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A Systematic Review of Limited Sampling Strategies for Platinum Agents Used in Cancer Chemotherapy

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Abstract

Despite evidence in the literature suggesting that a strong correlation exists between the pharmacokinetic parameters and pharmacodynamic effect of anticancer agents, many of these agents are still dosed by body surface area. Therapeutic drug monitoring with the aim of pharmacokinetic-guided dosing would not only maintain target concentrations associated with efficacy but may potentially minimise the likelihood of dose-related systemic toxicities.

The pharmacokinetic parameter that displays the best correlation with the pharmacodynamics of anticancer drugs is the area under the plasma concentration-time curve (AUC). However, accurate determination of the AUC requires numerous blood samples over an extended interval, which is not feasible in clinical practice. Therefore, limited sampling strategies (LSSs) have been proposed as a means to accurately and precisely estimate pharmacokinetic parameters with a minimal number of blood samples. LSSs have been developed for many drugs, particularly ciclosporin and other immunosuppressants, as well as for certain anticancer drugs. This systematic review evaluates LSSs developed for the platinum compounds and categorises 18 pertinent citations according to criteria adapted from the US Preventive Services Task Force. Thirteen citations (four level I, six level II-1, three level II-2) pertained to LSSs for carboplatin, four citations (one level II-1, one level II-2, two level III) to cisplatin LSSs, and one citation (level II-2) to nedaplatin.

Based on the current evidence, it appears that LSSs may be useful for pharmacokinetic-guided dosage adjustments of carboplatin in both adults and children with cancer. Although some validation studies suggest that LSSs can be extended to different cancer populations or different chemotherapy regimens, other studies dispute this finding.

Although the use of LSSs to predict the pharmacokinetic parameters of cisplatin and nedaplatin appear promising, the quality of evidence from published studies does not support routine implementation at this time.

LSSs represent one approach in which clinicians can make specific dosage adjustments for individual patients to optimise outcomes. However, the limitations of these strategies must also be taken into consideration. There is also a need for prospective studies to demonstrate that application of LSSs for platinum agents ultimately improves patient response and decreases systemic toxicities.

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References

  1. Canal P, Chatelut E, Guichard S. Practical treatment guide for dose individualisation in cancer chemotherapy. Drugs 1998 Dec; 56(6): 1019–38

    Article  PubMed  CAS  Google Scholar 

  2. Ranson MR, Scarffe JH. Population and Bayesian pharmacokinetics in oncology. Clin Oncol (R Coll Radiol) 1994; 6(4): 254–60

    Article  CAS  Google Scholar 

  3. van den Bongard HJ, Mathot RA, Beijnen JH, et al. Pharmacokinetically guided administration of chemotherapeutic agents. Clin Pharmacokinet 2000 Nov; 39(5): 345–67

    Article  PubMed  Google Scholar 

  4. Rousseau A, Marquet P, Debord J, et al. Adaptive control methods for the dose individualisation of anticancer agents. Clin Pharmacokinet 2000 Apr; 38(14): 315–53

    Article  PubMed  CAS  Google Scholar 

  5. Johnsson A, Hoglund P, Grubb A, et al. Cisplatin pharmacokinetics and pharmacodynamics in patients with squamous-cell carcinoma of the head/neck or esophagus. Cancer Chemother Pharmacol 1996 Nov; 39(1-2): 25–33

    Article  PubMed  CAS  Google Scholar 

  6. Rousseau A, Marquet P. Application of pharmacokinetic modelling to the routine therapeutic drug monitoring of anticancer drugs. Fundam Clin Pharmacol 2002 Aug; 16(4): 253–62

    Article  PubMed  CAS  Google Scholar 

  7. Nannan Panday VR, van Warmerdam LJ, Huizing MT, et al. A limited-sampling model for the pharmacokinetics of carboplatin administered in combination with paclitaxel. J Cancer Res Clin Oncol 1999 Nov; 125(11): 615–20

