Oral treatment with etoposide in small cell lung cancer – dilemmas and solutions

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Background. Etoposide is a chemotherapeutic agent, widely used for the treatment of various malignancies, including small cell lung cancer (SCLC), an aggressive disease with poor prognosis. Oral etoposide administration exhibits advantages for the quality of life of the patient as well as economic benefits. However, widespread use of oral etoposide is limited by incomplete and variable bioavailability. Variability in bioavailability was observed both within and between patients. This suggests that some patients may experience suboptimal tumor cytotoxicity, whereas other patients may be at risk for excess toxicity.

Conclusions. The article highlights dilemmas as well as solutions regarding oral treatment with etoposide by presenting and analyzing relevant literature data. Numerous studies have shown that bioavailability of etoposide is influenced by genetic, physiological and environmental factors. Several strategies were explored to improve bioavailability and to reduce pharmacokinetic variability of oral etoposide, including desired and undesired drug interactions (e.g. with ketoconazole), development of suitable drug delivery systems, use of more water-soluble prodrug of etoposide, and influence on gastric emptying. In addition to genotype-based dose administration, etoposide is suitable for pharmacokinetically guided dosing, which enables dose adjustments in individual patient.

Further, it is established that oral and intravenous schedules of etoposide in SCLC patients do not result in significant differences in treatment outcome, while results of toxicity are inconclusive. To conclude, the main message of the article is that better prediction of the pharmacokinetics of oral etoposide may encourage its wider use in routine clinical practice.

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  • 1. Chabner BA Bertino J Cleary J Ortiz T Lane A Supko JG et al. Chapter 61. Cytotoxic agents. In: Brunton LL Chabner BA Knollmann BC editors. Goodman & Gilman’s The pharmacological basis of therapeutics. 12th edition. New York: McGraw-Hill; 2011. Available from: http://www.accessmedicine.com/content.aspx?aID=16680251. Accessed April 16 2012.

  • 2. Sørensen M Pijls-Johannesma M Felip E. Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis treatment and follow-up. AnnOncol 2010; 21(Suppl 5): v120-5.

  • 3. Kuo YH Lin ZZ Yang YY Shao YY Shau WY Kuo RN et al. Survival of patients with small cell lung carcinoma in Taiwan. Oncology 2012; 82: 19-24.

  • 4. Kagohashi K Ohara G Satoh H Sekizawa K. Chemotherapy for small-cell lung cancer with paraneoplastic nephritic syndrome. Radiol Oncol 2004; 38: 153-4.

  • 5. Dolenšek M Bavčar Vodovnik T. [Imaging detetection in early lung cancer]. [Slovenian]. Radiol Oncol 2006; 40(Suppl 1): S53-8.

  • 6. Panov SZ. Molecular biology of the lung cancer. Radiol Oncol 2005; 39: 197-210.

  • 7. Terčelj M. [Early detetection of lung cancer]. [Slovenian]. Radiol Oncol 2006; 40(Suppl 1): S59-66.

  • 8. Warde P Payne D. Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 1992; 10: 890-5.

  • 9. Noda K Nishiwaki Y Kawahara M Negoro S Sugiura T Yokoyama A et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002; 346: 85-91.

  • 10. Hanna N Bunn PA Jr Langer C Einhorn L Guthrie T Jr Beck T et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/ cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 2006; 24: 2038-43.

  • 11. Califano R Abidin AZ Peck R Faivre-Finn C Lorigan P. Management of small cell lung cancer. Recent Developments for Optimal Care. Drugs 2012; 72: 471-90.

  • 12. Toffoli G Corona G Basso B Boiocchi M. Pharmacokinetic optimisation of treatment with oral etoposide. Clin Pharmacokinet 2004; 43: 441-6.

  • 13. Montecucco A Biamonti G. Cellular response to etoposide treatment. Cancer Lett 2007; 252: 9-18.

  • 14. Hande KR. The importance of drug scheduling in cancer chemotherapy: etoposide as an example. Oncologist 1996; 1: 234-9.

