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Pharmacokinetically based dosing of weekly paclitaxel to reduce drug-related neurotoxicity based on a single sample strategy

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Abstract

Purpose

The present simulation study was initiated to develop a limited sampling strategy and pharmacokinetically based dosing algorithm of weekly paclitaxel based on pharmacokinetic (PK) and chemotherapy-induced peripheral neuropathy (CIPN) data from a large database.

Methods

We used paclitaxel plasma concentrations from 200 patients with solid tumors receiving weekly paclitaxel infusions to build a population PK model and a proportional odds model on CIPN. Different limited sampling strategies were tested on their accuracy to estimate the individual paclitaxel time-above-threshold-concentration of 0.05 µmol/L (T c>0.05µM), which is a common threshold for paclitaxel. A dosing algorithm was developed based on the population distribution of paclitaxel T c>0.05µM and the correlation between paclitaxel T c>0.05µM and CIPN. A trial simulation based on paclitaxel PK and CIPN was performed using empirical Bayes estimations, applying the proposed dosing algorithm and a single 24-h paclitaxel PK sample.

Results

A single paclitaxel plasma concentration taken 18–30 h after the start of chemotherapy infusion adequately predicted T c>0.05µM. By using an empirical dosing algorithm to target an average paclitaxel T c>0.05µM between 10 and 14 h, Bayesian simulations of repetitive (adapted) dosing suggested a potential reduction of grade 2 CIPN from 9.6 to 4.4 %.

Conclusions

This simulation study proposes a pharmacokinetically based dosing algorithm for weekly paclitaxel and shows potential improvement of the benefit/risk ratio by using empirical Bayesian models.

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References

  1. van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, Cuesta MA, Blaisse RJ, Busch OR, ten Kate FJ, Creemers GJ, Punt CJ, Plukker JT, Verheul HM, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJ, Rozema T, Biermann K, Beukema JC, Piet AH, van Rij CM, Reinders JG, Tilanus HW, van der Gaast A, Group C (2012) Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 366:2074–2084

    Article  PubMed  Google Scholar 

  2. Belani CP, Ramalingam S, Perry MC, LaRocca RV, Rinaldi D, Gable PS, Tester WJ (2008) Randomised, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J Clin Oncol 26:468–473

    Article  CAS  PubMed  Google Scholar 

  3. Katsumata N, Yasuda M, Isonishi S, Takahashi F, Michimae H, Kimura E, Aoki D, Jobo T, Kodama S, Terauchi F, Sugiyama T, Ochiai K, Japanese Gynecologic Oncology G (2013) Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol 14:1020–1026

    Article  CAS  PubMed  Google Scholar 

  4. Katsumata N, Yasuda M, Takahashi F, Isonishi S, Jobo T, Aoki D, Tsuda H, Sugiyama T, Kodama S, Kimura E, Ochiai K, Noda K, Japanese Gynecologic Oncology G (2009) Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 374:1331–1338

    Article  CAS  PubMed  Google Scholar 

  5. Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE (2008) Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358:1663–1671

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C (2008) Randomised phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol 26:1642–1649

    Article  CAS  PubMed  Google Scholar 

  7. Gianni L, Kearns CM, Giani A, Capri G, Viganó L, Locatelli A, Bonadonna G, Egorin MJ (1995) Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 13:180–190

    CAS  PubMed  Google Scholar 

  8. Saito K, Kikuchi Y, Fujii K, Kita T, Furuya K (2006) Effect of paclitaxel on vascular endothelial growth factor (VEGF) and interleukin (IL)-8 in serum of patients with recurrent ovarian cancer: a comparison of weekly vs triweekly regimens. Target Oncol 1:86–89

    Article  Google Scholar 

  9. Huang TC, Campbell TC (2012) Comparison of weekly versus every 3 weeks paclitaxel in the treatment of advanced solid tumors: a meta-analysis. Cancer Treat Rev 38:613–617

    Article  CAS  PubMed  Google Scholar 

  10. Schuette W, Blankenburg T, Guschall W, Dittrich I, Schroeder M, Schweisfurth H, Chemaissani A, Schumann C, Dickgreber N, Appel T, Ukena D (2006) Multicenter randomised trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin. Clin Lung Cancer 7:338–343

    Article  CAS  PubMed  Google Scholar 

  11. Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH (2008) Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol 26:60–65