    Article  PubMed  CAS  Google Scholar 

  8. Doz F, Urien S, Chatelut E, et al. A limited-sampling method for evaluation of the area under the curve of ultrafilterable carboplatin in children. Cancer Chemother Pharmacol 1998 Jul; 42(3): 250–4

    Article  PubMed  CAS  Google Scholar 

  9. van Warmerdam LJ, ten Bokkel Huinink WW, Maes RA, et al. Limited-sampling models for anticancer agents. J Cancer Res Clin Oncol 1994; 120(7): 427–33

    Article  PubMed  Google Scholar 

  10. Panetta JC, Iacono LC, Adamson PC, et al. The importance of pharmacokinetic limited sampling models for childhood cancer drug development. Clin Cancer Res 2003 Nov 1; 9(14): 5068–77

    PubMed  CAS  Google Scholar 

  11. Cole M, Boddy AV, Kearns K, et al. Potential clinical impact of taking multiple blood samples for research studies in pediatric oncology: how much do we really know? Pediatr Blood Cancer 2006 Jun; 46(7): 723–7

    Article  PubMed  Google Scholar 

  12. Mahmood I. Limited sampling model for the estimation of pharmacokinetic parameters in children. Ther Drug Monit 2000 Oct; 22(5): 532–6

    Article  PubMed  CAS  Google Scholar 

  13. David OJ, Johnston A. Limited sampling strategies for estimating cyclosporin area under the concentration-time curve: review of current algorithms. Ther Drug Monit 2001 Apr; 23(2): 100–14

    Article  PubMed  CAS  Google Scholar 

  14. Dumont RJ, Ensom MH. Methods for clinical monitoring of cyclosporin in transplant patients. Clin Pharmacokinet 2000 May; 38(5): 427–47

    Article  PubMed  CAS  Google Scholar 

  15. Monchaud C, Rousseau A, Leger F, et al. Limited sampling strategies using Bayesian estimation or multilinear regression for cyclosporin AUC(0–12) monitoring in cardiac transplant recipients over the first year post-transplantation. Eur J Clin Pharmacol 2003 Apr; 58(12): 813–20

    PubMed  CAS  Google Scholar 

  16. Arizon del Prado JM, Aumente Rubio MD, Cardenas Aranzana M, et al. New strategies of cyclosporine monitoring in heart transplantation: initial results. Transplant Proc 2003 Aug; 35(5): 1984–7

    Article  Google Scholar 

  17. Ting LSL, Villeneuve E, Ensom MHH. Beyond cyclosporine: a systematic review of limited sampling strategies for other immunosuppressants. Therap Drug Monit 2006 Jun; 28(3): 419–30

    Article  CAS  Google Scholar 

  18. Chattergoon DS, Saunders EF, Klein J, et al. An improved limited sampling method for individualised busulphan dosing in bone marrow transplantation in children. Bone Marrow Transplant 1997 Sep; 20(5): 347–54

    Article  PubMed  CAS  Google Scholar 

  19. Baille P, Bruno R, Schellens JH, et al. Optimal sampling strategies for Bayesian estimation of docetaxel (taxotere) clearance. Clin Cancer Res 1997 Sep; 3(9): 1535–8

    PubMed  CAS  Google Scholar 

  20. Di Paolo A, Danesi R, Vannozzi F, et al. Limited sampling model for the analysis of 5-fluorouracil pharmacokinetics in adjuvant chemotherapy for colorectal cancer. Clin Pharmacol Ther 2002 Dec; 72(6): 627–37

    Article  PubMed  Google Scholar 

  21. Gauvin A, Pinguet F, Culine S, et al. Bayesian estimate of vinorelbine pharmacokinetic parameters in elderly patients with advanced metastatic cancer. Clin Cancer Res 2000 Jul; 6(7): 2690–5

    PubMed  CAS  Google Scholar 

  22. Launay MC, Milano G, Iliadis A, et al. A limited sampling procedure for estimating adriamycin pharmacokinetics in cancer patients. Br J Cancer 1989 Jul; 60(1): 89–92