  • 15. Greco FA Johnson DH Hande KR Porter LL Hainsworth JD Wolff SN. High-dose etoposide (VP-16) in small-cell lung cancer. Semin Oncol 1985; 12(Suppl 2): 42-4.

  • 16. Slevin ML Clark PI Joel SP Malik S Osborne RJ Gregory WM et al. A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer. J Clin Oncol 1989; 7: 1333-40.

  • 17. Miller AA Herndon JE II Hollis DR Ellerton J Langleben A Richards F II et al. Schedule dependency of 21-day oral versus 3-day intravenous etoposide in combination with intravenous cisplatin in extensive stage small-cell lung cancer: A randomized phase III study of the cancer and leukemia group B. Clin Oncol 1995; 13: 1871-9.

  • 18. Seiter K. Toxicity of the topoisomerase II inhibitors. Expert Opin Drug Saf 2005; 4: 219-34.

  • 19. 19 Clark PI. Current role of oral etoposide in the management of small cell lung cancer. Drugs 1999: 58(Suppl 3): 17-20.

  • 20. Greco FA Hainsworth JD. Prolonged administration of low-daily dose etoposide: a superior dosing schedule? Cancer Chemother Pharmacol 1994; 34: 101-4.

  • 21. Sørensen M Felip E. Small-cell lung cancer: ESMO Clinical Recommendations for diagnosis treatment and follow-up. Ann Oncol 2009; 20(Suppl 4): iv71-2.

  • 22. Liu G Franssen E Fitch MI Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 1997; 15: 110-5.

  • 23. Payne SA. A study of quality of life in cancer patients receiving palliative chemotherapy. Soc Sci Med 1992; 35: 1505-9.

  • 24. Johnson DH Ruckdeschel JC Keller JH Lyman GH Kallas GJ Macdonald J et al. A randomized trial to compare intravenous and oral etoposide in combination with cisplatin for the treatment of small cell lung cancer. Cancer 1991; 67: 245-9.

  • 25. Pashko S Johnson DH. Potential cost savings of oral versus intravenous etoposide in the treatment of small cell lung cancer. Pharmacoeconomics 1992; 1: 293-7.

  • 26. Fujiwara Y Ohune T Okusaki K Niitani K Sumiyoski H Takemoto V et al. Bioavailability of 50- and 75-mg oral etoposide in lung cancer patients. Cancer Chemother Pharmacol 1996; 37: 327-31.

  • 27. Joel SP Clark PI Heap L Webster L Robbins S Craft H et al. Pharmacological attempts to improve the bioavailability of oral etoposide. CancerChemother Pharmacol 1995; 37: 125-33.

  • 28. Harvey VJ Slevin ML Joel SP Barnett MJ Smythe MM Ang LM et al. The pharmacokinetics of oral etoposide (VP16-213). Proc Am Soc Clin Oncol 1984; 3: 24.

  • 29. Hande KR Krozely MG Greco FA Hainsworth JD Johnson DH. Bioavailability of low-dose oral etoposide. J Clin Oncol 1993; 11: 374-7.

  • 30. Hande K Messenger M Wagner J Krozely M Kaul S. Inter- and intrapatient variability in etoposide kinetics with oral and intravenous drug administration. Clin Cancer Res 1999; 5: 2742-7.

  • 31. Würthwein G Krümpelmann S Tillmann B Real E Schulze-Westhoff P Jürgens H et al. Population pharmacokinetic approach to compare oral and i.v. administration of etoposide. Anti-Cancer Drugs 1999; 10: 807-14.

  • 32. Slevin ML Joel SP Whomsley R Devenport K Harvey VJ Osborne RJ et al. The effect of dose on the bioavailability of oral etoposide: confirmation of a clinically relevant observation. Cancer Chemother Pharmacol 1989; 24: 329-31.

  • 33. Desoize B Maréchal F Cattan A. Correlations between clinical pharmacodynamics and pharmacokinetics of cisplatin and etoposide. Ann Biol Clin 1993; 51: 125-8.

  • 34. You B Tranchand B Girard P Falandry C Ribba B Chabaud S et al. Etoposide pharmacokinetics and survival in patients with small cell lung cancer: A multicentre study. Lung Cancer 2008; 62: 261-72.