    Article  CAS  PubMed  Google Scholar 

  12. Budd GT, Barlow WE, Moore HCF, Hobday TJ, Stewart JA, Isaacs C, Salim M, Cho JK, Rinn K, Albain KS, Chew HK, Burton G, Moore TD, Srkalovic G, McGregor BA, Flaherty LE, Livingston RB, Lew D, Gralow J, Hortobagyi GN (2013) Comparison of two schedules of paclitaxel as adjuvant therapy for breast cancer. J Clin Oncol 31. Abstract Number CRA1008

  13. Chan J, Brady M, Penson R, Monk B, Boente M, Walker J, Davidson S, DiSilvestro P, O’Malley D, Morgan M, Pearl M, DeGeest K, Michael H (2013) Phase III trial of every-3-weeks paclitaxel vs. dose-dense weekly paclitaxel with carboplatin ± bevacizumab in epithelial ovarian, peritoneal, fallopian tube cancer: GOG 262 (NCT01167712). Int J Gynecol Cancer 23: Suppl 1

  14. Pignata S, Scambia G, Katsaros D, Gallo C, Pujade-Lauraine E, De Placido S, Bologna A, Weber B, Raspagliesi F, Panici PB, Cormio G, Sorio R, Cavazzini MG, Ferrandina G, Breda E, Murgia V, Sacco C, Cinieri S, Salutari V, Ricci C, Pisano C, Greggi S, Lauria R, Lorusso D, Marchetti C, Selvaggi L, Signoriello S, Piccirillo MC, Di Maio M, Perrone F, on behalf of the Multicentre Italian Trials in Ovarian c, Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens et du s, Mario Negri Gynecologic O, European Network of Gynaecological Oncological Trial G, Gynecologic Cancer InterGroup I (2014) Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 15:396–405

    Article  CAS  PubMed  Google Scholar 

  15. Mielke S, Sparreboom A, Steinberg SM, Gelderblom H, Unger C, Behringer D, Mross K (2005) Association of Paclitaxel pharmacokinetics with the development of peripheral neuropathy in patients with advanced cancer. Clin Cancer Res 11:4843–4850

    Article  CAS  PubMed  Google Scholar 

  16. Mielke S, Sparreboom A, Behringer D, Mross K (2005) Paclitaxel pharmacokinetics and response to chemotherapy in patients with advanced cancer treated with a weekly regimen. Anticancer Res 25:4423–4427

    CAS  PubMed  Google Scholar 

  17. Augusto C, Pietro M, Cinzia M, Sergio C, Sara C, Luca G, Scaioli V (2008) Peripheral neuropathy due to paclitaxel: study of the temporal relationships between the therapeutic schedule and the clinical quantitative score (QST) and comparison with neurophysiological findings. J Neurooncol 86:89–99

    Article  CAS  PubMed  Google Scholar 

  18. Joerger M, Kraff S, Huitema AD, Feiss G, Moritz B, Schellens JH, Beijnen JH, Jaehde U (2012) Evaluation of a pharmacology-driven dosing algorithm of 3-weekly paclitaxel using therapeutic drug monitoring: a pharmacokinetic-pharmacodynamic simulation study. Clin Pharmacokinet 51:607–617

    Article  CAS  PubMed  Google Scholar 

  19. de Graan AJ, Elens L, Sprowl JA, Sparreboom A, Friberg LE, van der Holt B, de Raaf PJ, de Bruijn P, Engels FK, Eskens FA, Wiemer EA, Verweij J, Mathijssen RH, van Schaik RH (2013) CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity. Clin Cancer Res 19:3316–3324

    Article  PubMed Central  PubMed  Google Scholar 

  20. Henningsson A, Karlsson MO, Vigano L, Gianni L, Verweij J, Sparreboom A (2001) Mechanism-based pharmacokinetic model for paclitaxel. J Clin Oncol 19:4065–4073

    CAS  PubMed  Google Scholar 

  21. Henningsson A, Sparreboom A, Sandstrom M, Freijs A, Larsson R, Bergh J, Nygren P, Karlsson MO (2003) Population pharmacokinetic modelling of unbound and total plasma concentrations of paclitaxel in cancer patients. Eur J Cancer 39:1105–1114

    Article  CAS  PubMed  Google Scholar 

  22. Tomz M, Wittenberg J, King G. Clarify: Software for Interpreting and Presenting Statistical Results. In, 2003

  23. Zelner BA (2009) Using simulation to interpret and present logit and probit results. Strateg Manag J 30:1335–1348

    Article  Google Scholar 

  24. Joerger M, Huitema AD, Richel DJ, Dittrich C, Pavlidis N, Briasoulis E, Vermorken JB, Strocchi E, Martoni A, Sorio R, Sleeboom HP, Izquierdo MA, Jodrell DI, Calvert H, Boddy AV, Hollema H, Fety R, Van der Vijgh WJ, Hempel G, Chatelut E, Karlsson M, Wilkins J, Tranchand B, Schrijvers AH, Twelves C, Beijnen JH, Schellens JH (2007) Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients: a study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group. Clin Cancer Res 13:6410–6418