    Article  PubMed  CAS  Google Scholar 

  23. Marchiset-Leca D, Leca FR, Galeani A, et al. A limited sampling strategy for the study of pirarubicin pharmacokinetics in humans. Cancer Chemother Pharmacol 1995 May; 36(3): 233–8

    Article  PubMed  CAS  Google Scholar 

  24. Mick R, Gupta E, Vokes EE, et al. Limited-sampling models for irinotecan pharmacokinetics-pharmacodynamics: prediction of biliary index and intestinal toxicity. J Clin Oncol 1996 Jul; 14(7): 2012–9

    PubMed  CAS  Google Scholar 

  25. Yamamoto N, Tamura T, Nishiwaki Y, et al. Limited sampling model for the area under the concentration versus time curve of irinotecan and its application to a multicentric phase II trial. Clin Cancer Res 1997 Jul; 3(7): 1087–92

    PubMed  CAS  Google Scholar 

  26. Sloan JA, Atherton P, Reid J, et al. Limited sampling models for CPT-11, SN-38, and SN-38 glucuronide. Cancer Chemother Pharmacol 2001 Sep; 48(3): 241–9

    Article  PubMed  CAS  Google Scholar 

  27. Panetta JC, Wilkinson M, Pui CH, et al. Limited and optimal sampling strategies for etoposide and etoposide catechol in children with leukemia. J Pharmacokinet Pharmacodyn 2002 Apr; 29(2): 171–88

    Article  PubMed  CAS  Google Scholar 

  28. Tranchand B, Amsellem C, Chatelut E, et al. A limited-sampling strategy for estimation of etoposide pharmacokinetics in cancer patients. Cancer Chemother Pharmacol 1999 Mar; 43(4): 316–22

    Article  PubMed  CAS  Google Scholar 

  29. Judson I, Kelland LR. New developments and approaches in the platinum arena. Drugs 2000 Jun; 59 Suppl. 4: 29–36

    Article  PubMed  CAS  Google Scholar 

  30. Go RS, Adjei AA. Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol 1999 Jan; 17(1): 409–22

    PubMed  CAS  Google Scholar 

  31. Huitema ADR, Smits KD, Mathot RA, et al. The clinical pharmacology of alkylating agents in high-dose chemotherapy. Anticancer Drugs 2000 Aug; 11(7): 515–33

    Article  PubMed  CAS  Google Scholar 

  32. Duffull SB, Robinson BA. Clinical pharmacokinetics and dose optimisation of carboplatin. Clin Pharmacokinet 1997 Sep; 33(3): 161–83

    Article  PubMed  CAS  Google Scholar 

  33. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989 Nov; 7(11): 1748–56

    PubMed  CAS  Google Scholar 

  34. Chatelut E, Pivot X, Otto J, et al. A limited sampling strategy for determining carboplatin AUC and monitoring drug dosage. Eur J Cancer 2000 Jan; 36(2): 264–9

    Article  PubMed  CAS  Google Scholar 

  35. Newell DR, Pearson AD, Balmanno K, et al. Carboplatin pharmacokinetics in children: the development of a pediatric dosing formula. The United Kingdom Children’s Cancer Study Group. J Clin Oncol 1993 Dec; 11(12): 2314–23

    PubMed  CAS  Google Scholar 

  36. Grunkemeier GL, Wu Y. Bootstrap resampling methods: something for nothing? Ann Thorac Surg 2004 Apr; 77(4): 1142–4

    Article  PubMed  Google Scholar 

  37. Efron B, Gong G. A leisurely look at the bootstrap, the jackknife and cross-validation. Am Stat 1983; 37: 36–48

    Google Scholar 

  38. Thomson AH, Whiting B. Bayesian parameter estimation and population pharmacokinetics. Clin Pharmacokinet 1992 Jun; 22(5): 447–67

    Article  PubMed  CAS  Google Scholar 

  39. Ishizuka N, Ohashi Y. The continual reassessment method and its applications: a Bayesian methodology for phase I cancer clinical trials. Stat Med 2001 Sep 15-30; 20(17-18): 2661–81