  • 35. Roden DM. Chapter 5. Principles of Clinical Pharmacology. In: Longo DL Fauci AS Kasper DL Hauser SL Jameson JL Loscalzo J editors. Harrison’s principles of internal medicine. 18th edition. New York: McGraw- Hill; 2012. Available form: http://www.accessmedicine.com/content.aspx?aID=9092427. Accessed April 16 2012.

  • 36. Franke RM Gardner ER Sparreboom A. Pharmacogenetics of drug transporters. Curr Pharm Des 2010; 16: 220-30.

  • 37. Brinkmann U Roots I Eichelbaum M. Pharmacogenetics of the human drug-transporter gene MDR1: impact of polymorphisms on pharmacotherapy. Drug Discov Today 2001; 6: 835-9.

  • 38. Dietrich CG Geier A Oude Elferink RPJ. ABC of oral bioavailability: transporters as gatekeepers in the gut. Gut 2003; 52: 1788-95.

  • 39. Kunta J Yan J Makhey VD Sinko PJ. Active efflux kinetics of etoposide from rabbit small intestine and colon. Biopharm Drug Dispos 2000; 21: 83-93.

  • 40. Allen JD van Dort SC Buitelaar M van Tellingen O Schinkel AH. Mouse breast cancer resistance protein (Bcrp1/Abcg2) mediates etoposide resistance and transport but etoposide oral availability is limited primarily by P-glycoprotein. Cancer Res 2003; 63: 1339-44.

  • 41. Guo A Marinaro W Hu P Sinko PJ. Delineating the contribution of secretory transporters in the efflux of etoposide using Madin-Darby canine kidney (MDCK) cells overexpressing P-glycoprotein (Pgp) multidrug resistanceassociated protein (MRP1) and canalicular multispecific organic anion transporter (cMOAT). Drug Metab Dispos 2002; 30: 457-63.

  • 42. Cui Y Konig J Buchholz JK Spring H Leier I Keppler D. Drug resistance and ATP-dependent conjugate transport mediated by the apikal multidrug resistance protein MRP2 permanently expressed in human and canine cells. Mol Pharmacol 1999; 55: 929-37.

  • 43. Kool M van der Linden M de Haas M Scheffer GL de Vree JM Smith AJ et al. MRP3 an organic anion transporter able to transport anti-cancer drugs. Proc Nat Acad Sci USA 1999; 96: 6914-9.

  • 44. Wijnholds J Scheffer GL van der Valk M van der Valk P Beijnen JH Scheper RJ et al. Multidrug resistance protein 1 protects the oropharyngeal mucosal layer and the testicular tubules against drug-induced damage. JExp Med 1998; 188: 797-808.

  • 45. Stephens RH O’Neill CA Bennett J Humphrey M Henry B Rowland M. Resolution of P-glycoprotein effects on drug permeability using intestinal tissues from mdr1a (-/-) mice. Br J Pharmacol 2002; 135: 2038-46.

  • 46. Lagas JS Fan L Wagenaar E Vlaming MLH van Tellingen O Beijnen JH et al. P-glycoprotein (P-gp/Abcb1) Abcc2 and Abcc3 determine the pharmacokinetics of etoposide. Clin Cancer Res 2010; 16: 130-40.

  • 47. Relling MV Nemec J Schuetz EG Schuetz JD Gonzalez FJ Korzekwa KR. O-demethylation of epipodophyllotoxins is catalyzed by human cytochrome P450 3A4. Mol Pharmacol 1994; 45: 352-8.

  • 48. Zhuo X Zheng N Felix CA Blair IA. Kinetics and regulation of cytochrome P450-mediated etoposide metabolism. Drug Metab Dispos 2004; 32: 993-1000.

  • 49. Kawashiro T Yamashita K Zhao X-J Koyama E Tani M Chiba K et al. A study on the metabolism of etoposide and possible interactions with antitumor or supporting agents by human liver microsomes. J Pharmacol ExpTher 1998; 286: 1294-300.

