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Population Pharmacokinetics of the BEACOPP Polychemotherapy Regimen in Hodgkin’s Lymphoma and its Effect on Myelotoxicity

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Abstract

Background and objective

The BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) chemotherapy regimen for the treatment of advanced Hodgkin’s lymphoma has a superior outcome, but its toxicity (mainly haematotoxicity) is pronounced and highly variable. The present study was conducted to address the role of pharmacokinetics in individual toxicity.

Study design

Three plasma samples and a 24-hour urine collection for day 1 of the first three cycles of chemotherapy were analysed in 30 patients, and the pharmacokinetic parameters of the respective drugs were estimated by population pharmacokinetic methods (nonlinear mixed-effects model [NONMEM] software). Demographic data, doses and durations of infusion were also recorded. The effect of these parameters on platelet counts was estimated by analysis of covariance using a general linear model.

Results

The pharmacokinetic parameters and respective covariates were similar to the published data. The body surface area, peak concentrations of etoposide, urinary recovery of dechloroethylcyclophosphamide (formed by cytochrome P450 [CYP] 3A4) relative to the cyclophosphamide dose and number of cycles had a significant effect on toxicity. These factors explained 37% of the interindividual variability in the change in platelet counts from day 1 to day 8 of each cycle.

Conclusion

The results show that the individual pharmacokinetics of BEACOPP drugs are an important link between dosage and toxicity. Accordingly, individualisation of treatment based on pharmacokinetics may result in more uniform toxicity. Individualisation may also allow escalation of the mean dose, which is probably related to better efficacy. As a consequence of the present study, infusion rates should be standardised, and the potential of a dose reduction in the first cycle and of CYP3A4 phenotyping should be addressed in clinical studies.

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Acknowledgements

The study was supported in part by the Deutsche Krebshilfe (Grant #70-2337-Fu I), the Köln Fortune Programme of the Medical Faculty of the University of Cologne, and the W. Doerenkamp Foundation, (Cologne, Germany). We are grateful to the patients who participated in this study despite the burden of their disease, and we gratefully acknowledge the support of the following individuals during the conduct of the study in the various German study centres: Dr Zaigler, Mr Menzel, Department of Pharmacology, University Hospital, University of Cologne, Cologne; Dr Breuer, Dr Bredenfeld, Dr Rüffer, Dr Wolf, Dr Weihrauch, Dr Sieber, Dr Tesch, 1st Department of Internal Medicine, University Hospital, University of Cologne, Cologne; Dr Malchau, Department of Clinical Chemistry, University Hospital, University of Cologne, Cologne; Mrs Nisters-Backes, Mrs Koch, Mrs Remmler, German Hodgkin-Lymphoma Study Group, Cologne; Dr Günther, Med. Klinik, Kreiskrankenhaus Reutlingen, Reutlingen; Dr Haedicke, Med. Klinik II, Städtische Kliniken Braunschweig, Braunschweig; Dr Nischik, Dr Gott, Klinik für Hämatologie, Klinikum Minden, Minden; Dr Franzen, Dr Linnemann, Evangelisches Krankenhaus, Mülheim an der Ruhr; Dr Grunewald, Med. Klinik II, Kliniken St Marien, Amberg; Dr Baumgartner, Mrs Jerusalem, Dr Kleinschmidt, Mr Varvenne, Med. Klinik, Rheinische Friedrich-Wilhelms-Universität, Bonn; Dr Hansen, Med. Klinik, Diakonie-Krankenhaus Schwäbisch-Hall, Schwäbisch-Hall; Dr Eberhard, Med. Klinik, Katharinen-Hospital, Stuttgart; Dr Boissevain, 5. Med. Klinik, Klinikum Nord Nürnberg, Nürnberg; Dr Brase, St Elisabeth-Krankenhaus, Saarlouis; Dr Schwonzen, St Walburga-Krankenhaus, Meschede; Dr Schmitz, Dr Steinmetz, Cologne; Dr Sandner, Med. Klinik, Krankenhaus München-Harlaching, München-Harlaching; Dr Grothaus-Pinke, Klinik für Knochenmarkstransplantation, Idar-Oberstein; Dr Mayer, Thoraxklinik Heidelberg, Heidelberg; Dr Ehrsam, Med. Klinik 1, Universität Dresden, Dresden; Dr Orth, Med. Klinik II, Krankenhaus Nordwest, Frankfurt am Main; Dr Hickel, Med. Klinik V, Universitätsklinik Heidelberg, Heidelberg. The authors have no conflicts of interest that are directly relevant to the content of this study.

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Author notes

  1. Dirk Kasel

    Present address: Department of Pharmacokinetics, Grünenthal GmbH, Aachen, Germany

Authors and Affiliations

  1. Department of Pharmacology, University Hospital, University of Cologne, Cologne, Germany

    Stefan Wilde, Alexander Jetter, Stephan Rietbrock, Dirk Kasel &  Uwe Fuhr

  2. 1st Department of Internal Medicine, University Hospital, University of Cologne, Cologne, Germany

    Andreas Engert, Andreas Josting, Beate Klimm & Volker Diehl

  3. German Hodgkin Study Group, Cologne, Germany

    Andreas Engert, Andreas Josting & Beate Klimm

  4. Department of Pharmaceutical and Medical Chemistry, University of Münster, Münster, Germany

    Georg Hempel

  5. Department of Clinical Pharmacy, Free University of Berlin, Berlin, Germany

    Stefanie Reif & Ulrich Jaehde

  6. Department of Clinical Pharmacy, University of Bonn, Bonn, Germany

    Ulrich Jaehde

  7. Department of Clinical Pharmacology, University of Jena, Jena, Germany

    Ute Merkel

  8. Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

    Dagmar Busse & Matthias Schwab

  9. Department of Clinical Pharmacology, University Hospital, Tübingen, Germany

    Matthias Schwab

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Correspondence to Uwe Fuhr.

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Wilde, S., Jetter, A., Rietbrock, S. et al. Population Pharmacokinetics of the BEACOPP Polychemotherapy Regimen in Hodgkin’s Lymphoma and its Effect on Myelotoxicity. Clin Pharmacokinet 46, 319–333 (2007). https://doi.org/10.2165/00003088-200746040-00005

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