    Article  CAS  PubMed  Google Scholar 

  25. Joerger M, Huitema AD, van den Bongard DH, Schellens JH, Beijnen JH (2006) Quantitative effect of gender, age, liver function, and body size on the population pharmacokinetics of paclitaxel in patients with solid tumors. Clin Cancer Res 12:2150–2157

    Article  CAS  PubMed  Google Scholar 

  26. Park SB, Goldstein D, Krishnan AV, Lin CS, Friedlander ML, Cassidy J, Koltzenburg M, Kiernan MC (2013) Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA Cancer J Clin 63:419–437

    Article  PubMed  Google Scholar 

  27. Wolf S, Barton D, Kottschade L, Grothey A, Loprinzi C (2008) Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies. Eur J Cancer 44:1507–1515

    Article  CAS  PubMed  Google Scholar 

  28. de Jonge ME, van den Bongard HJ, Huitema AD, Mathot RA, Rosing H, Baas P, van Zandwijk N, Beijnen JH, Schellens JH (2004) Bayesian pharmacokinetically guided dosing of paclitaxel in patients with non-small cell lung cancer. Clin Cancer Res 10:2237–2244

    Article  PubMed  Google Scholar 

  29. Woo MH, Relling MV, Sonnichsen DS, Rivera GK, Pratt CB, Pui CH, Evans WE, Pappo AS (1999) Phase I targeted systemic exposure study of paclitaxel in children with refractory acute leukemias. Clin Cancer Res 5:543–549

    CAS  PubMed  Google Scholar 

  30. Joerger M, Huitema AD, Huizing MT, Willemse PH, de Graeff A, Rosing H, Schellens JH, Beijnen JH, Vermorken JB (2007) Safety and pharmacology of paclitaxel in patients with impaired liver function: a population pharmacokinetic-pharmacodynamic study. Br J Clin Pharmacol 64:622–633

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Authors and Affiliations

  1. Institute of Pharmacy, Clinical Pharmacy, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany

    Stefanie Kraff & Ulrich Jaehde

  2. Department of Medical Oncology, Erasmus University Medical Center Rotterdam/Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    Annemieke J. M. Nieuweboer, Ron H. J. Mathijssen & Anne-Joy de Graan

  3. Department of Pulmonary Medicine, Cantonal Hospital, St. Gallen, Switzerland

    Florent Baty

  4. Department of Clinical Chemistry, Erasmus University Medical Center Rotterdam/Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    Ron H. N. van Schaik

  5. Department of Oncology and Hematology, Cantonal Hospital, Rorschacherstrasse 95, 9007, St.Gallen, Switzerland

    Markus Joerger

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  1. Stefanie Kraff
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Corresponding author

Correspondence to Markus Joerger.

Electronic supplementary material

Below is the link to the electronic supplementary material.

280_2015_2724_MOESM1_ESM.pdf

Online Resource 1 Graphical evaluation of the final paclitaxel PK model: A) Goodness-of-fit plot: predicted population paclitaxel plasma concentrations versus observed individual paclitaxel plasma concentrations; B) Goodnes-of-fit plot: predicted individual paclitaxel plasma concentrations versus observed individual paclitaxel plasma concentrations; C) Visual predictive check of log-transformed paclitaxel plasma concentrations. The 5th and 95th percentiles (broken lines) and the median (solid line) obtained from 1000 simulations are shown, along with the actual observations (black circles) (PDF 146 kb)

280_2015_2724_MOESM2_ESM.pdf

Online Resource 2 Boxplot of paclitaxel Tc>0.05µM by grade of paclitaxel chemotherapy-induced peripheral neuropathy (CIPN). The median is indicated by the horizontal line within the box. The bottom and top edges of the box represent the 25th and 75th percentiles of the Tc>0.05µM. The maximum length of each whisker is 1.5 times the interquartile range with any data value larger than that marked as an outlier (PDF 27 kb)

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Kraff, S., Nieuweboer, A.J.M., Mathijssen, R.H.J. et al. Pharmacokinetically based dosing of weekly paclitaxel to reduce drug-related neurotoxicity based on a single sample strategy. Cancer Chemother Pharmacol 75, 975–983 (2015). https://doi.org/10.1007/s00280-015-2724-9

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  • DOI: https://doi.org/10.1007/s00280-015-2724-9

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