  • 50. Mans DRA Retèl J van Maanen JMS Lafleur MVM van Schaik MA Pinedo HM et al. Role of the semi-quinone free radical of the anti-tumor agent etoposide (VP-16-213) in the inactivation of single- and double-stranded ΦX174 DNA. Br J Cancer 1990; 62: 54-60.

  • 51. van Maanen JMS de Vries J Pappie D van den Akker E Lafleur MVM Retèl J et al. Cytochrome P-450-mediated O-demethylation: A route in the metabolic activation of etoposide (VP-16-213). Cancer Res 1987; 47: 4658-62.

  • 52. Haim N Nemec J Roman J Sinha BK. In vitro metabolism of etoposide (VP-16-213) by liver microsomes and irreversible binding of reactive intermediates to microsomal proteins. Biochem Pharmacol 1987; 36: 527-36.

  • 53. Mans DR Lafleur MV Westmijze EJ Horn IR Bets D Schuurhuis GJ et al. Reactions of glutathione with the catehol the ortho-quinone and the semi-quinone free radical of etoposide. Consequences for DNA inactivation. Biochem Pharmacol 1992; 43: 1761-8.

  • 54. Wen Z Tallman MN Ali SY Smith PC. UDP-glucuronosyltransferase 1A1 Is the principal enzyme responsible for etoposide glucuronidation in human liver and intestinal microsomes: Structural characterization of phenolic and alcoholic glucuronides of etoposide and estimation of enzyme kinetics. Drug Metab Dispos 2007; 35: 371-80.

  • 55. Watanabe Y Nakajima M Ohashi N Kume T Yokoi T. Glucuronidation of etoposide in human liver microsomes is specifically catalyzed by UDPglucuronosyltransferase 1A1. Drug Metab Dispos 2003; 31: 589-95.

  • 56. Del Amo EM Heikkinen AT Mönkkönen J. In vitro-in vivo correlation in p-glycoprotein mediated transport in intestinal absorption. Eur J PharmSci 2009; 36: 200-11.

  • 57. Matheny CJ Lamb MW Brouwer KR Pollack GM. Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Pharmacotherapy 2001; 21: 778-96.

  • 58. Kerb R. Implications of genetic polymorphisms in drug transporters for pharmacotherapy. Cancer Lett 2006; 234: 4-33.

  • 59. Robert J Le Morvan V Smith D Pourquier P Bonnet J. Predicting drug response and toxicity based on gene polymorphisms. Crit Rev Oncol Hematol 2005; 54: 171-96.

  • 60. Strother RM Jones D Li L Younger A Einhorn LH Williams S et al. Effect of the C3435T genetic polymorphism in MDR1 on etoposide pharmacokinetics. J Clin Oncol 2008; 26 (May 20 suppl; abstr 2500).

  • 61. Hoffmeyer S Burk O von Richter O Arnold H Brockmoller J Johne A et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000; 97: 3473-8.

  • 62. Nakamura T Sakaeda T Horinouchi M Tamura T Aoyama N Shirakawa T et al. Effect of the mutation (C3435T) at exon 26 on the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects. Clin Pharmacol Ther 2002; 71: 297-303.

  • 63. Gerritsen-van Schieveen P Royer B. Level of evidence for therapeutic drug monitoring for etoposide after oral administration. Fundam Clin Pharmacol 2011; 25: 277-82.

  • 64. Aita P Robieux I Sorio R Tumolo S Corona G Cannizzaro R et al. Pharmacokinetics of oral etoposide in patients with hepatocellular carcinoma. Cancer Chemother Pharmacol 1999; 43: 287-94.

  • 65. Taal BG Beijnen JH Teller FG ten Bokkel Huinink WW Dubbelman R Boot H. Bioavailability of oral etoposide in gastric cancer. Eur J Cancer 1994; 30A: 420-1.

  • 66. Ando M Minami H Ando Y Sakai S Shimono Y Sugiura S et al. Pharmacological analysis of etoposide in elderly patients with lung cancer. Clin Cancer Res 1999; 5: 1690-5.

  • 67. Fijiwara Y Ohune T Niitani K Okusaki K Sumiyoshi H Ohashi N. Clinical pharmacological profile of etoposide in the elderly. Proc Am Soc Clin Oncol 1996; 15: 174.