    Article  PubMed  CAS  Google Scholar 

  40. Sheiner LB, Beal SL. Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm 1981 Aug; 9(4): 503–12

    PubMed  CAS  Google Scholar 

  41. US Preventive Services Task Force. Guide to preventive services: report of the US Preventive Services Task Force. 2nd ed. Baltimore (MD): Williams & Wilkins, 1996

  42. Izqueirdo MA, Sanchez A, Llort G, et al. Comparison of different methods for AUC dosing of carboplatin (CBDCA). Proc Am Soc Clin Oncol 1996; 16: 204a

    Google Scholar 

  43. Riccardi A, Lasorella A, Tornesello A, et al. A single-sample assay for the calculation of free carboplatin AUC in children. Proc Am Soc Clin Oncol 1996; 15: 176

    Google Scholar 

  44. Pivot X, Chamorey E, Guardiola E, et al. Phase I and pharmacokinetic study of the association of capecitabine-cisplatin in head and neck cancer patients. Ann Oncol 2003 Oct; 14(10): 1578–86

    Article  PubMed  CAS  Google Scholar 

  45. Lagrange JL, Medecin B, Etienne MC, et al. Cisplatin nephrotoxicity: a multivariate analysis of potential predisposing factors. Pharmacotherapy 1997 Nov–Dec; 17(16): 1246–53

    PubMed  CAS  Google Scholar 

  46. Pivot X, Marghali N, Etienne MC, et al. A multivariate analysis for predicting cisplatin-induced delayed emesis. Oncol Rep 2000 May–Jun; 7(3): 515–9

    PubMed  CAS  Google Scholar 

  47. Rubie H, Doz F, Vassal G, et al. Individual dosing of carboplatin based on drug monitoring in children receiving high-dose chemotherapy. Eur J Cancer 2003 Jul; 39(10): 1433–8

    Article  PubMed  CAS  Google Scholar 

  48. Yamamoto R, Kaneuchi M, Nishiya M, et al. Clinical trial and pharmacokinetic study of combination paclitaxel and carboplatin in patients with epithelial ovarian cancer. Cancer Chemother Pharmacol 2002 Aug; 50(2): 137–42

    Article  PubMed  Google Scholar 

  49. Duffull SB, Begg EJ, Robinson BA, et al. A sequential Bayesian algorithm for dose individualisation of carboplatin. Cancer Chemother Pharmacol 1997 Jan; 39(4): 317–26

    Article  PubMed  CAS  Google Scholar 

  50. Chatelut E, Canal P, Brunner V, et al. Prediction of carboplatin clearance from standard morphological and biological patient characteristics. J Natl Cancer Inst 1995 Apr; 87(8): 573–80

    Article  PubMed  CAS  Google Scholar 

  51. Egorin MJ, Van Echo DA, Olman EA, et al. Prospective validation of a pharmacologically based dosing scheme for the cis-diamminedichloroplatinum(II) analogue diamminecyclobu-tanedicarboxylatoplatinum. Cancer Res 1985 Dec; 45(12 Pt 1): 6502–6

    PubMed  CAS  Google Scholar 

  52. de Jonge ME, Huitema AD, Tukker AC, et al. Accuracy, feasibility, and clinical impact of prospective Bayesian pharmacokinetically guided dosing of cyclophosphamide, thiotepa, and carboplatin in high-dose chemotherapy. Clin Cancer Res. 2005 Jan 1; 11(1): 273–83

    PubMed  Google Scholar 

  53. Miyazaki M, Fujiwara Y, Takahashi T, et al. Limited-sampling models for estimation of the carboplatin area under the curve. Anticancer Res 1997 Nov-Dec; 17(6D): 4571–5

    PubMed  CAS  Google Scholar 

  54. Asai G, Ando Y, Saka H, et al. Estimation of the area under the concentration-versus-time curve of carboplatin following irinotecan using a limited sampling model. Eur J Clin Pharmacol 1998 Nov-Dec; 54(9-10): 725–7

    Article  PubMed  CAS  Google Scholar 

  55. Guillet P, Monjanel S, Nicoara A, et al. A Bayesian dosing method for carboplatin given by continuous infusion for 120 h. Cancer Chemother Pharmacol 1997 May; 40(2): 143–9

