability of cisplatin and its monohydrated complex in blood, plasma and ultrafiltrate–implications for quantitative analysis. J Pharm Biomed Anal 13:639–644

    Article  PubMed  CAS  Google Scholar 

  19. Pierre PV, Wallin I, Eksborg S, Ehrsson H (2011) Quantitative liquid chromatographic determination of intact cisplatin in blood with microwave-assisted post-column derivatization and UV detection. J Pharm Biomed Anal 56:126–130

    Article  PubMed  CAS  Google Scholar 

  20. Andersson A, Ehrsson H (1994) Determination of cisplatin and cis-diammineaquachloroplatinum(II) ion by liquid chromatography using post-column derivatization with diethyldithiocarbamate. J Chromatogr B 652:203–210

    Article  CAS  Google Scholar 

  21. Ehrsson H, Wallin I, Andersson A, Edlund P (1995) Cisplatin, transplatin, and their hydrated complexes: Separation and identification using porous graphitic carbon and electrospray mass spectrometry. Anal Chem 67:3608–3611

    Article  CAS  Google Scholar 

  22. Bergerat JP, Barlogie B, Göhde W, Johnston DA, Drewinko B (1979) In vitro cytokinetic response of human colon cancer cells to cis-dichlorodiammineplatinum(II). Cancer Res 39:4356–4363

    PubMed  CAS  Google Scholar 

  23. Niell HB, Wood CA, Mickey DD, Soloway MS (1982) Time- and concentration-dependent inhibition of the clonogenic growth of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide-induced murine bladder tumor cell lines by cis-diamminedichloroplatinum(II). Cancer Res 42:807–811

    PubMed  CAS  Google Scholar 

  24. Barlogie B, Corry PM, Drewinko B (1980) In vitro thermochemotherapy of human colon cancer cells with cis-dichlorodiammineplatinum(II) and mitomycin C. Cancer Res 40:1165–1168

    PubMed  CAS  Google Scholar 

  25. Royer B, Delroeux D, Guardiola E et al (2008) Improvement in intraperitoneal intraoperative cisplatin exposure based on pharmacokinetic analysis in patients with ovarian cancer. Cancer Chemother Pharmacol 61:415–421

    Article  PubMed  CAS  Google Scholar 

  26. Van der Speeten K, Stuart OA, Sugarbaker PH (2009) Pharmacokinetics and pharmacodynamics of perioperative cancer chemotherapy in peritoneal surface malignancy. Cancer J 15:216–224

    Article  PubMed  Google Scholar 

  27. De Waal WA, Maessen FJ, Kraak JC (1990) Analytical methodologies for the quantitation of platinum anti-cancer drugs and related compounds in biological media. J Pharm Biomed Anal 8:1–30

    Article  PubMed  Google Scholar 

  28. Cole WC, Wolf W (1980) Preparation and metabolism of a cisplatin/serum protein complex. Chem Biol Interact 30:223–235

    Article  PubMed  CAS  Google Scholar 

  29. Fournier C, Vennin P, Hecquet B (1988) Correlation between free platinum AUC and total platinum measurement 24 h after i.v. bolus injection of cisplatin in humans. Cancer Chemother Pharmacol 21:75–77

    Article  PubMed  CAS  Google Scholar 

  30. Cho HK, Lush RM, Bartlett DL et al (1999) Pharmacokinetics of cisplatin administered by continuous hyperthermic peritoneal perfusion (CHPP) to patients with peritoneal carcinomatosis. J Clin Pharmacol 39:394–401

    Article  PubMed  CAS  Google Scholar 

  31. Cotte E, Colomban O, Guitton J, Tranchand B, Bakrin N, Gilly FN, Glehen O, Tod M (2011) Population pharmacokinetics and pharmacodynamics of cisplatinum during hyperthermic intraperitoneal chemotherapy using a closed abdominal procedure. J Clin Pharmacol 51:9–18

    Article  PubMed  CAS  Google Scholar 

  32. Yachnin JR, Wallin I, Lewensohn R, Sirzén F, Ehrsson H (1998) The kinetics and cytotoxicity of cisplatin and its monohydrated complex. Cancer Lett 132:175–180

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

ALF funding through the Uppsala University hospital was used during this study, as well as funding from Apoteket AB.

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Authors and Affiliations

  1. Department of Surgical Sciences, Uppsala University Hospital, 751 85, Uppsala, Sweden

    P. H. Cashin & H. Mahteme

  2. Research Department, Karolinska Pharmacy, Karolinska Institute, Stockholm, Sweden

    H. Ehrsson & I. Wallin

  3. Department of Oncology, Radiology and Clinical Immunology, Section of Oncology, Uppsala University, Uppsala, Sweden

    P. Nygren

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  1. P. H. Cashin
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  2. H. Ehrsson
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Correspondence to P. H. Cashin.

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Cashin, P.H., Ehrsson, H., Wallin, I. et al. Pharmacokinetics of cisplatin during hyperthermic intraperitoneal treatment of peritoneal carcinomatosis. Eur J Clin Pharmacol 69, 533–540 (2013). https://doi.org/10.1007/s00228-012-1405-4

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  • DOI: https://doi.org/10.1007/s00228-012-1405-4

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