  • 68. Miyazaki M Fujiwara Y Oguri T Takahashi T Ohune T Sumiyoshi H et al. Clinical pharmacological profile of etoposide in elderly patients with lung cancer. Asia Pac J Clin Oncol 2005; 1: 92-7.

  • 69. Blower P de Wit R Goodin S Aapro M. Drug-drug interactions in oncology: Why are they important and can they be minimized? Crit Rev OncolHematol 2005; 55: 117-42.

  • 70. Thomas HD Porter DJ Bartelink I Nobbs JR Cole M Elliott S et al. Randomized cross-over clinical trial to study potential pharmacokinetic interactions between cisplatin or carboplatin and etoposide. Br J ClinPharmacol 2002 53: 83-91.

  • 71. Bisogno G Cowie F Boddy A Thomas HD Dick G Pinkerton CR. High-dose cyclosporin with etoposide - toxicity and pharmacokinetic interaction in children with solid tumors. Br J Cancer 1998; 77: 2304-9.

  • 72. Kan WM Liu YT Hsiao CL Shieh CY Kuo JH Huang JD et al. Effect of hydroxizide on the transport of etoposide in rat small intestine. AnticancerDrugs 2011; 12: 267-73.

  • 73. Leu BL Huang JD. Inhibition of intestinal P-glycoprotein and effects on etoposide absorption. Cancer Chemother Pharmacol 1995; 35: 432-6.

  • 74. Zhang J Zhou F Wu X Gu Y Ai H Zheng Y et al. 20(S)-Ginsenoside Rh2 noncompetitively inhibits P-glycoprotein in vitro and in vivo: A case for herb-drug interactions. Drug Metab Dispos 2010; 38: 2179-87.

  • 75. Li C Li X Choi JS. Enhanced bioavailability of etoposide after oral or intravenous administration of etoposide with kaempferol in rats. Arch PharmRes 2009; 32: 133-8.

  • 76. Li X Yun JK Choi JS. Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos 2007; 28: 151-6.

  • 77. Li X Choi JS. Effects of quercetin on the pharmacokinetics of Etoposide after oral or intravenous administration of etoposide in rats. AnticancerRes 2009; 29: 1411-5.

  • 78. Piao YJ Li X Choi JS. Effects of verapamil on etoposide pharmacokinetics after intravenous and oral administration in rats. Eur J Drug MetabPharmacokinet 2008; 33: 159-64.

  • 79. Keller RP Altermatt HJ Donatsch P Zihlmann H Laissue JA Hiestand PC. Pharmacologic interactions between the resistance-modifying cyclosporine SDZ PSC 833 and etoposide (VP 16-213) enhance in vivo cytostatic activity and toxicity. Int J Cancer 1992; 51: 433-8.

  • 80. Peng Yong W Desai AA Innocenti F Ramirez J Shepard D Kobayashi K et al. Pharmacokinetic modulation of oral etoposide by ketoconazole in patients with advanced cancer. Cancer Chemother Pharmacol 2007; 60: 811-9.

  • 81. Harvey VJ Slevin ML Joel SP Johnston A Wrigley PFM. The effect of food and concurent chemotherapy on the bioavailability of oral etoposide. Br JCancer 1985; 52: 363-7.

  • 82. Reif S Nicolson MC Bisset D Reid M Kloft C Jaehde U et al. Effects of grapefruit juice intake on etoposide bioavailability. Eur J Clin Pharmacol 2002; 58: 491-4.

  • 83. Najar IA Sharma SC Singh GD Koul S Gupta PN Javed S et al. Involvment of P-glycoprotein and CYP3A4 in the enhancement of etoposide bioavailability by a piperine analogue. Chem Biol Interact 2011; 190: 84-90.

  • 84. Lee CK Ki SH Choi JS. Effects of oral curcumin on the pharmacokinetics of intravenous and oral etoposide in rats: possible role of intestinal CYP3A and P-gp inhibition by curcumin. Biopharm Drug Dispos 2011; 32: 245-51.