    Article  PubMed  CAS  Google Scholar 

  56. Huitema AD, Mathot RA, Tibben MM, et al. Validation of techniques for the prediction of carboplatin exposure: application of Bayesian methods. Clin Pharmacol Ther 2000 Jun; 67(6): 621–30

    Article  PubMed  CAS  Google Scholar 

  57. Peng B, Boddy AV, Cole M, et al. Comparison of methods for the estimation of carboplatin pharmacokinetics in paediatric cancer patients. Eur J Cancer 1995 Oct; 31A(11): 1804–10

    Article  PubMed  CAS  Google Scholar 

  58. Sorensen BT, Stromgren A, Jakobsen P, et al. A limited sampling method for estimation of the carboplatin area under the curve. Cancer Chemother Pharmacol 1993 Jul; 31(4): 324–7

    Article  PubMed  CAS  Google Scholar 

  59. Ghazal-Aswad S, Calvert AH, Newell DR. A single-sample assay for the estimation of the area under the free carboplatin plasma concentration versus time curve. Cancer Chemother Pharmacol 1996 Feb; 37(5): 429–34

    Article  PubMed  CAS  Google Scholar 

  60. Shen M, Schilder RJ, Obasaju C, et al. Population pharmacokinetic and limited sampling models for carboplatin administered in high-dose combination regimens with peripheral blood stem cell support. Cancer Chemother Pharmacol 2002 Sep; 50(3): 243–50

    Article  PubMed  CAS  Google Scholar 

  61. Etienne MC, Leger F, Pivot X, et al. Pharmacokinetics of low-dose carboplatin and applicability of a method of calculation for estimating individual drug clearance. Ann Oncol 2003 Apr; 14(4): 643–7

    Article  PubMed  CAS  Google Scholar 

  62. Desoize B, Dufour R, Urien S, et al. Evaluation of two dose individualisation methods for carboplatin. Anticancer Res 1996 Jul–Aug; 16(4A): 2073–8

    PubMed  CAS  Google Scholar 

  63. Fournier C, Vennin P, Hecquet B. Correlation between free platinum AUC and total platinum measurement 24 h after i.v. bolus injection of cisplatin in humans. Cancer Chemother Pharmacol 1988 Feb; 21(1): 75–7

    Article  PubMed  CAS  Google Scholar 

  64. Monjanel-Mouterde S, Ciccolini J, Bagarry D, et al. Population pharmacokinetics of cisplatin after 120-h infusion: application to routine adaptive control with feedback. J Clin Pharm Ther 2003 Apr; 28(2): 109–16

    Article  PubMed  CAS  Google Scholar 

  65. Desoize B, Dumont P, Manot L, et al. Comparison of two dose prediction models for cisplatin. Anticancer Res 1994 Nov–Dec; 14(6A): 2285–90

    PubMed  CAS  Google Scholar 

  66. Ishibashi T, Fukumura K, Yano Y, et al. Optimal sampling and limited sampling strategies for estimation of unbound platinum AUC after nedaplatin infusion. Anticancer Res 2005 Mar–Apr; 25(2B): 1283–9

    PubMed  CAS  Google Scholar 

  67. Johansen MJ, Madden T, Mehra RC, et al. Phase I pharmacokinetic study of multicycle high-dose carboplatin followed by peripheral-blood stem-cell infusion in patients with cancer. J Clin Oncol 1997 Apr; 15(4): 1481–91

    PubMed  CAS  Google Scholar 

  68. Miyazaki M, Oguri T, Kurata T, et al. Validation of the limited-sampling models for carboplatin AUC in combination chemotherapy with taxanes. Anticancer Res 2004 May–Jun; 24(3b): 1911–4

    PubMed  CAS  Google Scholar 

  69. Panday VR, van Warmerdam LJ, Huizing MT, et al. A single 24-hour plasma sample does not predict the carboplatin AUC from carboplatin-paclitaxel combinations or from a high-dose carboplatin-thiotepa-cyclophosphamide regimen. Cancer Che-mother Pharmacol 1999 Mar; 43(5): 435–8