  • 85. Rodman JH Murry DJ Madden T Santana VM. Altered etoposide pharmacokinetics and time to engraftment in pediatric patients undergoing autologous bone marrow transplantation. J Clin Oncol 1994; 12: 2390-7.

  • 86. Shah JC Chen JR Chow D. Preformulation study of etoposide: Identification of physicochemical characteristics responsible for the low and erratic oral bioavailability of etoposide. Pharm Res 1989; 6: 408-12.

  • 87. Slevin ML. The clinical pharmacology of etoposide. Cancer 1991; 67: 319-29.

  • 88. Joel SP Clark PI Slevin ML. Stability of the i.v. and oral formulations of etoposide in solution. Cancer Chemother Pharmacol 1995; 37: 117-24.

  • 89. Arai R Kodema N Tsuruta M Furuse K Nishiwaki Y Nemoto E et al. A cooperative phase II study of NK 171 (etoposide) in small cell lung cancer - comparison of results between the intravenous administration and the oral administration. Lung Cancer 1986; 2: 110.

  • 90. Furuse K. [A Phase II study of etoposide (NK171) in small cell lung cancer - comparison of results between intravenous administration and oral administration]. [Japanese]. Gan To Kagaku Ryoho 1985; 12: 2352-7.

  • 91. Ohno S Sugama Y Sugiyama Y Kitamura S. Comparison of chronic oral and intravenous etoposide administration in combination with cisplatin for the treatment of small cell lung cancer. [Abstract]. Lung Cancer 1991; 7(Suppl 1): 118.

  • 92. Miller AA Herndon JE 2nd Hollis DR Ellerton J Langleben A Richards F 2nd et al. Schedule dependency of 21-day oral versus 3-day intravenous etoposide in combination with intravenous cisplatin in extensive-stage small-cell lung cancer: A randomized phase III study of the cancer and leukemia group B. J Clin Oncol 1995; 13: 1871-9.

  • 93. Girling DJ. Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomised trial. Medical Research Council Lung Cancer Working Party. Lancet 1996; 348: 563-6.

  • 94. Souhami RL Spiro SG Rudd RM Ruiz de Elvira MC James LE Gower NH et al. Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl CancerInst 1997 89: 577-80.

  • 95. Sparreboom A de Jonge MJA Verweij J. The use of oral cytotoxic and cytostatic drugs in cancer treatment. Eur J Cancer 2002; 38: 18-22.

  • 96. Zhang T Chen J Zhang Y Shen Q Pan W. Characterization and evaluation of nanostructured lipid carrier as a vehicle for oral delivery of etoposide. Eur J Pharm Sci 2011; 43: 174-97.

  • 97. Wu Z Guo D Deng L Zhang Y Yang Q Chen J. Preparation and evaluation of a self-emulsifying drug delivery sistem of etoposide-phospholipid complex. Drug Dev Ind Pharm 2011; 37: 103-12.

  • 98. Zhang F Koh GY Hollingsworth J Russo PS Stout RW Liu Z. Reformulation of etoposide with solubility-enhancing rubusoside. Int J Pharm 2012; 434: 453-9.

  • 99. Mo R Xiao Y Sun M Zhang C Ping Q. Enhancing effect of N-octyl-O-sulfate chitosan on etoposide absorption. Int J Pharm 2011; 409: 38-45.

  • 100. Chabot GG Armand JP Terret C de Forni M Abigerges D Winograd B et al. Etoposide bioavailability after oral administration of the prodrug etoposide phosphate in cancer patients during a phase I study. J Clin Oncol 1996; 14: 2020-30.

  • 101. 96 Sessa C Zucchetti M Cerny T Pagani O Cavalli F De Fusco M et al. Phase I clinical and harmacokinetic study of oral etoposide phosphate. JClin Oncol 1995; 13: 200-9.

  • 102. de Jong RS Mulder NH Uges DRA Kaul S Winograd B Sleijfer DTh et al. Randomized comparison of etoposide pharmacokinetics after oral etoposide phosphate and oral etoposide. Br J Cancer 1997; 75: 1660-6.