    Article  CAS  Google Scholar 

  70. van Warmerdam LJ, Rodenhuis S, van Tellingen O, et al. Validation of a limited sampling model for carboplatin in a high-dose chemotherapy combination. Cancer Chemother Pharmacol 1994 Nov; 35(2): 179–81

    Article  PubMed  Google Scholar 

  71. Desoize B, Berthiot G, Manot L, et al. Evaluation of a prediction model of cisplatin dose based on total platinum plasma concentration. Eur J Cancer 1996 Sep; 32A(10): 1734–8

    Article  PubMed  CAS  Google Scholar 

  72. Ishibashi T, Yano Y, Oguma T. A formula for predicting optimal dosage of nedaplatin based on renal function in adult cancer patients. Cancer Chemother Pharmacol 2002 Sep; 50(3): 230–6

    Article  PubMed  CAS  Google Scholar 

  73. O’Dwyer PJ, Stevenson JP, Johnson SW. Clinical pharmacokinetics and administration of established platinum drugs. Drugs 2000 Jun; 59 Suppl. 4: 19–27

    Article  PubMed  Google Scholar 

  74. Favre R, Charbit M, Rinaldi Y, et al. Pharmacokinetics in phase IV studies for the preview of a therapeutic protocol [in French]. Bull Cancer 1988; 75(6): 541–50

    PubMed  CAS  Google Scholar 

  75. Welters MJ, Braakhuis BJ, Jacobs-Bergmans AJ, et al. The potential of platinum-DNA adduct determination in ex vivo treated tumour fragments for the prediction of sensitivity to cisplatin chemotherapy. Ann Oncol 1999 Jan; 10(1): 97–103

    Article  PubMed  CAS  Google Scholar 

  76. Gupta-Burt S, Shamkhani H, Reed E, et al. Relationship between patient response in ovarian and breast cancer and platinum drug-DNA adduct formation. Cancer Epidemiol Biomarkers Prev 1993 May-June; 2(3): 229–34

    PubMed  CAS  Google Scholar 

  77. Ishibashi T, Yano Y, Oguma T. Determination of optimal dosage for nedaplatin based on pharmacokinetic and tox-icodynamic analysis. Anticancer Res 2005 Mar-Apr; 25(2B): 1273–81

    PubMed  CAS  Google Scholar 

  78. Ishibashi T, Yano Y, Oguma T. Population pharmacokinetics of platinum after nedaplatin administration and model validation in adult patients. Br J Clin Pharmacol 2003 Aug; 56(2): 205–13

    Article  PubMed  CAS  Google Scholar 

  79. Calvert AH, Egorin MJ. Carboplatin dosing formulae: gender bias and the use of creatinine-based methodologies. Eur J Cancer 2002 Jan; 38(1): 11–6

    Article  PubMed  CAS  Google Scholar 

  80. Chatelut E, Boddy AV, Peng B, et al. Population pharmacokinetics of carboplatin in children. Clin Pharmacol Ther 1996 Apr; 59(4): 436–43

    Article  PubMed  CAS  Google Scholar 

  81. Chevreau C, Thomas F, Couteau C, et al. Ototoxicity of highdose carboplatin. J Clin Oncol 2005 May; 23(15): 3649–50

    Article  PubMed  Google Scholar 

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Acknowledgements

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada

    Gabriel W. Loh, Lillian S. L. Ting &  Mary H. H. Ensom

  2. Department of Pharmacy, Children’s and Women’s Health Centre of British Columbia, 4500 Oak Street, Vancouver, British Columbia, V6H 3N1, Canada

    Mary H. H. Ensom

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Correspondence to Mary H. H. Ensom.

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Loh, G.W., Ting, L.S.L. & Ensom, M.H.H. A Systematic Review of Limited Sampling Strategies for Platinum Agents Used in Cancer Chemotherapy. Clin Pharmacokinet 46, 471–494 (2007). https://doi.org/10.2165/00003088-200746060-00002

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