  • 103. Mathijssen RHN de Jong FA Loos WJ van der Bol JM Verweij J Sparreboom A. Flat-fixed dosing versus body surface area-based dosing of anticancer drugs in adults: does it make a difference? Oncologist 2007; 12: 913-23.

  • 104. Lowis SP Price L Pearson ADJ Newell DR Cole M. A study of the feasibility and accuracy of pharmacokinetically guided etoposide dosing in children. Br J Cancer 1998; 77: 2318-23.

  • 105. El-Yazigi A Ezzat A Berry J Raines DA Yusuf A Al-Rawithi S et al. Optimization of oral etoposide dosage in elderly patients with non-Hodgkin’s lymphoma using the fraction of dose absorbed measured for each patient. J Clin Pharmacol 2000; 40: 153-60.

  • 106. Holz JB Köppler H Schmidt L Fritsch HW Pflüger KH Jungclas H. Limited sampling models for reliable estimation of etoposide area under the curve. Eur J Cancer 1995; 31A: 1794-8.

  • 107. Gentili D Zucchetti M Torri V Sessa C de Jong J Cavalli F et al. A limited sampling model for the pharmacokinetics of etoposide given orally. CancerChemother Pharmacol 1993; 32: 482-6.

  • 108. Millward MJ Newell DR Yuen K Matthews JP Balmanno K Charlton CJ et al. Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer. Cancer Chemother Pharmacol 1995; 37: 161-7.

  • 109. Minami H Ando Y Sakai S Shimokata K. Clinical and pharmacologic analysis of hyperfractionated daily oral etoposide. J Clin Oncol 1995; 13: 191-9.

  • 110. Tranchand B Amsellem C Chatelut E Freyer G Iliadis A Ligneau B et al. A limited-sampling strategy for estimation of etoposide pharmacokinetics in cancer patients. Cancer Chemother Pharmacol 1999; 43: 316-22.

  • 111. Palle J Frost BM Gustafsson G Hellebostad M Kanerva J Liliemark E. Etoposide pharmacokinetics in children treated for acute myeloid leukaemia. Anticancer Drugs 2006; 17: 1087-94.

  • 112. Lowis SP Pearson ADJ Newell DR Cole M. Etoposide pharmacokinetics: the development and prospective validation of a dosing equation. CancerRes 1993; 53: 4881-9.

  • 113. Ando Y Minami H Saka H Ando M Sakai S Shimokata K. Therapeutic drug monitoring in 21-day oral etoposide treatment for lung cancer. Jpn J CancerRes 1996; 87: 856-61.

  • 114. Lowis SP Price L Pearson ADJ Newell DR Cole M. A study of the feasibility and accuracy of pharmacokinetically guided etoposide dosing in children. Br J Cancer 1998; 77: 2318-23.

  • 115. Aarons L. Population pharmacokinetics: theory and practice. Br J ClinPharmacol 1991; 31: 669-70.

  • 116. Nguyen I Chatelut E Chevreau C Tranchand B Lochon I Bachaud JM et al. Population pharmacokinetics of total and unbound etoposide. CancerChemother Pharmacol 1998; 41: 125-32.

  • 117. Toffoli G Corona G Sorio R Robieux I Basso B Colussi AM et al. Population pharmacokinetics and pharmacodynamics of oral etoposide. JClin Pharmacol 2001; 52: 511-9.

  • 118. Ciccolini J Monjanel-Mouterde S Bun SS Blanc C Duffaud F Favre R et al. Population pharmacokientics of etoposide: application to therapeutic drug monitoring. Ther Drug Monit 2002; 24: 709-14.

  • 119. Nebert DW. Polymorphisms in drug-metabolizing enzymes: what is their clinical relevance and why do they exist? Am J Hum Genet 1997; 60: 265-71.

  • 120. Miller AA Tolley EA Niell HB Griffin JP Mauer AM. Pharmacodynamics of prolonged oral etoposide in patients with advanced non-small-cell lung cancer. J Clin Oncol 1993; 11: 1179-88.

  • 121. Miller AA Tolley EA Niell HB. Therapeutic drug monitoring of 21-day oral etoposide in patients with advanced non-small cell lung cancer. Clin CancerRes 1998; 4: 1705-10.

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